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Zhao T, Zhang X, Liu X, Wang Q, Hu X, Luo Z. Advancements in Diagnostics and Therapeutics for Cancer of Unknown Primary in the Era of Precision Medicine. MedComm (Beijing) 2025; 6:e70161. [PMID: 40242159 PMCID: PMC12000684 DOI: 10.1002/mco2.70161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 03/07/2025] [Accepted: 03/12/2025] [Indexed: 04/18/2025] Open
Abstract
Cancer of unknown primary (CUP), a set of histologically confirmed metastases that cannot be identified or traced back to its primary despite comprehensive investigations, accounts for 2-5% of all malignancies. CUP is the fourth leading cause of cancer-related deaths worldwide, with a median overall survival (OS) of 3-16 months. CUP has long been challenging to diagnose principally due to the occult properties of primary site. In the current era of molecular diagnostics, advancements in methodologies based on cytology, histology, gene expression profiling (GEP), and genomic and epigenomic analysis have greatly improved the diagnostic accuracy of CUP, surpassing 90%. Our center conducted the world's first phase III trial and demonstrated improved progression-free survival and favorable OS by GEP-guided site-specific treatment of CUP, setting the foundation of site-specific treatment in first-line management for CUP. In this review, we detailed the epidemiology, etiology, pathogenesis, as well as the histologic, genetic, and clinical characteristics of CUP. We also provided an overview of the advancements in the diagnostics and therapeutics of CUP over the past 50 years. Moving forward, we propose optimizing diagnostic modalities and exploring further-line treatment regimens as two focus areas for future studies on CUP.
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Affiliation(s)
- Ting Zhao
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Xiaowei Zhang
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Xin Liu
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Qifeng Wang
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
- Department of PathologyFudan University Shanghai Cancer CenterShanghaiChina
| | - Xichun Hu
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Zhiguo Luo
- Department of Medical OncologyFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
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Ding Y, Zhou K, Fu K, Liao X, Xiong S, Yang C, Hu M, Liang G, Zeng X, Li Y, Wang D, Li Y. Case Report: Personalized diagnosis and treatment strategies for three cases of cancer of unknown primary based on molecular testing techniques. Front Oncol 2025; 15:1505271. [PMID: 40224175 PMCID: PMC11985444 DOI: 10.3389/fonc.2025.1505271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 03/10/2025] [Indexed: 04/15/2025] Open
Abstract
Cancer of unknown primary (CUP) is a malignancy characterized by metastatic disease at diagnosis with an unidentified primary site, accounting for 3-5% of all cancers. Despite significant advancements in cancer diagnosis and treatment in recent years, CUP management has been challenging due to its complexity and heterogeneity; therefore, its prognosis remains poor. This report presents three cases of CUP. The first case involved a 59-year-old female whose abdominal metastatic cancer was identified to be originating from a primary cervical cancer using a 90-gene panel; the disease was controlled with targeted immunotherapy. The second case was a 56-year-old male with cervical lymph node metastatic cancer; genetic testing suggested renal cancer as the primary site, and dual-targeted therapy resulted in approximately 28% tumor reduction. The third case involved a 71-year-old female with subcutaneous metastatic cancer, which was confirmed by genetic profiling to be related to breast cancer; she achieved stable disease after chemotherapy. Diagnosis and treatment of these three CUP cases demonstrated that molecular testing could significantly improve treatment outcomes and extend patient survival. Precision medicine based on molecular detection has shown substantial value in identifying the primary site of CUP, developing personalized treatment plans, and managing the disease. However, treatment costs and patient compliance remain challenging, necessitating further research to optimize both diagnostic and therapeutic strategies.
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Affiliation(s)
- Yao Ding
- Phase I Clinical Trial Ward, Chongqing University Cancer Hospital, Chongqing, China
| | - Kexue Zhou
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Kaiwen Fu
- Department of Pathology, Chongqing University Cancer Hospital, Chongqing, China
| | - Xingyun Liao
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Shuanglong Xiong
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Chengxiang Yang
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Mingyang Hu
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Guanzhong Liang
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Xianghua Zeng
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Yongsheng Li
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Donglin Wang
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Yan Li
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China
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Napoletano S, Dannhauser D, Netti PA, Causa F. Integrative analysis of miRNA expression data reveals a minimal signature for tumour cells classification. Comput Struct Biotechnol J 2024; 27:233-242. [PMID: 39866665 PMCID: PMC11760817 DOI: 10.1016/j.csbj.2024.12.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 12/20/2024] [Accepted: 12/21/2024] [Indexed: 01/28/2025] Open
Abstract
MicroRNAs (miRNAs) are pivotal biomarkers for cancer screening. Identifying distinctive expression patterns of miRNAs in specific cancer types can serve as an effective strategy for classification and characterization. However, the development of a minimal signature of miRNAs for accurate cancer classification remains challenging, hindered by the lack of integrated approaches that systematically analyse miRNA expression levels of miRNAs alongside their associated biological pathways. In this study, we present a comprehensive integrative approach that utilizes transcriptomic data from lung, breast, and melanoma cancer cell lines to identify specific expression patterns. By combining bioinformatics, dimensionality reduction techniques, machine learning, and experimental validation, we pinpoint miRNAs linked to critical biological pathways. Our results demonstrate a highly significant differentiation of cancer types, achieving 100 % classification accuracy with minimal training time using a streamlined miRNA signature. Validation of the miRNA profile confirms that each of the three identified miRNAs regulates distinct biological pathways with minimal overlap. This specificity highlights their unique roles in tumour biology and set the stage for further exploration of miRNAs interactions and their contributions to tumourigenesis across diverse cancer types. Our work paves the way for multi-cancer classification, emphasizing the transformative potential of miRNA research in oncology. Beyond advancing the understanding of tumour biology, our step-by-step guide offers a robust tool for a wide range of users to investigate precise diagnostics and promising therapeutic strategies.
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Affiliation(s)
- Sabrina Napoletano
- Interdisciplinary Research Centre on Biomaterials (CRIB), Università degli Studi di Napoli "Federico II", Piazzale Tecchio 80, Naples 80125, Italy
- Center for Advanced Biomaterials for Healthcare@CRIB, Istituto Italiano di Tecnologia (IIT), Largo Barsanti e Matteucci 53, Naples 80125, Italy
| | - David Dannhauser
- Interdisciplinary Research Centre on Biomaterials (CRIB), Università degli Studi di Napoli "Federico II", Piazzale Tecchio 80, Naples 80125, Italy
- Dipartimento di Ingegneria Chimica del Materiali e della Produzione Industriale (DICMAPI), University "Federico II", Piazzale Tecchio 80, Naples 80125, Italy
- Center for Advanced Biomaterials for Healthcare@CRIB, Istituto Italiano di Tecnologia (IIT), Largo Barsanti e Matteucci 53, Naples 80125, Italy
| | - Paolo Antonio Netti
- Interdisciplinary Research Centre on Biomaterials (CRIB), Università degli Studi di Napoli "Federico II", Piazzale Tecchio 80, Naples 80125, Italy
- Dipartimento di Ingegneria Chimica del Materiali e della Produzione Industriale (DICMAPI), University "Federico II", Piazzale Tecchio 80, Naples 80125, Italy
- Center for Advanced Biomaterials for Healthcare@CRIB, Istituto Italiano di Tecnologia (IIT), Largo Barsanti e Matteucci 53, Naples 80125, Italy
| | - Filippo Causa
- Interdisciplinary Research Centre on Biomaterials (CRIB), Università degli Studi di Napoli "Federico II", Piazzale Tecchio 80, Naples 80125, Italy
- Dipartimento di Ingegneria Chimica del Materiali e della Produzione Industriale (DICMAPI), University "Federico II", Piazzale Tecchio 80, Naples 80125, Italy
- Center for Advanced Biomaterials for Healthcare@CRIB, Istituto Italiano di Tecnologia (IIT), Largo Barsanti e Matteucci 53, Naples 80125, Italy
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Sivakumaran T, Tothill RW, Mileshkin LR. The evolution of molecular management of carcinoma of unknown primary. Curr Opin Oncol 2024; 36:456-464. [PMID: 39007224 DOI: 10.1097/cco.0000000000001066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
PURPOSE OF REVIEW There is significant need to improve diagnostic and therapeutic options for patients with cancer of unknown primary (CUP). In this review, we discuss the evolving landscape of molecular profiling in CUP. RECENT FINDINGS Molecular profiling is becoming accepted into the diagnostic work-up of CUP patients with tumour mutation profiling now described in international CUP guidelines. Although tissue-of-origin (ToO) molecular tests utilising gene-expression and DNA methylation have existed some time, their clinical benefit remains unclear. Novel technologies utilising whole genome sequencing and machine learning algorithms are showing promise in determining ToO, however further research is required prior to clinical application. A recent international clinical trial found patients treated with molecularly-guided therapy based on comprehensive-panel DNA sequencing had improved progression-free survival compared to chemotherapy alone, confirming utility of performing genomic profiling early in the patient journey. Small phase 2 trials have demonstrated that some CUP patients are responsive to immunotherapy, but the best way to select patients for treatment is not clear. SUMMARY Management of CUP requires a multifaceted approach incorporating clinical, histopathological, radiological and molecular sequencing results to assist with identifying the likely ToO and clinically actionable genomic alternations. Rapidly identifying a subset of CUP patients who are likely to benefit from site specific therapy, targeted therapy and/or immunotherapy will improve patient outcomes.
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Affiliation(s)
| | - Richard W Tothill
- Sir Peter MacCallum Department of Oncology
- University of Melbourne Centre for Cancer Research
- Department of Clinical Pathology, The University of Melbourne, Melbourne, Australia
| | - Linda R Mileshkin
- Peter MacCallum Cancer Centre
- Sir Peter MacCallum Department of Oncology
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Naddeo M, Broseghini E, Venturi F, Vaccari S, Corti B, Lambertini M, Ricci C, Fontana B, Durante G, Pariali M, Scotti B, Milani G, Campione E, Ferracin M, Dika E. Association of miR-146a-5p and miR-21-5p with Prognostic Features in Melanomas. Cancers (Basel) 2024; 16:1688. [PMID: 38730639 PMCID: PMC11083009 DOI: 10.3390/cancers16091688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 04/12/2024] [Accepted: 04/21/2024] [Indexed: 05/13/2024] Open
Abstract
BACKGROUND Cutaneous melanoma (CM) is one of the most lethal tumors among skin cancers and its incidence is rising worldwide. Recent data support the role of microRNAs (miRNAs) in melanoma carcinogenesis and their potential use as disease biomarkers. METHODS We quantified the expression of miR-146a-5p and miR-21-5p in 170 formalin-fixed paraffin embedded (FFPE) samples of CM, namely 116 superficial spreading melanoma (SSM), 26 nodular melanoma (NM), and 28 lentigo maligna melanoma (LMM). We correlated miRNA expression with specific histopathologic features including Breslow thickness (BT), histological subtype, ulceration and regression status, and mitotic index. RESULTS miR-146a-5p and miR-21-5p were significantly higher in NM compared to SSM and LMM. The positive correlation between miR-146a-5p and miR-21-5p expression and BT was confirmed for both miRNAs in SSM. Considering the ulceration status, we assessed that individual miR-21-5p expression was significantly higher in ulcerated CMs. The increased combined expression of the two miRNAs was strongly associated with ulceration (p = 0.0093) and higher mitotic rate (≥1/mm2) (p = 0.0005). We demonstrated that the combination of two-miRNA expression and prognostic features (BT and ulceration) can better differentiate cutaneous melanoma prognostic groups, considering overall survival and time-to-relapse clinical outcomes. Specifically, miRNA expression can further stratify prognostic groups among patients with BT ≥ 0.8 mm but without ulceration. Our findings provide further insights into the characterization of CM with specific prognostic features. The graphical abstract was created with BioRender.com.
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Affiliation(s)
- Maria Naddeo
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40126 Bologna, Italy; (M.N.); (E.B.)
| | - Elisabetta Broseghini
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40126 Bologna, Italy; (M.N.); (E.B.)
| | - Federico Venturi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy; (F.V.); (M.L.); (C.R.); (B.F.); (G.D.)
- Oncologic Dermatology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40126 Bologna, Italy; (S.V.); (B.S.); (G.M.)
| | - Sabina Vaccari
- Oncologic Dermatology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40126 Bologna, Italy; (S.V.); (B.S.); (G.M.)
| | - Barbara Corti
- Division of Pathology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40126 Bologna, Italy;
| | - Martina Lambertini
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy; (F.V.); (M.L.); (C.R.); (B.F.); (G.D.)
- Oncologic Dermatology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40126 Bologna, Italy; (S.V.); (B.S.); (G.M.)
| | - Costantino Ricci
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy; (F.V.); (M.L.); (C.R.); (B.F.); (G.D.)
- Pathology Unit, Ospedale Maggiore, 40133 Bologna, Italy
| | - Beatrice Fontana
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy; (F.V.); (M.L.); (C.R.); (B.F.); (G.D.)
| | - Giorgio Durante
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy; (F.V.); (M.L.); (C.R.); (B.F.); (G.D.)
| | - Milena Pariali
- Center for Applied Biomedical Research, S. Orsola-Malpighi University Hospital, 40126 Bologna, Italy;
| | - Biagio Scotti
- Oncologic Dermatology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40126 Bologna, Italy; (S.V.); (B.S.); (G.M.)
| | - Giulia Milani
- Oncologic Dermatology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40126 Bologna, Italy; (S.V.); (B.S.); (G.M.)
| | - Elena Campione
- Dermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy;
| | - Manuela Ferracin
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40126 Bologna, Italy; (M.N.); (E.B.)
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy; (F.V.); (M.L.); (C.R.); (B.F.); (G.D.)
| | - Emi Dika
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy; (F.V.); (M.L.); (C.R.); (B.F.); (G.D.)
- Oncologic Dermatology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40126 Bologna, Italy; (S.V.); (B.S.); (G.M.)
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Rydzewski NR, Shi Y, Li C, Chrostek MR, Bakhtiar H, Helzer KT, Bootsma ML, Berg TJ, Harari PM, Floberg JM, Blitzer GC, Kosoff D, Taylor AK, Sharifi MN, Yu M, Lang JM, Patel KR, Citrin DE, Sundling KE, Zhao SG. A platform-independent AI tumor lineage and site (ATLAS) classifier. Commun Biol 2024; 7:314. [PMID: 38480799 PMCID: PMC10937974 DOI: 10.1038/s42003-024-05981-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 02/27/2024] [Indexed: 03/17/2024] Open
Abstract
Histopathologic diagnosis and classification of cancer plays a critical role in guiding treatment. Advances in next-generation sequencing have ushered in new complementary molecular frameworks. However, existing approaches do not independently assess both site-of-origin (e.g. prostate) and lineage (e.g. adenocarcinoma) and have minimal validation in metastatic disease, where classification is more difficult. Utilizing gradient-boosted machine learning, we developed ATLAS, a pair of separate AI Tumor Lineage and Site-of-origin models from RNA expression data on 8249 tumor samples. We assessed performance independently in 10,376 total tumor samples, including 1490 metastatic samples, achieving an accuracy of 91.4% for cancer site-of-origin and 97.1% for cancer lineage. High confidence predictions (encompassing the majority of cases) were accurate 98-99% of the time in both localized and remarkably even in metastatic samples. We also identified emergent properties of our lineage scores for tumor types on which the model was never trained (zero-shot learning). Adenocarcinoma/sarcoma lineage scores differentiated epithelioid from biphasic/sarcomatoid mesothelioma. Also, predicted lineage de-differentiation identified neuroendocrine/small cell tumors and was associated with poor outcomes across tumor types. Our platform-independent single-sample approach can be easily translated to existing RNA-seq platforms. ATLAS can complement and guide traditional histopathologic assessment in challenging situations and tumors of unknown primary.
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Affiliation(s)
- Nicholas R Rydzewski
- Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Department of Human Oncology, University of Wisconsin, Madison, WI, USA
| | - Yue Shi
- Department of Human Oncology, University of Wisconsin, Madison, WI, USA
| | - Chenxuan Li
- Department of Human Oncology, University of Wisconsin, Madison, WI, USA
| | | | - Hamza Bakhtiar
- Department of Human Oncology, University of Wisconsin, Madison, WI, USA
| | - Kyle T Helzer
- Department of Human Oncology, University of Wisconsin, Madison, WI, USA
| | - Matthew L Bootsma
- Department of Human Oncology, University of Wisconsin, Madison, WI, USA
| | - Tracy J Berg
- Department of Human Oncology, University of Wisconsin, Madison, WI, USA
| | - Paul M Harari
- Department of Human Oncology, University of Wisconsin, Madison, WI, USA
- Carbone Cancer Center, University of Wisconsin, Madison, WI, USA
| | - John M Floberg
- Department of Human Oncology, University of Wisconsin, Madison, WI, USA
- Carbone Cancer Center, University of Wisconsin, Madison, WI, USA
| | - Grace C Blitzer
- Department of Human Oncology, University of Wisconsin, Madison, WI, USA
- Carbone Cancer Center, University of Wisconsin, Madison, WI, USA
| | - David Kosoff
- Carbone Cancer Center, University of Wisconsin, Madison, WI, USA
- Department of Medicine, University of Wisconsin, Madison, WI, USA
| | - Amy K Taylor
- Carbone Cancer Center, University of Wisconsin, Madison, WI, USA
- Department of Medicine, University of Wisconsin, Madison, WI, USA
| | - Marina N Sharifi
- Carbone Cancer Center, University of Wisconsin, Madison, WI, USA
- Department of Medicine, University of Wisconsin, Madison, WI, USA
| | - Menggang Yu
- Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, USA
| | - Joshua M Lang
- Carbone Cancer Center, University of Wisconsin, Madison, WI, USA
- Department of Medicine, University of Wisconsin, Madison, WI, USA
| | - Krishnan R Patel
- Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Deborah E Citrin
- Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Kaitlin E Sundling
- Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, USA
- Wisconsin State Laboratory of Hygiene, University of Wisconsin, Madison, WI, USA
| | - Shuang G Zhao
- Department of Human Oncology, University of Wisconsin, Madison, WI, USA.
- Carbone Cancer Center, University of Wisconsin, Madison, WI, USA.
- William S. Middleton Veterans Hospital, Madison, WI, USA.
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Ma W, Wu H, Chen Y, Xu H, Jiang J, Du B, Wan M, Ma X, Chen X, Lin L, Su X, Bao X, Shen Y, Xu N, Ruan J, Jiang H, Ding Y. New techniques to identify the tissue of origin for cancer of unknown primary in the era of precision medicine: progress and challenges. Brief Bioinform 2024; 25:bbae028. [PMID: 38343328 PMCID: PMC10859692 DOI: 10.1093/bib/bbae028] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 12/10/2023] [Accepted: 01/11/2024] [Indexed: 02/15/2024] Open
Abstract
Despite a standardized diagnostic examination, cancer of unknown primary (CUP) is a rare metastatic malignancy with an unidentified tissue of origin (TOO). Patients diagnosed with CUP are typically treated with empiric chemotherapy, although their prognosis is worse than those with metastatic cancer of a known origin. TOO identification of CUP has been employed in precision medicine, and subsequent site-specific therapy is clinically helpful. For example, molecular profiling, including genomic profiling, gene expression profiling, epigenetics and proteins, has facilitated TOO identification. Moreover, machine learning has improved identification accuracy, and non-invasive methods, such as liquid biopsy and image omics, are gaining momentum. However, the heterogeneity in prediction accuracy, sample requirements and technical fundamentals among the various techniques is noteworthy. Accordingly, we systematically reviewed the development and limitations of novel TOO identification methods, compared their pros and cons and assessed their potential clinical usefulness. Our study may help patients shift from empirical to customized care and improve their prognoses.
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Affiliation(s)
- Wenyuan Ma
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hui Wu
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yiran Chen
- Department of Surgical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hongxia Xu
- Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining, China
| | - Junjie Jiang
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bang Du
- Real Doctor AI Research Centre, School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Mingyu Wan
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaolu Ma
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaoyu Chen
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lili Lin
- Department of Nuclear Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinhui Su
- Department of Nuclear Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xuanwen Bao
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yifei Shen
- Department of Laboratory Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Nong Xu
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jian Ruan
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haiping Jiang
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yongfeng Ding
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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8
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Rezaie M, Nasehi M, Shimia M, Ebrahimnezhad M, Yousefi B, Majidinia M. Polyphenols Modulate the miRNAs Expression that Involved in Glioblastoma. Mini Rev Med Chem 2024; 24:1953-1969. [PMID: 38639278 DOI: 10.2174/0113895575304605240408105201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 03/11/2024] [Accepted: 03/16/2024] [Indexed: 04/20/2024]
Abstract
Glioblastoma multiforme (GBM), a solid tumor that develops from astrocytes, is one of the most aggressive types of brain cancer. While there have been improvements in the efficacy of treating GBM, many problems remain, especially with traditional therapy methods. Therefore, recent studies have extensively focused on developing novel therapeutic agents for combating glioblastoma. Natural polyphenols have been studied for their potential as chemopreventive and chemotherapeutic agents due to their wide range of positive qualities, including antioxidant, antiinflammatory, cytotoxic, antineoplastic, and immunomodulatory activities. These natural compounds have been suggested to act via modulated various macromolecules within cells, including microRNAs (miRNAs), which play a crucial role in the molecular milieu. In this article, we focus on how polyphenols may inhibit tumor growth by influencing the expression of key miRNAs that regulate oncogenes and tumor suppressor genes.
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Affiliation(s)
- Maede Rezaie
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Mohammad Nasehi
- Cognitive and Neuroscience Research Center, Amir-Almomenin Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Shimia
- Department of Neurosurgery, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohamad Ebrahimnezhad
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Bahman Yousefi
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
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9
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Pandey C, Tiwari P. Differential microRNAs Expression during Cancer Development, and Chemoprevention by Natural Compounds: A Comprehensive Review. J Environ Pathol Toxicol Oncol 2024; 43:65-80. [PMID: 39016142 DOI: 10.1615/jenvironpatholtoxicoloncol.2024050357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/18/2024] Open
Abstract
MicroRNAs are short non-coding RNAs that inhibit gene expression at the post-transcriptional level. Abnormal microRNA expression has been associated with different human diseases, including cancer. Epigenetic changes, mutation, transcriptional deregulation, DNA copy number abnormalities, and defects in the biogenesis machinery play an important role in abnormal microRNA expression. Modulation of microRNAs by natural agents has emerged to enhance the efficacy of conventional chemotherapy through combinatorial therapeutic approach. This review summarizes the current understanding of abnormal microRNA expression in cancer, the different cellular mechanisms of microRNA, and their prevention by natural compounds. Understanding microRNA expression patterns during cancer development may help to identify stage-specific molecular markers. Natural compounds that exert regulatory effects by modulating microRNAs can be used in better cancer chemopreventive strategies by directly targeting microRNAs or as a way to increase sensitivity to existing chemotherapy regimens.
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Affiliation(s)
- Chhaya Pandey
- School of Environmental Biology, Awadhesh Pratap Singh University, Rewa-486001, Madhya Pradesh, India
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10
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Ren M, Cai X, Jia L, Bai Q, Zhu X, Hu X, Wang Q, Luo Z, Zhou X. Comprehensive analysis of cancer of unknown primary and recommendation of a histological and immunohistochemical diagnostic strategy from China. BMC Cancer 2023; 23:1175. [PMID: 38041048 PMCID: PMC10691136 DOI: 10.1186/s12885-023-11563-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 10/24/2023] [Indexed: 12/03/2023] Open
Abstract
BACKGROUND Previous studies on cancer of unknown primary (CUP) mainly focus on treatment and prognosis in western populations and lacked clinical evaluation of different IHC markers, so this study aimed to evaluate characteristics of CUP and recommend a diagnostic strategy from a single center in China. METHODS AND RESULTS Data of 625 patients with CUP were retrospectively collected and reviewed. The patients ranged in age from 20 to 91 years, with a female-to-male ratio of 1.3:1. The predominant histological type was poor or undifferentiated adenocarcinomas (308; 49.3%). The results of Canhelp-Origin molecular testing for the identification of the tissue of origin in 262 of 369 patients (71.0%) were considered predictable (similarity score > 45), with the most common predicted primary tumor site being the breast (57, 21.8%). Unpredictable molecular results correlated with more aggressive clinical parameters and poor survival. Thee positivity rates of several targeted antibodies (GATA3, GCDFP15, TTF1, Napsin A, and PAX8), based on the clinically predicted site, were lower than those reported for the corresponding primary tumors. Nonetheless, TRPS1 and INSM1 were reliable markers of predicted breast carcinoma (75.0%) and neuroendocrine tumors (83.3%), respectively. P16 expression, as well as HPV and EBER testing contributed significantly to the diagnosis of squamous cell carcinomas. Survival analysis revealed that older ages (> 57), ≥ 3 metastatic sites, non-squamous cell carcinomas, bone/liver/lung metastases, unpredictable molecular results, and palliative treatment correlated with poor overall survival. CONCLUSIONS We recommend a CUP diagnostic strategy involving the use of targeted antibody panels as per histological findings that is potentially applicable in clinical practice. The markers TRPS1, INSM1, and P16 expression, as well as HPV and EBER testing are particularly valuable in this aspect. Molecular testing is also predictive of survival rates.
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Affiliation(s)
- Min Ren
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Institute of Pathology, Fudan University, Shanghai, 200032, China
| | - Xu Cai
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Institute of Pathology, Fudan University, Shanghai, 200032, China
| | - Liqing Jia
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Institute of Pathology, Fudan University, Shanghai, 200032, China
| | - Qianming Bai
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Institute of Pathology, Fudan University, Shanghai, 200032, China
| | - Xiaoli Zhu
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Institute of Pathology, Fudan University, Shanghai, 200032, China
| | - Xichun Hu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Qifeng Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Institute of Pathology, Fudan University, Shanghai, 200032, China.
| | - Zhiguo Luo
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
| | - Xiaoyan Zhou
- Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Institute of Pathology, Fudan University, Shanghai, 200032, China.
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11
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Shademan B, Karamad V, Nourazarian A, Masjedi S, Isazadeh A, Sogutlu F, Avcı CB. MicroRNAs as Targets for Cancer Diagnosis: Interests and Limitations. Adv Pharm Bull 2023; 13:435-445. [PMID: 37646065 PMCID: PMC10460809 DOI: 10.34172/apb.2023.047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 04/02/2022] [Accepted: 07/01/2022] [Indexed: 09/01/2023] Open
Abstract
MicroRNAs are small RNAs with ability to attach to the large number of RNA that regulate gene expression on post-transcriptional level via inhibition or degradation of specific mRNAs. MiRNAs in cells are the primary regulators of functions such as cell growth, differentiation, and apoptosis and considerably influence cell function. The expression levels of microRNAs change in human diseases, including cancer. These changes highlight their essential role in cancer pathogenesis. Ubiquitous irregular expression profiles of miRNAs have been detected in various human cancers using genome-wide identification techniques, which are emerging as novel diagnostic and prognostic cancer biomarkers of high specificity and sensitivity. The measurable miRNAs with enhanced stability in blood, tissues, and other body fluids provide a comprehensive source of miRNA-dependent biomarkers for human cancers. The leading role of miRNAs as potential biomarkers in human cancers is discussed in this article. In addition, the interests and difficulties of miRNAs as biomarkers have been explored.
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Affiliation(s)
- Behrouz Shademan
- Department of Medical Biology, Faculty of Medicine, EGE University, Izmir, Turkey
| | - Vahidreza Karamad
- Department of Medical Biology, Faculty of Medicine, EGE University, Izmir, Turkey
| | - Alireza Nourazarian
- Department of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, Iran
| | - Sepideh Masjedi
- Department of Cellular and Molecular Biology Sciences, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
| | - Alireza Isazadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatma Sogutlu
- Department of Medical Biology, Faculty of Medicine, EGE University, Izmir, Turkey
| | - Cigir Biray Avcı
- Department of Medical Biology, Faculty of Medicine, EGE University, Izmir, Turkey
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12
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Michuda J, Breschi A, Kapilivsky J, Manghnani K, McCarter C, Hockenberry AJ, Mineo B, Igartua C, Dudley JT, Stumpe MC, Beaubier N, Shirazi M, Jones R, Morency E, Blackwell K, Guinney J, Beauchamp KA, Taxter T. Validation of a Transcriptome-Based Assay for Classifying Cancers of Unknown Primary Origin. Mol Diagn Ther 2023; 27:499-511. [PMID: 37099070 PMCID: PMC10300170 DOI: 10.1007/s40291-023-00650-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2023] [Indexed: 04/27/2023]
Abstract
INTRODUCTION Cancers assume a variety of distinct histologies, and may originate from a myriad of sites including solid organs, hematopoietic cells, and connective tissue. Clinical decision-making based on consensus guidelines such as the National Comprehensive Cancer Network (NCCN) is often predicated on a specific histologic and anatomic diagnosis, supported by clinical features and pathologist interpretation of morphology and immunohistochemical (IHC) staining patterns. However, in patients with nonspecific morphologic and IHC findings-in addition to ambiguous clinical presentations such as recurrence versus new primary-a definitive diagnosis may not be possible, resulting in the patient being categorized as having a cancer of unknown primary (CUP). Therapeutic options and clinical outcomes are poor for patients with CUP, with a median survival of 8-11 months. METHODS Here, we describe and validate the Tempus Tumor Origin (Tempus TO) assay, an RNA-sequencing-based machine learning classifier capable of discriminating between 68 clinically relevant cancer subtypes. Model accuracy was assessed using primary and/or metastatic samples with known subtype. RESULTS We show that the Tempus TO model is 91% accurate when assessed on both a retrospectively held out cohort and a set of samples sequenced after model freeze that collectively contained 9210 total samples with known diagnoses. When evaluated on a cohort of CUPs, the model recapitulated established associations between genomic alterations and cancer subtype. DISCUSSION Combining diagnostic prediction tests (e.g., Tempus TO) with sequencing-based variant reporting (e.g., Tempus xT) may expand therapeutic options for patients with cancers of unknown primary or uncertain histology.
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13
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Pauli C. [CUP syndrome-diagnostics from the perspective of pathology]. RADIOLOGIE (HEIDELBERG, GERMANY) 2023; 63:336-345. [PMID: 37079060 PMCID: PMC10129915 DOI: 10.1007/s00117-023-01143-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Accepted: 03/21/2023] [Indexed: 04/21/2023]
Abstract
PROBLEM Histologic and immunohistologic workup of tumor material from metastases of a previously unknown primary tumor is important for identifying their origin, but is often insufficient for this purpose without clinical oncologic and radiologic evaluation. PROCEDURE In the initial cancer of unknown primary (CUP) situation, histologic and immunohistochemical workup together with clinicoradiologic correlations contribute significantly to the identification of the primary tumor. There are now accepted guidelines to follow when there is an initial CUP situation. Molecular diagnostic tools can be used to investigate changes at the nucleic acid level, which can provide clues about the primary tumor, including potential targets for therapy. If, despite broad and interdisciplinary diagnostics, it is not possible to identify the primary tumor, the diagnosis is CUP syndrome. If a true CUP situation is present, it is important to assign the tumor to a tumor class or a specific therapy-sensitive subgroup as best as possible so that the best possible treatment can be given. However, for a final assignment to a primary tumor or a final classification as CUP, a comparison with medical oncological and imaging findings is indispensable. CONCLUSION When CUP is suspected, close interdisciplinary collaboration between pathology, medical oncology, and imaging is essential to achieve a viable classification as CUP or identification of a presumptive primary tumor, in the interest of providing the most specific and effective therapy for affected individuals.
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Affiliation(s)
- Chantal Pauli
- Institut für Pathologie und Molekularpathologie, Universitätsspital Zürich, Rämistrasse 100, 8091, Zürich, Schweiz.
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14
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ROSKOVA IVANA, VECERA MAREK, RADOVA LENKA, TRACHTOVA KAROLINA, SIEGL FRANTISEK, HERMANOVA MARKETA, HENDRYCH MICHAL, KREN LEOS, VYBIHAL VACLAV, VALEKOVA HANA, KASPAROVA PETRA, KOLOUSKOVA IVANA, KAZDA TOMAS, SLABY ONDREJ, JANCALEK RADIM, SANA JIRI, SMRCKA MARTIN. Small RNA Sequencing Identifies a Six-MicroRNA Signature Enabling Classification of Brain Metastases According to their Origin. Cancer Genomics Proteomics 2023; 20:18-29. [PMID: 36581345 PMCID: PMC9806667 DOI: 10.21873/cgp.20361] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 11/19/2022] [Accepted: 11/22/2022] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND/AIM Brain metastases (BMs) are the most frequent intracranial tumors in adults and one of the greatest challenges for modern oncology. Most are derived from lung, breast, renal cell, and colorectal carcinomas and melanomas. Up to 14% of patients are diagnosed with BMs of unknown primary, which are commonly characterized by an early and aggressive metastatic spread. It is important to discover novel biomarkers for early identification of BM origin, allowing better management of patients with this disease. Our study focused on microRNAs (miRNAs), which are very stable in frozen native and FFPE tissues and have been shown to be sensitive and specific diagnostic biomarkers of cancer. We aimed to identify miRNAs with significantly different expression in the five most frequent groups of BMs and develop a diagnostic classifier capable of sensitive and specific classification of BMs. MATERIALS AND METHODS Total RNA enriched for miRNAs was isolated using the mirVana miRNA Isolation Kit from 71 fresh-frozen histopathologically confirmed BM tissues originating in 5 cancer types. Sequencing libraries were prepared using the QIAseq miRNA Library Kit and sequenced on the NextSeq 500 platform. MiRNA expression was further validated by RT-qPCR. RESULTS Differential analysis identified 373 miRNAs with significantly different expression between 5 BM groups (p<0.001). A classifier model was developed based on the expression of 6 miRNAs (hsa-miR-141-3p, hsa-miR-141-5p, hsa-miR-146a-5p, hsa-miR-194-5p, hsa-miR-200b-3p and hsa-miR-365b-5p) with the ability to correctly classify 91.5% of samples. Subsequent validation confirmed both significantly different expression of selected miRNAs in 5 BM groups as well as their diagnostic potential. CONCLUSION To date, our study is the first to analyze miRNA expression in various types of BMs using small RNA sequencing to develop a diagnostic classifier and, thus, to help stratify BMs of unknown primary. The presented results confirm the importance of studying the dysregulated expression of miRNAs in BMs and the diagnostic potential of the validated 6-miRNA signature.
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Affiliation(s)
- IVANA ROSKOVA
- Department of Neurosurgery, University Hospital Brno, Brno, Czech Republic,Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - MAREK VECERA
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - LENKA RADOVA
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - KAROLINA TRACHTOVA
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - FRANTISEK SIEGL
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - MARKETA HERMANOVA
- Faculty of Medicine, Masaryk University, Brno, Czech Republic,First Department of Pathology, St. Anne’s University Hospital, Brno, Czech Republic
| | - MICHAL HENDRYCH
- Faculty of Medicine, Masaryk University, Brno, Czech Republic,First Department of Pathology, St. Anne’s University Hospital, Brno, Czech Republic
| | - LEOS KREN
- Department of Pathology, University Hospital Brno, Brno, Czech Republic
| | - VACLAV VYBIHAL
- Department of Neurosurgery, University Hospital Brno, Brno, Czech Republic
| | - HANA VALEKOVA
- Faculty of Medicine, Masaryk University, Brno, Czech Republic,Department of Neurosurgery, St. Anne’s University Hospital, Brno, Czech Republic
| | - PETRA KASPAROVA
- The Fingerland Department of Pathology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
| | | | - TOMAS KAZDA
- Faculty of Medicine, Masaryk University, Brno, Czech Republic,Department of Radiation Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - ONDREJ SLABY
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic,Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - RADIM JANCALEK
- Faculty of Medicine, Masaryk University, Brno, Czech Republic,Department of Neurosurgery, St. Anne’s University Hospital, Brno, Czech Republic
| | - JIRI SANA
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic,Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - MARTIN SMRCKA
- Department of Neurosurgery, University Hospital Brno, Brno, Czech Republic,Faculty of Medicine, Masaryk University, Brno, Czech Republic
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15
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Oryani MA, Tavasoli A, Ghalavand MA, Ashtiani RZ, Rezaee A, Mahmoudi R, Golvari H, Owrangi S, Soleymani-Goloujeh M. Epigenetics and its therapeutic potential in colorectal cancer. Epigenomics 2022; 14:683-697. [PMID: 35473313 DOI: 10.2217/epi-2022-0067] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
It is estimated that colorectal cancer (CRC) is the leading cause of cancer-related death around the globe. 'Epigenetics' refers to changes in the chromosome rather than the DNA sequence, which may be transmitted down to daughter cells. Epigenetics is an essential part of controlling the development and variation of a single cell. ncRNAs have a role in epigenetic regulation in CRC, which will be discussed in this review in the context of DNA methylation and histone modifications. A greater survival rate for CRC patients might be achieved by addressing epigenetic mediators, as the authors show. In this review, they aim to thoroughly examine the role of epigenetics in the prognosis, diagnosis and treatment of CRC.
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Affiliation(s)
- Mahsa Akbari Oryani
- Department of Pathology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Afsaneh Tavasoli
- Department of Biotechnology, Faculty of Pharmacy, Alborz University of Medical Sciences, Karaj, Iran
| | - Mohammad Amin Ghalavand
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Alisam Rezaee
- Faculty of Medical Sciences & Technologies, Science & Research Branch, Islamic Azad University, Tehran, Iran
| | | | - Hossein Golvari
- School of Nursing & Paramedical Sciences, Mazandaran University of Medical Sciences, Sari, Iran
| | - Soroor Owrangi
- Student Research Committee, Fasa University of Medical Sciences, Fasa, Iran
| | - Mehdi Soleymani-Goloujeh
- Department of Stem Cells & Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology & Technology, ACECR, Tehran, Iran
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16
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Bae JM, Ahn JY, Lee H, Jang H, Han H, Jeong J, Cho NY, Kim K, Kang GH. Identification of tissue of origin in cancer of unknown primary using a targeted bisulfite sequencing panel. Epigenomics 2022; 14:615-628. [PMID: 35473295 DOI: 10.2217/epi-2021-0477] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: To construct a targeted bisulfite sequencing panel predicting origin of cancer of unknown primary. Methods: A bisulfite sequencing panel targeting 2793 tissue-specific markers was performed in 100 clinical samples. Results: The authors' prediction model showed 0.85 accuracy for the 'first-ranked' tissue type and 0.93 accuracy for the 'second-ranked' tissue type using 2793 tissue-specific markers and 0.84 accuracy for the 'first-ranked' tissue type and 0.92 accuracy for the 'second-ranked' tissue type when the number of tissue-specific markers was reduced to 514. Conclusion: Targeted bisulfite sequencing is a useful method for predicting the tissue of origin in patients with cancer of unknown primary.
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Affiliation(s)
- Jeong Mo Bae
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Ji Young Ahn
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea
| | - Heonyi Lee
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea
| | | | | | | | - Nam-Yun Cho
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Kwangsoo Kim
- Transdisciplinary Department of Medicine and Advanced Technology, Seoul National University Hospital, Seoul, Korea
| | - Gyeong Hoon Kang
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
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17
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Ding Y, Jiang J, Xu J, Chen Y, Zheng Y, Jiang W, Mao C, Jiang H, Bao X, Shen Y, Li X, Teng L, Xu N. Site-specific therapy in cancers of unknown primary site: a systematic review and meta-analysis. ESMO Open 2022; 7:100407. [PMID: 35248824 PMCID: PMC8897579 DOI: 10.1016/j.esmoop.2022.100407] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 01/22/2022] [Accepted: 01/25/2022] [Indexed: 12/01/2022] Open
Abstract
Background Cancer of unknown primary site (CUP) is a term applied to characterize pathologically confirmed metastatic cancer with unknown primary tumor origin. It remains uncertain whether patients with CUP benefit from site-specific therapy guided by molecular profiling. Patients and methods A systematic search in PubMed, Web of Science, Embase, Cochrane Library, and ClinicalTrials.gov, and of conference abstracts from January 1976 to January 2021 was performed to identify studies investigating the efficacy of site-specific therapy on patients with CUP. The quality of included studies was evaluated using the Cochrane risk of bias tool and Newcastle–Ottawa scale. Eligible studies were weighted and pooled for meta-analysis. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were assessed to compare the efficacy of site-specific therapy with empiric therapy in patients with CUP. In addition, subgroup analyses were conducted. Results Five studies comprising 1114 patients were identified, of which 454 patients received site-specific therapy, and 660 patients received empiric therapy. Our meta-analysis revealed that site-specific therapy was not significantly associated with improved PFS [HR 0.93, 95% confidence interval (CI) 0.74-1.17, P = 0.534] and OS (HR 0.75, 95% CI 0.55-1.03, P = 0.069), compared with empiric therapy. However, during subgroup analysis significantly improved OS was associated with site-specific therapy in the high-accuracy predictive assay subgroup (HR 0.46, 95% CI 0.26-0.81, P = 0.008) compared with the low accuracy predictive assay subgroup (HR 0.93, 95% CI 0.75-1.15, P = 0.509). Furthermore, compared with patients with less responsive tumor types, more survival benefit from site-specific therapy was found in patients with more responsive tumors (HR 0.67, 95% CI 0.46-0.97, P = 0.037). Conclusions Our results suggest that site-specific therapy is not significantly associated with improved survival outcomes; however, it might benefit patients with CUP with responsive tumor types.
Studies evaluating the role of site-specific therapy guided by molecular profiling in CUP provided contradictory results. Site-specific therapy is not significantly associated with improved survival outcomes in the overall CUP population. Molecularly defined site-specific therapy may improve OS only when high-accuracy assays assign CUP to responsive tumor types.
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Affiliation(s)
- Y Ding
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - J Jiang
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - J Xu
- Department of Thoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Y Chen
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Y Zheng
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - W Jiang
- Department of Colorectal Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou; China
| | - C Mao
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - H Jiang
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - X Bao
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Y Shen
- Centre of Clinical Laboratory, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou; China; Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou; China; Institute of Laboratory Medicine, Zhejiang University, Hangzhou; China
| | - X Li
- Department of Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - L Teng
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
| | - N Xu
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
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Vibert J, Pierron G, Benoist C, Gruel N, Guillemot D, Vincent-Salomon A, Le Tourneau C, Livartowski A, Mariani O, Baulande S, Bidard FC, Delattre O, Waterfall JJ, Watson S. Identification of Tissue of Origin and Guided Therapeutic Applications in Cancers of Unknown Primary Using Deep Learning and RNA Sequencing (TransCUPtomics). J Mol Diagn 2021; 23:1380-1392. [PMID: 34325056 DOI: 10.1016/j.jmoldx.2021.07.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 05/14/2021] [Accepted: 07/14/2021] [Indexed: 01/04/2023] Open
Abstract
Cancers of unknown primary (CUP) are metastatic cancers for which the primary tumor is not found despite thorough diagnostic investigations. Multiple molecular assays have been proposed to identify the tissue of origin (TOO) and inform clinical care; however, none has been able to combine accuracy, interpretability, and easy access for routine use. We developed a classifier tool based on the training of a variational autoencoder to predict tissue of origin based on RNA-sequencing data. We used as training data 20,918 samples corresponding to 94 different categories, including 39 cancer types and 55 normal tissues. The TransCUPtomics classifier was applied to a retrospective cohort of 37 CUP patients and 11 prospective patients. TransCUPtomics exhibited an overall accuracy of 96% on reference data for TOO prediction. The TOO could be identified in 38 (79%) of 48 CUP patients. Eight of 11 prospective CUP patients (73%) could receive first-line therapy guided by TransCUPtomics prediction, with responses observed in most patients. The variational autoencoder added further utility by enabling prediction interpretability, and diagnostic predictions could be matched to detection of gene fusions and expressed variants. TransCUPtomics confidently predicted TOO for CUP and enabled tailored treatments leading to significant clinical responses. The interpretability of our approach is a powerful addition to improve the management of CUP patients.
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Affiliation(s)
- Julien Vibert
- INSERM U830, Équipe Labellisée Ligue Nationale Contre le Cancer, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, Institut Curie Research Center, Paris, France
| | - Gaëlle Pierron
- Somatic Genetics Unit, Department of Genetics, Institut Curie Hospital, Paris, France
| | - Camille Benoist
- Clinical Bioinformatic Unit, Department of Diagnostic and Theranostic Medecine, Institut Curie Hospital, Paris, France
| | - Nadège Gruel
- INSERM U830, Équipe Labellisée Ligue Nationale Contre le Cancer, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, Institut Curie Research Center, Paris, France; Department of Translational Research, PSL Research University, Institut Curie Research Center, Paris, France
| | - Delphine Guillemot
- Somatic Genetics Unit, Department of Genetics, Institut Curie Hospital, Paris, France
| | - Anne Vincent-Salomon
- Department of Diagnostic and Theranostic Medecine, Institut Curie Hospital, Paris, France
| | - Christophe Le Tourneau
- Department of Drug Development and Innovation, INSERM U900, Paris-Saclay University, Institut Curie Hospital and Research Center, Paris and Saint-Cloud
| | - Alain Livartowski
- Department of Medical Oncology, Institut Curie Hospital, Paris, France
| | - Odette Mariani
- Department of Diagnostic and Theranostic Medecine, Institut Curie Hospital, Paris, France
| | - Sylvain Baulande
- Institut Curie Genomics of Excellence (ICGex) Platform, PSL Research University, Institut Curie Research Center, Paris, France
| | - François-Clément Bidard
- Department of Medical Oncology, Institut Curie Hospital, Paris, France; INSERM CIC-BT 1428, UVSQ, Paris-Saclay University, Saint-Cloud, France
| | - Olivier Delattre
- INSERM U830, Équipe Labellisée Ligue Nationale Contre le Cancer, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, Institut Curie Research Center, Paris, France; Somatic Genetics Unit, Department of Genetics, Institut Curie Hospital, Paris, France
| | - Joshua J Waterfall
- Department of Translational Research, PSL Research University, Institut Curie Research Center, Paris, France; INSERM U830, PSL Research University, Institut Curie Research Center, Paris, France
| | - Sarah Watson
- INSERM U830, Équipe Labellisée Ligue Nationale Contre le Cancer, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, Institut Curie Research Center, Paris, France; Department of Medical Oncology, Institut Curie Hospital, Paris, France.
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19
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Laprovitera N, Riefolo M, Porcellini E, Durante G, Garajova I, Vasuri F, Aigelsreiter A, Dandachi N, Benvenuto G, Agostinis F, Sabbioni S, Berindan Neagoe I, Romualdi C, Ardizzoni A, Trerè D, Pichler M, D'Errico A, Ferracin M. MicroRNA expression profiling with a droplet digital PCR assay enables molecular diagnosis and prognosis of cancers of unknown primary. Mol Oncol 2021; 15:2732-2751. [PMID: 34075699 PMCID: PMC8486570 DOI: 10.1002/1878-0261.13026] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 04/30/2021] [Accepted: 05/28/2021] [Indexed: 12/16/2022] Open
Abstract
Metastasis is responsible for the majority of cancer‐related deaths. Particularly, challenging is the management of metastatic cancer of unknown primary site (CUP), whose tissue of origin (TOO) remains undetermined even after extensive investigations and whose therapy is rather unspecific and poorly effective. Molecular approaches to identify the most probable TOO of CUPs can overcome some of these issues. In this study, we applied a predetermined set of 89 microRNAs (miRNAs) to infer the TOO of 53 metastatic cancers of unknown or uncertain origin. The miRNA expression was assessed with droplet digital PCR in 159 samples, including primary tumors from 17 tumor classes (reference set) and metastases of known and unknown origin (test set). We combined two different statistical models for class prediction to obtain the most probable TOOs: the nearest shrunken centroids approach of Prediction Analysis of Microarrays (PAMR) and the least absolute shrinkage and selection operator (LASSO) models. The molecular test was successful for all formalin‐fixed paraffin‐embedded samples and provided a TOO identification within 1 week from the biopsy procedure. The most frequently predicted origins were gastrointestinal, pancreas, breast, lung, and bile duct. The assay was applied also to multiple metastases from the same CUP, collected from different metastatic sites: The predictions showed a strong agreement, intrinsically validating our assay. The final CUPs' TOO prediction was compared with the clinicopathological hypothesis of primary site. Moreover, a panel of 13 miRNAs proved to have prognostic value and be associated with overall survival in CUP patients. Our study demonstrated that miRNA expression profiling in CUP samples could be employed as diagnostic and prognostic test. Our molecular analysis can be performed on request, concomitantly with standard diagnostic workup and in association with genetic profiling, to offer valuable indications about the possible primary site, thereby supporting treatment decisions.
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Affiliation(s)
- Noemi Laprovitera
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Italy.,Department of Life Sciences and Biotechnologies, University of Ferrara, Italy
| | - Mattia Riefolo
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Italy.,Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy
| | - Elisa Porcellini
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Italy
| | - Giorgio Durante
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Italy
| | | | - Francesco Vasuri
- Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy
| | - Ariane Aigelsreiter
- Diagnostic and Research Institute of Pathology, Medical University of Graz, Austria
| | - Nadia Dandachi
- Division of Oncology, Medical University of Graz, Austria
| | | | | | - Silvia Sabbioni
- Department of Life Sciences and Biotechnologies, University of Ferrara, Italy
| | - Ioana Berindan Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | | | - Andrea Ardizzoni
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Italy.,Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy
| | - Davide Trerè
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Italy
| | - Martin Pichler
- Division of Oncology, Medical University of Graz, Austria
| | - Antonietta D'Errico
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Italy.,Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy
| | - Manuela Ferracin
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Italy
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20
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Lack of Conserved miRNA Deregulation in HPV-Induced Squamous Cell Carcinomas. Biomolecules 2021; 11:biom11050764. [PMID: 34065237 PMCID: PMC8160722 DOI: 10.3390/biom11050764] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/12/2021] [Accepted: 05/15/2021] [Indexed: 12/26/2022] Open
Abstract
Squamous cell carcinomas (SCCs) in the anogenital and head and neck regions are associated with high-risk types of human papillomaviruses (HR-HPV). Deregulation of miRNA expression is an important contributor to carcinogenesis. This study aimed to pinpoint commonly and uniquely deregulated miRNAs in cervical, anal, vulvar, and tonsillar tumors of viral or non-viral etiology, searching for a common set of deregulated miRNAs linked to HPV-induced carcinogenesis. RNA was extracted from tumors and nonmalignant tissues from the same locations. The miRNA expression level was determined by next-generation sequencing. Differential expression of miRNAs was calculated, and the patterns of miRNA deregulation were compared between tumors. The total of deregulated miRNAs varied between tumors of different locations by two orders of magnitude, ranging from 1 to 282. The deregulated miRNA pool was largely tumor-specific. In tumors of the same location, a low proportion of miRNAs were exclusively deregulated and no deregulated miRNA was shared by all four types of HPV-positive tumors. The most significant overlap of deregulated miRNAs was found between tumors which differed in location and HPV status (HPV-positive cervical tumors vs. HPV-negative vulvar tumors). Our results imply that HPV infection does not elicit a conserved miRNA deregulation in SCCs.
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21
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Dika E, Broseghini E, Porcellini E, Lambertini M, Riefolo M, Durante G, Loher P, Roncarati R, Bassi C, Misciali C, Negrini M, Rigoutsos I, Londin E, Patrizi A, Ferracin M. Unraveling the role of microRNA/isomiR network in multiple primary melanoma pathogenesis. Cell Death Dis 2021; 12:473. [PMID: 33980826 PMCID: PMC8115306 DOI: 10.1038/s41419-021-03764-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 04/19/2021] [Accepted: 04/19/2021] [Indexed: 12/16/2022]
Abstract
Malignant cutaneous melanoma (CM) is a potentially lethal form of skin cancer whose worldwide incidence has been constantly increasing over the past decades. During their lifetime, about 8% of CM patients will develop multiple primary melanomas (MPMs), usually at a young age and within 3 years from the first tumor/diagnosis. With the aim of improving our knowledge on MPM biology and pathogenesis, we explored the miRNome of 24 single and multiple primary melanomas, including multiple tumors from the same patient, using a small RNA-sequencing approach. From a supervised analysis, 22 miRNAs were differentially expressed in MPM compared to single CM, including key miRNAs involved in epithelial-mesenchymal transition. The first and second melanoma from the same patient presented a different miRNA profile. Ten miRNAs, including miR-25-3p, 149-5p, 92b-3p, 211-5p, 125a-5p, 125b-5p, 205-5p, 200b-3p, 21-5p, and 146a-5p, were further validated in 47 single and multiple melanoma samples. Pathway enrichment analysis of miRNA target genes revealed a more differentiated and less invasive status of MPMs compared to CMs. Bioinformatic analyses at the miRNA isoform (isomiR) level detected a panel of highly expressed isomiRs belonging to miRNA families implicated in human tumorigenesis, including miR-200, miR-30, and miR-10 family. Moreover, we identified hsa-miR-125a-5p|0|-2 isoform as tenfold over-represented in melanoma than the canonical form and differentially expressed in MPMs arising in the same patient. Target prediction analysis revealed that the miRNA shortening could change the pattern of target gene regulation, specifically in genes implicated in cell adhesion and neuronal differentiation. Overall, we provided a putative and comprehensive characterization of the miRNA/isomiR regulatory network of MPMs, highlighting mechanisms of tumor development and molecular features differentiating this subtype from single melanomas.
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Affiliation(s)
- Emi Dika
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
- Dermatology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Elisabetta Broseghini
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Elisa Porcellini
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Martina Lambertini
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
- Dermatology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Mattia Riefolo
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Giorgio Durante
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Phillipe Loher
- Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Roberta Roncarati
- Department of Translational Medicine and for Romagna, and "Laboratorio per le Tecnologie delle Terapie Avanzate" (LTTA), University of Ferrara, Ferrara, Italy
- CNR, Institute of Genetics and Biomedical Research, National Research Council of Italy, Milan, Italy
| | - Cristian Bassi
- Department of Translational Medicine and for Romagna, and "Laboratorio per le Tecnologie delle Terapie Avanzate" (LTTA), University of Ferrara, Ferrara, Italy
| | - Cosimo Misciali
- Dermatology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Massimo Negrini
- Department of Translational Medicine and for Romagna, and "Laboratorio per le Tecnologie delle Terapie Avanzate" (LTTA), University of Ferrara, Ferrara, Italy
| | - Isidore Rigoutsos
- Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Eric Londin
- Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Annalisa Patrizi
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
- Dermatology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Manuela Ferracin
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
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22
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Park JW, Jeong JM, Cho KS, Cho SY, Cheon JH, Choi DH, Park SJ, Kim HK. MiR-30a and miR-200c differentiate cholangiocarcinomas from gastrointestinal cancer liver metastases. PLoS One 2021; 16:e0250083. [PMID: 33852640 PMCID: PMC8046207 DOI: 10.1371/journal.pone.0250083] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 03/30/2021] [Indexed: 11/19/2022] Open
Abstract
Prior studies have demonstrated the utility of microRNA assays for predicting some cancer tissue origins, but these assays need to be further optimized for predicting the tissue origins of adenocarcinomas of the liver. We performed microRNA profiling on 195 frozen primary tumor samples using 14 types of tumors that were either adenocarcinomas or differentiated from adenocarcinomas. The 1-nearest neighbor method predicted tissue-of-origin in 33 samples of a test set, with an accuracy of 93.9% at feature selection p values ranging from 10-4 to 10-10. According to binary decision tree analyses, the overexpression of miR-30a and the underexpression of miR-200 family members (miR-200c and miR-141) differentiated intrahepatic cholangiocarcinomas from extrahepatic adenocarcinomas. When binary decision tree analyses were performed using the test set, the prediction accuracy was 84.8%. The overexpression of miR-30a and the reduced expressions of miR-200c, miR-141, and miR-425 could distinguish intrahepatic cholangiocarcinomas from liver metastases from the gastrointestinal tract.
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Affiliation(s)
- Jun Won Park
- National Cancer Center of Korea, Goyang, Republic of Korea
- Department of Biomedical Convergence, Kangwon National University, Kangwon, Republic of Korea
| | - Jong Min Jeong
- National Cancer Center of Korea, Goyang, Republic of Korea
| | - Kye Soo Cho
- National Cancer Center of Korea, Goyang, Republic of Korea
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Soo Young Cho
- National Cancer Center of Korea, Goyang, Republic of Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dong Ho Choi
- Departments of Surgery, Hanyang University School of Medicine, Seoul, Republic of Korea
| | - Sang Jae Park
- National Cancer Center of Korea, Goyang, Republic of Korea
| | - Hark Kyun Kim
- National Cancer Center of Korea, Goyang, Republic of Korea
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23
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Bukkuri A, Andor N, Darcy IK. Applications of Topological Data Analysis in Oncology. Front Artif Intell 2021; 4:659037. [PMID: 33928240 PMCID: PMC8076640 DOI: 10.3389/frai.2021.659037] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/16/2021] [Indexed: 12/12/2022] Open
Abstract
The emergence of the information age in the last few decades brought with it an explosion of biomedical data. But with great power comes great responsibility: there is now a pressing need for new data analysis algorithms to be developed to make sense of the data and transform this information into knowledge which can be directly translated into the clinic. Topological data analysis (TDA) provides a promising path forward: using tools from the mathematical field of algebraic topology, TDA provides a framework to extract insights into the often high-dimensional, incomplete, and noisy nature of biomedical data. Nowhere is this more evident than in the field of oncology, where patient-specific data is routinely presented to clinicians in a variety of forms, from imaging to single cell genomic sequencing. In this review, we focus on applications involving persistent homology, one of the main tools of TDA. We describe some recent successes of TDA in oncology, specifically in predicting treatment responses and prognosis, tumor segmentation and computer-aided diagnosis, disease classification, and cellular architecture determination. We also provide suggestions on avenues for future research including utilizing TDA to analyze cancer time-series data such as gene expression changes during pathogenesis, investigation of the relation between angiogenic vessel structure and treatment efficacy from imaging data, and experimental confirmation that geometric and topological connectivity implies functional connectivity in the context of cancer.
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Affiliation(s)
- Anuraag Bukkuri
- Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, United States
| | - Noemi Andor
- Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, United States
| | - Isabel K. Darcy
- Department of Mathematics, University of Iowa, Iowa City, IA, United States
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24
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Redefining cancer of unknown primary: Is precision medicine really shifting the paradigm? Cancer Treat Rev 2021; 97:102204. [PMID: 33866225 DOI: 10.1016/j.ctrv.2021.102204] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 03/27/2021] [Accepted: 03/30/2021] [Indexed: 12/12/2022]
Abstract
The concept of Cancer of Unknown Primary (CUP) has evolved with the advent of medical oncology. CUP can be difficult to diagnose and represents 2 to 5% of new cancers, therefore not exceptionally rare. Within CUPs can be identified a subset of favourable prognosis tumours, however the vast majority of CUP patients belongs to a poor prognosis group. CUP features significant oncological challenges, such as unravelling biological and transversal issues, and most importantly, improving patient's outcomes. In that regard, CUP patients' outcomes regrettably showed minimal improvement for decades and CUP remains a cancer group of very poor prognosis. The biology of CUP has two main hypotheses. One is that CUP is a subgroup of a given primary cancer, where the primary is present but cannot be seen due to its small size. The other, the "true" CUP hypothesis, states that CUP share features that make them a specific entity, whatever their tissue of origin. A true biological signature has not yet been described, but chromosomal instability is a hallmark of poor prognosis CUP group. Precision oncology, despite achieving identifying the putative origin of the CUP, so far failed to globally improve outcomes of patients. Targeting molecular pathways based on molecular analysis in CUP management is under investigation. Immunotherapy has not shown ground-breaking results, to date. Accrual is also a crucial issue in CUP trials. Herein we review CUP history, biological features and remaining questions in CUP biology, the two main approaches of molecular oncology in CUP management, in order to draw perspectives in the enormous challenge of improving CUP patient outcomes.
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25
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Rajendiran S, Maji S, Haddad A, Lotan Y, Nandy RR, Vishwanatha JK, Chaudhary P. MicroRNA-940 as a Potential Serum Biomarker for Prostate Cancer. Front Oncol 2021; 11:628094. [PMID: 33816263 PMCID: PMC8017318 DOI: 10.3389/fonc.2021.628094] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 02/23/2021] [Indexed: 12/22/2022] Open
Abstract
Prostate cancer is one of the leading causes of death despite an astoundingly high survival rate for localized tumors. Though prostate specific antigen (PSA) test, performed in conjunction with digital rectal examinations, is reasonably accurate, there are major caveats requiring a thorough assessment of risks and benefits prior to conducting the test. MicroRNAs, a class of small non-coding RNAs, are stable molecules that can be detected in circulation by non-invasive methods and have gained importance in cancer prognosis and diagnosis in the recent years. Here, we investigate circulating miR-940, a miRNA known to play a role in prostate cancer progression, in both cell culture supernatants as well as patient serum and urine samples to determine the utility of miR-940 as a new molecular marker for prostate cancer detection. We found that miR-940 was significantly higher in serum from cancer patients, specifically those with clinically significant tumors (GS ≥ 7). Analysis of receiver operating characteristic curve demonstrated that miR-940 in combination with PSA had a higher area under curve value (AUC: 0.818) than the miR-940 alone (AUC: 0.75) for the diagnosis of prostate cancer. This study provides promising results suggesting the use of miR-940 for prostate cancer diagnosis.
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Affiliation(s)
- Smrithi Rajendiran
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Sayantan Maji
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Ahmed Haddad
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Yair Lotan
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Rajesh R Nandy
- School of Public Health, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Jamboor K Vishwanatha
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX, United States.,Texas Center for Health Disparities, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Pankaj Chaudhary
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX, United States.,Texas Center for Health Disparities, University of North Texas Health Science Center, Fort Worth, TX, United States
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26
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Rishabh K, Khadilkar S, Kumar A, Kalra I, Kumar AP, Kunnumakkara AB. MicroRNAs as Modulators of Oral Tumorigenesis-A Focused Review. Int J Mol Sci 2021; 22:ijms22052561. [PMID: 33806361 PMCID: PMC7961687 DOI: 10.3390/ijms22052561] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 02/24/2021] [Accepted: 02/26/2021] [Indexed: 12/23/2022] Open
Abstract
Oral cancers constitute the majority of head and neck tumors, with a relatively high incidence and poor survival rate in developing countries. While the five-year survival rates of the oral cancer patients have increased to 65%, the overall survival for advanced stages has been at 27% for the past ten years, emphasizing the necessity for further understanding the etiology of the disease, diagnosis, and formulating possible novel treatment regimens. MicroRNAs (miRNAs), a family of small non-coding RNA, have emerged as master modulators of gene expression in various cellular and biological process. Aberrant expression of these dynamic molecules has been associated with many human diseases, including oral cancers. The deregulated miRNAs have been shown to control various oncogenic processes, including sustaining proliferative signaling, evading growth suppressors, resisting cell death activating invasion and metastasis, and inducing angiogenesis. Hence, the aberrant expression of miRNAs associated with oral cancers, makes them potential candidates for the investigation of functional markers, which will aid in the differential diagnosis, prognosis, and development of novel therapeutic regimens. This review presents a holistic insight into our understanding of the role of miRNAs in regulating various hallmarks of oral tumorigenesis.
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Affiliation(s)
- Kumar Rishabh
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam 781039, India; (K.R.); (S.K.); (A.K.); (I.K.)
| | - Soham Khadilkar
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam 781039, India; (K.R.); (S.K.); (A.K.); (I.K.)
| | - Aviral Kumar
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam 781039, India; (K.R.); (S.K.); (A.K.); (I.K.)
| | - Ishu Kalra
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam 781039, India; (K.R.); (S.K.); (A.K.); (I.K.)
| | - Alan Prem Kumar
- Cancer Science Institute of Singapore, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore
- National University Cancer Institute, National University Health System, Singapore 119074, Singapore
- Correspondence: authors: (A.P.K.); (A.B.K.)
| | - Ajaikumar B. Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam 781039, India; (K.R.); (S.K.); (A.K.); (I.K.)
- Correspondence: authors: (A.P.K.); (A.B.K.)
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27
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Saini V, Dawar R, Suneja S, Gangopadhyay S, Kaur C. Can microRNA become next-generation tools in molecular diagnostics and therapeutics? A systematic review. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2021. [DOI: 10.1186/s43042-020-00125-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Abstract
Background
MicroRNAs (miRNAs) represent a novel class of single-stranded RNA molecules of 18–22 nucleotides that serve as powerful tools in the regulation of gene expression. They are important regulatory molecules in several biological processes.
Main body
Alteration in the expression profiles of miRNAs have been found in several diseases. It is anticipated that miRNA expression profiling can become a novel diagnostic tool in the future.
Hence, this review evaluates the implications of miRNAs in various diseases and the recent advances in miRNA expression level detection and their target identification. A systematic approach to review existing literature available on databases such as Medline, PubMed, and EMBASE was conducted to have a better understanding of mechanisms mediating miRNA-dependent gene regulation and their role as diagnostic markers and therapeutic agents.
Conclusion
A clear understanding of the complex multilevel regulation of miRNA expression is a prerequisite to explicate the origin of a wide variety of diseases. It is understandable that miRNAs offer potential targets both in diagnostics and therapeutics of a multitude of diseases. The inclusion of specific miRNA expression profiles as biomarkers may lead to crucial advancements in facilitating disease diagnosis and classification, monitoring its prognosis, and treatment. However, standardization of methods has a pivotal role in the success of extensive use of miRNA expression profiling in routine clinical settings.
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28
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Laprovitera N, Riefolo M, Ambrosini E, Klec C, Pichler M, Ferracin M. Cancer of Unknown Primary: Challenges and Progress in Clinical Management. Cancers (Basel) 2021; 13:451. [PMID: 33504059 PMCID: PMC7866161 DOI: 10.3390/cancers13030451] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/30/2020] [Accepted: 01/19/2021] [Indexed: 12/11/2022] Open
Abstract
Distant metastases are the main cause of cancer-related deaths in patients with advanced tumors. A standard diagnostic workup usually contains the identification of the tissue-of-origin of metastatic tumors, although under certain circumstances, it remains elusive. This disease setting is defined as cancer of unknown primary (CUP). Accounting for approximately 3-5% of all cancer diagnoses, CUPs are characterized by an aggressive clinical behavior and represent a real therapeutic challenge. The lack of determination of a tissue of origin precludes CUP patients from specific evidence-based therapeutic options or access to clinical trial, which significantly impacts their life expectancy. In the era of precision medicine, it is essential to characterize CUP molecular features, including the expression profile of non-coding RNAs, to improve our understanding of CUP biology and identify novel therapeutic strategies. This review article sheds light on this enigmatic disease by summarizing the current knowledge on CUPs focusing on recent discoveries and emerging diagnostic strategies.
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Affiliation(s)
- Noemi Laprovitera
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy; (N.L.); (M.R.); (E.A.)
- Department of Life Sciences and Biotechnologies, University of Ferrara, 44121 Ferrara, Italy
| | - Mattia Riefolo
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy; (N.L.); (M.R.); (E.A.)
| | - Elisa Ambrosini
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy; (N.L.); (M.R.); (E.A.)
| | - Christiane Klec
- Division of Oncology, Medical University of Graz, 8036 Graz, Austria; (C.K.); (M.P.)
| | - Martin Pichler
- Division of Oncology, Medical University of Graz, 8036 Graz, Austria; (C.K.); (M.P.)
| | - Manuela Ferracin
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy; (N.L.); (M.R.); (E.A.)
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Ravegnini G, Serrano C, Ricci R, Zhang Q, Terrenato I, Graziosi A, Valori G, Landolfi S, Hrelia P, Angelini S. miRNA landscape in primary tumors and matched metastases in gastrointestinal stromal tumors. Epigenomics 2021; 13:369-377. [PMID: 33432846 DOI: 10.2217/epi-2020-0303] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: Gastrointestinal stromal tumor management is extremely challenging, particularly the metastatic disease. The underlying mechanism in metastasis spread remains largely unknown. We aimed to characterize miRNAs involved in the metastatic process in gastrointestinal stromal tumor. Material & methods: Eight primary tumors and 18 synchronous metastases were analyzed through miRNA Taqman arrays or assays. Results: miRNAs profiles revealed similar expression in primary site and metastases. Pair-wise correlation coefficient between primary tumor and metastases was significant for each patient (p < 0.0001 for all profiled patients). Conclusion: Our study, the largest including primary tumors and metastases so far performed, highlighted perpetuation of miRNAs features in metastatic lesions and that the primary origin appears to be the main determinant of the metastases miRNA profile.
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Affiliation(s)
- Gloria Ravegnini
- Department of Pharmacy & Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Cèsar Serrano
- Sarcoma Translational Research Laboratory, Vall d'Hebron Institute of Oncology, 08035 Barcelona, Spain.,Department of Medical Oncology, Vall d'Hebron University Hospital, 08035 Barcelona, Spain
| | - Riccardo Ricci
- UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, 00168 Rome, Italy
| | - Qianqian Zhang
- UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, 00168 Rome, Italy
| | - Irene Terrenato
- Biostatistics-Scientific Direction, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Agnese Graziosi
- Department of Pharmacy & Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Giorgia Valori
- Department of Pharmacy & Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Stefania Landolfi
- Department of Pathology, Vall d'Hebron University Hospital, 08035 Barcelona, Spain
| | - Patrizia Hrelia
- Department of Pharmacy & Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Sabrina Angelini
- Department of Pharmacy & Biotechnology, University of Bologna, 40126 Bologna, Italy
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Sasi S, Singh S, Walia T, Meena RC, Thakur S. Role of MicroRNA In Situ Hybridization in Colon Cancer Diagnosis. COLON CANCER DIAGNOSIS AND THERAPY 2021:67-89. [DOI: 10.1007/978-3-030-63369-1_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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31
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Albakova Z, Siam MKS, Sacitharan PK, Ziganshin RH, Ryazantsev DY, Sapozhnikov AM. Extracellular heat shock proteins and cancer: New perspectives. Transl Oncol 2020; 14:100995. [PMID: 33338880 PMCID: PMC7749402 DOI: 10.1016/j.tranon.2020.100995] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 11/08/2020] [Accepted: 12/07/2020] [Indexed: 02/07/2023] Open
Abstract
High expression of extracellular heat shock proteins (HSPs) indicates highly aggressive tumors. HSP profiling of extracellular vesicles (EVs) derived from various biological fluids and released by immune cells may open new perspectives for an identification of diagnostic, prognostic and predictive biomarkers of cancer. Identification of specific microRNAs targeting HSPs in EVs may be a promising strategy for the discovery of novel biomarkers of cancer. Heat shock proteins (HSPs) are a large family of molecular chaperones aberrantly expressed in cancer. The expression of HSPs in tumor cells has been shown to be implicated in the regulation of apoptosis, immune responses, angiogenesis and metastasis. Given that extracellular vesicles (EVs) can serve as potential source for the discovery of clinically useful biomarkers and therapeutic targets, it is of particular interest to study proteomic profiling of HSPs in EVs derived from various biological fluids of cancer patients. Furthermore, a divergent expression of circulating microRNAs (miRNAs) in patient samples has opened new opportunities in exploiting miRNAs as diagnostic tools. Herein, we address the current literature on the expression of extracellular HSPs with particular interest in HSPs in EVs derived from various biological fluids of cancer patients and different types of immune cells as promising targets for identification of clinical biomarkers of cancer. We also discuss the emerging role of miRNAs in HSP regulation for the discovery of blood-based biomarkers of cancer. We outline the importance of understanding relationships between various HSP networks and co-chaperones and propose the model for identification of HSP signatures in cancer. Elucidating the role of HSPs in EVs from the proteomic and miRNAs perspectives may provide new opportunities for the discovery of novel biomarkers of cancer.
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Affiliation(s)
- Zarema Albakova
- Department of Biology, Lomonosov Moscow State University, 199192 Moscow, Russia.
| | | | - Pradeep Kumar Sacitharan
- The Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom; Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Rustam H Ziganshin
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia
| | - Dmitriy Y Ryazantsev
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia
| | - Alexander M Sapozhnikov
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia
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32
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Liang Y, Wang H, Yang J, Li X, Dai C, Shao P, Tian G, Wang B, Wang Y. A Deep Learning Framework to Predict Tumor Tissue-of-Origin Based on Copy Number Alteration. Front Bioeng Biotechnol 2020; 8:701. [PMID: 32850687 PMCID: PMC7419421 DOI: 10.3389/fbioe.2020.00701] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 06/04/2020] [Indexed: 12/18/2022] Open
Abstract
Cancer of unknown primary site (CUPS) is a type of metastatic tumor for which the sites of tumor origin cannot be determined. Precise diagnosis of the tissue origin for metastatic CUPS is crucial for developing treatment schemes to improve patient prognosis. Recently, there have been many studies using various cancer biomarkers to predict the tissue-of-origin (TOO) of CUPS. However, only a very few of them use copy number alteration (CNA) to trance TOO. In this paper, a two-step computational framework called CNA_origin is introduced to predict the tissue-of-origin of a tumor from its gene CNA levels. CNA_origin set up an intellectual deep-learning network mainly composed of an autoencoder and a convolution neural network (CNN). Based on real datasets released from the public database, CNA_origin had an overall accuracy of 83.81% on 10-fold cross-validation and 79% on independent datasets for predicting tumor origin, which improved the accuracy by 7.75 and 9.72% compared with the method published in a previous paper. Our results suggested that the autoencoder model can extract key characteristics of CNA and that the CNN classifier model developed in this study can predict the origin of tumors robustly and effectively. CNA_origin was written in Python and can be downloaded from https://github.com/YingLianghnu/CNA_origin.
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Affiliation(s)
- Ying Liang
- College of Computer and Information Engineering, Jiangxi Agricultural University, Nanchang, China
| | - Haifeng Wang
- Department of Urology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | | | - Xiong Li
- School of Software, East China Jiaotong University, Nanchang, China
| | - Chan Dai
- Geneis (Beijing) Co. Ltd., Beijing, China
| | - Peng Shao
- College of Computer and Information Engineering, Jiangxi Agricultural University, Nanchang, China
| | - Geng Tian
- Geneis (Beijing) Co. Ltd., Beijing, China
| | - Bo Wang
- Geneis (Beijing) Co. Ltd., Beijing, China
| | - Yinglong Wang
- College of Computer and Information Engineering, Jiangxi Agricultural University, Nanchang, China
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33
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Ratti M, Lampis A, Ghidini M, Salati M, Mirchev MB, Valeri N, Hahne JC. MicroRNAs (miRNAs) and Long Non-Coding RNAs (lncRNAs) as New Tools for Cancer Therapy: First Steps from Bench to Bedside. Target Oncol 2020; 15:261-278. [PMID: 32451752 PMCID: PMC7283209 DOI: 10.1007/s11523-020-00717-x] [Citation(s) in RCA: 294] [Impact Index Per Article: 58.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Non-coding RNAs represent a significant proportion of the human genome. After having been considered as 'junk' for a long time, non-coding RNAs are now well established as playing important roles in maintaining cellular homeostasis and functions. Some non-coding RNAs show cell- and tissue-specific expression patterns and are specifically deregulated under pathological conditions (e.g. cancer). Therefore, non-coding RNAs have been extensively studied as potential biomarkers in the context of different diseases with a focus on microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) for several years. Since their discovery, miRNAs have attracted more attention than lncRNAs in research studies; however, both families of non-coding RNAs have been established to play an important role in gene expression control, either as transcriptional or post-transcriptional regulators. Both miRNAs and lncRNAs can regulate key genes involved in the development of cancer, thus influencing tumour growth, invasion, and metastasis by increasing the activation of oncogenic pathways and limiting the expression of tumour suppressors. Furthermore, miRNAs and lncRNAs are also emerging as important mediators in drug-sensitivity and drug-resistance mechanisms. In the light of these premises, a number of pre-clinical and early clinical studies are exploring the potential of non-coding RNAs as new therapeutics. The aim of this review is to summarise the latest knowledge of the use of miRNAs and lncRNAs as therapeutic tools for cancer treatment.
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Affiliation(s)
- Margherita Ratti
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
- Medical Department, Division of Oncology, ASST di Cremona, Ospedale di Cremona, Cremona, Italy
| | - Andrea Lampis
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Michele Ghidini
- Division of Medical Oncology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Massimiliano Salati
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Milko B Mirchev
- Clinic of Gastroenterology, Medical University, Varna, Bulgaria
| | - Nicola Valeri
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
- Department of Medicine, The Royal Marsden NHS Foundation Trust, London, UK
| | - Jens C Hahne
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.
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Rassy E, Pavlidis N. Progress in refining the clinical management of cancer of unknown primary in the molecular era. Nat Rev Clin Oncol 2020; 17:541-554. [PMID: 32350398 DOI: 10.1038/s41571-020-0359-1] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/19/2020] [Indexed: 12/14/2022]
Abstract
Cancer of unknown primary (CUP) is an enigmatic disease entity encompassing heterogeneous malignancies without a detectable primary tumour, despite a thorough diagnostic workup. A minority of patients with CUP (15-20%) can be assigned a putative primary tissue of origin according to clinical and histopathological findings and typically have a more favourable prognosis with the use of corresponding tumour type-specific therapies. Thus, the majority of patients with CUP have disease that cannot be assigned to a culprit primary tumour, are treated with empirical chemotherapy and have a poor prognosis. In the molecular era, the use of (epi)genomic or transcriptomic CUP classifiers and DNA or RNA sequencing offers two, sometimes overlapping, therapeutic strategies: tumour type-specific therapy and biomarker-guided therapy. Published data reveal that the accuracy of site-of-origin predictions made using CUP classifiers ranges between 54% and 98% when compared with the assignment made according to the recommended clinicopathological criteria. These advances have led to promising results in non-randomized prospective studies evaluating the efficacy of tumour type-specific therapy; however, the favourable outcomes were not confirmed in randomized controlled studies comparing this approach with standard empirical chemotherapy. Currently, the evidence supporting the use of biomarker-guided therapies is limited to case reports and small case series. In this Review, we discuss the clinical management of CUP in the era of precision medicine. We focus on the advances in understanding the biology of CUP, the implications for the diagnosis and classification of CUP according to the tissue of origin and the shift away from empirical therapy towards tailored therapy.
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Affiliation(s)
- Elie Rassy
- Department of Medical Oncology, Institut Gustave Roussy, Villejuif, Paris, France.
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35
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Dika E, Riefolo M, Porcellini E, Broseghini E, Ribero S, Senetta R, Osella-Abate S, Scarfì F, Lambertini M, Veronesi G, Patrizi A, Fanti PA, Ferracin M. Defining the Prognostic Role of MicroRNAs in Cutaneous Melanoma. J Invest Dermatol 2020; 140:2260-2267. [PMID: 32275975 DOI: 10.1016/j.jid.2020.03.949] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 02/20/2020] [Accepted: 03/09/2020] [Indexed: 12/12/2022]
Abstract
Breslow thickness (BT) is the most important histopathologic factor for primary melanoma staging. BT determines the margins for wide local excision whether sentinel lymph node biopsy should be performed and subsequent melanoma staging, and patient management. The correct determination of a 0.8-mm cutoff in melanoma is important for pathologists because discrepancies leading to a change in stage can have significant clinical implications, including incorrect and/or inappropriate prognostic information, investigation, management, and follow-up. Difficulties in BT determination are mostly represented by the presence of regression or melanoma associated with a pre-existing nevus. This study aimed at investigating a molecular parameter, namely microRNA (miRNA) expression, in reference to BT assessment. Melanoma cell proliferation is influenced by miRNA dysregulation. Indeed, some miRNAs sustain and induce proliferative signals or repress growth-suppressive pathways, thereby promoting melanoma carcinogenesis. To identify the miRNAs correlating with BT, we analyzed our global miRNA expression data of 20 thin melanomas and identified two potential candidates, miR-21-5p and miR-146a-5p. We assessed the expression of these two specific miRNAs in 90 archive formalin-fixed and paraffin-embedded samples of superficially spreading melanomas (SSMs) and 25 nodular melanomas from two independent cohorts and correlated the individual and combined miRNA expression with BT and other tumor characteristics. The individually normalized expression of miR-21-5p and miR-146a-5p showed a highly significant and linear correlation with BT in SSM, and their combined expression value was more strongly correlated (Pearson's r = 0.799, 95% CI = 0.71-0.86) than their individual expressions. This correlation was not significant in nodular melanoma. In SSM, we observed that the combined miRNA expression above or below 1.5 was significantly associated with overall survival and successfully identified all patients with relapsing SSM. We concluded that the combined assessment of miR-21-5p and miR-146a-5p expression in superficially spreading melanoma, in association with BT measurement, could aid pathologists in SSM staging.
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Affiliation(s)
- Emi Dika
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy; Dermatology Unit, Sant'Orsola-Malpighi Hospital, Bologna, Italy.
| | - Mattia Riefolo
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Elisa Porcellini
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Elisabetta Broseghini
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Simone Ribero
- Department of Medical Sciences, Dermatologic Clinic, University of Turin, Turin, Italy
| | - Rebecca Senetta
- Department of Medical Sciences, Dermatologic Clinic, University of Turin, Turin, Italy
| | - Simona Osella-Abate
- Department of Medical Sciences, Dermatologic Clinic, University of Turin, Turin, Italy
| | - Federica Scarfì
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy; Dermatology Unit, Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Martina Lambertini
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy; Dermatology Unit, Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Giulia Veronesi
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy; Dermatology Unit, Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Annalisa Patrizi
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy; Dermatology Unit, Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Pier Alessandro Fanti
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy; Dermatology Unit, Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Manuela Ferracin
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
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Exploring the biological hallmarks of cancer of unknown primary: where do we stand today? Br J Cancer 2020; 122:1124-1132. [PMID: 32042068 PMCID: PMC7156745 DOI: 10.1038/s41416-019-0723-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 12/18/2019] [Indexed: 01/07/2023] Open
Abstract
Cancer of unknown primary (CUP) affects a small percentage of the general population. Nonetheless, a substantial number of these patients have a poor prognosis and consequently succumb to their illness within a year of diagnosis. The natural history of CUP is characterised by early metastasis from the unknown primary site, aggressive course and resistance to conventional chemotherapy. Unfortunately, the processes by which this orphan disease originates and progresses have not been fully elucidated and its biology remain unclear. Despite the conceptual progress in genetic and molecular profiling made over the past decade, recognition of the genetic and molecular abnormalities involved in CUP, as well as the identification of the tissue of origin remain unresolved issues. This review will outline the biology of CUP by exploring the hallmarks of cancer in order to rationalise the complexities of this enigmatic syndrome. This approach will help the reader to understand where research efforts currently stand and the pitfalls of this quest.
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Jiao W, Atwal G, Polak P, Karlic R, Cuppen E, Danyi A, de Ridder J, van Herpen C, Lolkema MP, Steeghs N, Getz G, Morris QD, Stein LD. A deep learning system accurately classifies primary and metastatic cancers using passenger mutation patterns. Nat Commun 2020; 11:728. [PMID: 32024849 PMCID: PMC7002586 DOI: 10.1038/s41467-019-13825-8] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 11/26/2019] [Indexed: 12/14/2022] Open
Abstract
In cancer, the primary tumour's organ of origin and histopathology are the strongest determinants of its clinical behaviour, but in 3% of cases a patient presents with a metastatic tumour and no obvious primary. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we train a deep learning classifier to predict cancer type based on patterns of somatic passenger mutations detected in whole genome sequencing (WGS) of 2606 tumours representing 24 common cancer types produced by the PCAWG Consortium. Our classifier achieves an accuracy of 91% on held-out tumor samples and 88% and 83% respectively on independent primary and metastatic samples, roughly double the accuracy of trained pathologists when presented with a metastatic tumour without knowledge of the primary. Surprisingly, adding information on driver mutations reduced accuracy. Our results have clinical applicability, underscore how patterns of somatic passenger mutations encode the state of the cell of origin, and can inform future strategies to detect the source of circulating tumour DNA.
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Affiliation(s)
- Wei Jiao
- Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Gurnit Atwal
- Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
- Vector Institute, Toronto, ON, Canada
| | - Paz Polak
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 15 1425 Madison Ave., New York, NY, USA
| | - Rosa Karlic
- Bioinformatics Group, Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, Horvatovac 102a, Zagreb, Croatia
| | - Edwin Cuppen
- Hartwig Medical Foundation, Science Park 408, Amsterdam, The Netherlands
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Alexandra Danyi
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Jeroen de Ridder
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Martijn P Lolkema
- Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands
| | - Neeltje Steeghs
- Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Gad Getz
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Quaid D Morris
- Vector Institute, Toronto, ON, Canada
- University of Toronto, Toronto, ON, Canada
| | - Lincoln D Stein
- Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
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38
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Penson A, Camacho N, Zheng Y, Varghese AM, Al-Ahmadie H, Razavi P, Chandarlapaty S, Vallejo CE, Vakiani E, Gilewski T, Rosenberg JE, Shady M, Tsui DWY, Reales DN, Abeshouse A, Syed A, Zehir A, Schultz N, Ladanyi M, Solit DB, Klimstra DS, Hyman DM, Taylor BS, Berger MF. Development of Genome-Derived Tumor Type Prediction to Inform Clinical Cancer Care. JAMA Oncol 2020; 6:84-91. [PMID: 31725847 PMCID: PMC6865333 DOI: 10.1001/jamaoncol.2019.3985] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 06/25/2019] [Indexed: 12/12/2022]
Abstract
IMPORTANCE Diagnosing the site of origin for cancer is a pillar of disease classification that has directed clinical care for more than a century. Even in an era of precision oncologic practice, in which treatment is increasingly informed by the presence or absence of mutant genes responsible for cancer growth and progression, tumor origin remains a critical factor in tumor biologic characteristics and therapeutic sensitivity. OBJECTIVE To evaluate whether data derived from routine clinical DNA sequencing of tumors could complement conventional approaches to enable improved diagnostic accuracy. DESIGN, SETTING, AND PARTICIPANTS A machine learning approach was developed to predict tumor type from targeted panel DNA sequence data obtained at the point of care, incorporating both discrete molecular alterations and inferred features such as mutational signatures. This algorithm was trained on 7791 tumors representing 22 cancer types selected from a prospectively sequenced cohort of patients with advanced cancer. RESULTS The correct tumor type was predicted for 5748 of the 7791 patients (73.8%) in the training set as well as 8623 of 11 644 patients (74.1%) in an independent cohort. Predictions were assigned probabilities that reflected empirical accuracy, with 3388 cases (43.5%) representing high-confidence predictions (>95% probability). Informative molecular features and feature categories varied widely by tumor type. Genomic analysis of plasma cell-free DNA yielded accurate predictions in 45 of 60 cases (75.0%), suggesting that this approach may be applied in diverse clinical settings including as an adjunct to cancer screening. Likely tissues of origin were predicted from targeted tumor sequencing in 95 of 141 patients (67.4%) with cancers of unknown primary site. Applying this method prospectively to patients under active care enabled genome-directed reassessment of diagnosis in 2 patients initially presumed to have metastatic breast cancer, leading to the selection of more appropriate treatments, which elicited clinical responses. CONCLUSIONS AND RELEVANCE These results suggest that the application of artificial intelligence to predict tissue of origin in oncologic practice can act as a useful complement to conventional histologic review to provide integrated pathologic diagnoses, often with important therapeutic implications.
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Affiliation(s)
- Alexander Penson
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Niedzica Camacho
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Youyun Zheng
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Anna M. Varghese
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Hikmat Al-Ahmadie
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Pedram Razavi
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sarat Chandarlapaty
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Christina E. Vallejo
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Efsevia Vakiani
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Teresa Gilewski
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | | | - Maha Shady
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Dana W. Y. Tsui
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Dalicia N. Reales
- Clinical Research Administration, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Adam Abeshouse
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Aijazuddin Syed
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ahmet Zehir
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nikolaus Schultz
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Marc Ladanyi
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - David B. Solit
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- Weill Cornell Medical College, Department of Medicine, Cornell University, New York, New York
| | - David S. Klimstra
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
- Weill Cornell Medical College, Department of Pathology and Laboratory Medicine, Cornell University, New York, New York
| | - David M. Hyman
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- Weill Cornell Medical College, Department of Medicine, Cornell University, New York, New York
| | - Barry S. Taylor
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Michael F. Berger
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
- Weill Cornell Medical College, Department of Pathology and Laboratory Medicine, Cornell University, New York, New York
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Li D, Zhong J, Zhang G, Lin L, Liu Z. Oncogenic Role and Prognostic Value of MicroRNA-937-3p in Patients with Breast Cancer. Onco Targets Ther 2019; 12:11045-11056. [PMID: 31853188 PMCID: PMC6916697 DOI: 10.2147/ott.s229510] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Accepted: 11/16/2019] [Indexed: 12/19/2022] Open
Abstract
Purpose Breast cancer is the most common female tumor in the world. MicroRNA has been reported to play an important role in the progression of breast cancer. The purpose of this study was to explore the role of miR-937-3p in breast cancer. Patients and methods Expression of miR-937-3p in breast cancer tissues and serums was detected from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO) and patients' samples. Kaplan-Meier plotter identified the association between miR-937-3p and prognosis. Results The analysis of TCGA, GEO and qRT-PCR suggested that the level of miR-937-3p was increased in breast cancer tissues and serum compared with adjacent normal breast tissues and healthy persons, respectively. The decreased expression of miR-937-3p inhibited breast cancer proliferation, migration and invasion. CCRL2 was the target of miR-937-3p. In contrast to miR-937-3p, the level of CCRL2 was decreased in breast cancer tissues. Luciferase reporter assay revealed that miR-937-3p directly bound to the 3'-UTR of CCRL2. Double knockdown of CCRL2 and miR-937-3p promoted breast cancer cell proliferation, migration and invasion, suggesting that miR-937-3p promoted breast cancer cell proliferation, migration and invasion by targeting CCRL2. The Kaplan-Meier survival analysis suggested that breast cancer patients with high level of miR-937-3p or low level of CCRL2 had a reduced overall survival (OS). Conclusion miR-937-3p plays an important role in the diagnosis and prognosis of breast cancer. Inhibition of miR-937-3p expression may be a novel targeted therapy for breast cancer.
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Affiliation(s)
- Deyu Li
- Department of Medical Oncology, Provincial Clinical College, Fujian Medical University, Fuzhou 350001, People's Republic of China.,Department of Medical Oncology, Fujian Provincial Hospital, Fuzhou 350001, People's Republic of China
| | - Jiangming Zhong
- Department of Medical Oncology, Provincial Clinical College, Fujian Medical University, Fuzhou 350001, People's Republic of China.,Department of Medical Oncology, Fujian Provincial Hospital, Fuzhou 350001, People's Republic of China
| | - Guifeng Zhang
- Department of Medical Oncology, Provincial Clinical College, Fujian Medical University, Fuzhou 350001, People's Republic of China.,Department of Medical Oncology, Fujian Provincial Hospital, Fuzhou 350001, People's Republic of China
| | - Li Lin
- Department of Medical Oncology, Provincial Clinical College, Fujian Medical University, Fuzhou 350001, People's Republic of China.,Department of Medical Oncology, Fujian Provincial Hospital, Fuzhou 350001, People's Republic of China
| | - Zhenhua Liu
- Department of Medical Oncology, Provincial Clinical College, Fujian Medical University, Fuzhou 350001, People's Republic of China.,Department of Medical Oncology, Fujian Provincial Hospital, Fuzhou 350001, People's Republic of China
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40
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Min L, Zhu S, Chen L, Liu X, Wei R, Zhao L, Yang Y, Zhang Z, Kong G, Li P, Zhang S. Evaluation of circulating small extracellular vesicles derived miRNAs as biomarkers of early colon cancer: a comparison with plasma total miRNAs. J Extracell Vesicles 2019; 8:1643670. [PMID: 31448068 PMCID: PMC6691764 DOI: 10.1080/20013078.2019.1643670] [Citation(s) in RCA: 171] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 07/10/2019] [Accepted: 07/11/2019] [Indexed: 02/06/2023] Open
Abstract
Early diagnosis of colon cancer (CC) is clinically important, as it can significantly improve patients’ survival rate and quality of life. Although the potential role for small extracellular vesicles (sEVs) in early detection of many diseases has been repeatedly mentioned, systematic screening of plasma sEVs derived early CC specific biomarkers has not yet been reported. In this work, plasma sEVs enriched fractions were derived from 15 early-stage (TisN0M0) CC patients and 10 normal controls (NC). RNA sequencing identified a total number of 95 sEVs enriched fraction derived miRNAs with differential expression between CC and NC, most of which (60/95) was in well accordance with tissue results in the Cancer Genome Atlas (TCGA) dataset. Among those miRNAs, we selected let-7b-3p, miR-139-3p, miR-145-3p, and miR-150-3p for further validation in an independent cohort consisting of 134 participants (58 CC and 76 NC). In the validation cohort, the AUC of 4 individual miRNAs ranged from 0.680 to 0.792. A logistic model combining two miRNAs (i.e. let-7b-3p and miR-145-3p) achieved an AUC of 0.901. Adding the 3rd miRNA into this model can further increase the AUC to 0.927. Side by side comparison revealed that sEVs miRNA profile outperformed cell-free plasma miRNA in the diagnosis of early CC. In conclusion, we suggested that circulating sEVs enriched fractions have a distinct miRNA profile in CC patients, and sEVs derived miRNA could be used as a promising biomarker to detect CC at an early stage.
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Affiliation(s)
- Li Min
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
| | - Shengtao Zhu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
| | - Lei Chen
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
| | - Xiang Liu
- Department of R&D, Echo Biotech Co., Ltd, Beijing, P. R. China
| | - Rui Wei
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
| | - Libo Zhao
- Department of R&D, Echo Biotech Co., Ltd, Beijing, P. R. China
| | - Yuqing Yang
- Department of R&D, Echo Biotech Co., Ltd, Beijing, P. R. China
| | - Zheng Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
| | - Guanyi Kong
- Department of R&D, Echo Biotech Co., Ltd, Beijing, P. R. China
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
| | - Shutian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
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41
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Wong QWL, Sun MA, Lau SW, Parsania C, Zhou S, Zhong S, Ge W. Identification and characterization of a specific 13-miRNA expression signature during follicle activation in the zebrafish ovary. Biol Reprod 2019; 98:42-53. [PMID: 29228146 DOI: 10.1093/biolre/iox160] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2017] [Accepted: 11/29/2017] [Indexed: 12/17/2022] Open
Abstract
Ovarian folliculogenesis is always of great interest in reproductive biology. However, the molecular mechanisms that control follicle development, particularly the early phase of follicle activation or recruitment, still remain poorly understood. In an attempt to decipher the gene networks and signaling pathways involved in such transition, we conducted a transcriptomic analysis (RNA-seq) on zebrafish primary growth (PG, stage I; inactive) and previtellogenic (PV, stage II; activated) follicles. A total of 118 unique microRNAs (miRNAs) (11 downregulated and 83 upregulated during PG/PV transition) and 56711 unique messenger RNAs (mRNAs) (1839 downregulated and 7243 upregulated during PG/PV transition) were identified. Real-time quantitative polymerase chain reaction analysis confirmed differential expression of 46 miRNAs from 66 candidates (66.67%). Among which, we chose to focus on 13 miRNAs (let-7a, -7b, -7c-5p, -7d-5p, -7h, -7i; miR-21, -23a-3p, -27c-3p, -107a-3p, -125b-5p, -145-3p, and -202-5p) that exhibited significant differential expression between PG and PV follicles (P ≤ 0.045*). With this 13-miRNA expression signature alone, PG follicles can be well differentiated from PV follicles by hierarchical clustering, suggesting their functional relevance during PG-to-PV transition. By overlaying predicted target genes and the differentially expressed mRNAs revealed by the RNA-seq analysis, especially those showing reciprocal miRNA-mRNA expression patterns, we shortlisted a panel of miRNA downstream targets for luciferase reporter validation. The reporter assay confirmed the interactions of let-7i:: atg4a (P = 0.01*), miR-202-5p::c23h20orf24 (P = 0.0004***), and miR-144-5p::ybx1 (P = 0.003**), implicating these potential miRNA-mRNA gene pairs in follicle activation during folliculogenesis. Our transcriptomic data analyses suggest that miRNA-mediated post-transcriptional control may represent an important mechanism underlying follicle activation.
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Affiliation(s)
- Queenie Wing-Lei Wong
- Centre of Reproduction, Development and Aging (CRDA), Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Ming-An Sun
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
| | - Shuk-Wa Lau
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
| | - Chirag Parsania
- Genomics & Bioinformatics Core, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Shaolong Zhou
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
| | - Silin Zhong
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
| | - Wei Ge
- Centre of Reproduction, Development and Aging (CRDA), Faculty of Health Sciences, University of Macau, Taipa, Macau, China
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42
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Vymetalkova V, Vodicka P, Vodenkova S, Alonso S, Schneider-Stock R. DNA methylation and chromatin modifiers in colorectal cancer. Mol Aspects Med 2019; 69:73-92. [PMID: 31028771 DOI: 10.1016/j.mam.2019.04.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 04/11/2019] [Accepted: 04/15/2019] [Indexed: 12/15/2022]
Abstract
Colorectal carcinogenesis is a multistep process involving the accumulation of genetic alterations over time that ultimately leads to disease progression and metastasis. Binding of transcription factors to gene promoter regions alone cannot explain the complex regulation pattern of gene expression during this process. It is the chromatin structure that allows for a high grade of regulatory flexibility for gene expression. Posttranslational modifications on histone proteins such as acetylation, methylation, or phosphorylation determine the accessibility of transcription factors to DNA. DNA methylation, a chemical modification of DNA that modulates chromatin structure and gene transcription acts in concert with these chromatin conformation alterations. Another epigenetic mechanism regulating gene expression is represented by small non-coding RNAs. Only very recently epigenetic alterations have been included in molecular subtype classification of colorectal cancer (CRC). In this chapter, we will provide examples of the different epigenetic players, focus on their role for epithelial-mesenchymal transition and metastatic processes and discuss their prognostic value in CRC.
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Affiliation(s)
- Veronika Vymetalkova
- Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Albertov 4, 128 00, Prague, Czech Republic; Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, 323 00, Pilsen, Czech Republic
| | - Pavel Vodicka
- Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Albertov 4, 128 00, Prague, Czech Republic; Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, 323 00, Pilsen, Czech Republic
| | - Sona Vodenkova
- Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic; Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Albertov 4, 128 00, Prague, Czech Republic
| | - Sergio Alonso
- Program of Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute, (IGTP-PMPPC), Campus Can Ruti, 08916, Badalona, Barcelona, Spain
| | - Regine Schneider-Stock
- Experimental Tumorpathology, Institute of Pathology, University Hospital of Friedrich-Alexander-University Erlangen-Nürnberg, Universitätsstrasse 22, 91054, Erlangen, Germany.
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43
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Moya L, Meijer J, Schubert S, Matin F, Batra J. Assessment of miR-98-5p, miR-152-3p, miR-326 and miR-4289 Expression as Biomarker for Prostate Cancer Diagnosis. Int J Mol Sci 2019; 20:E1154. [PMID: 30845775 PMCID: PMC6429489 DOI: 10.3390/ijms20051154] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 02/26/2019] [Indexed: 12/15/2022] Open
Abstract
Prostate cancer (PCa) is one of the most commonly diagnosed cancers worldwide, accounting for almost 1 in 5 new cancer diagnoses in the US alone. The current non-invasive biomarker prostate specific antigen (PSA) has lately been presented with many limitations, such as low specificity and often associated with over-diagnosis. The dysregulation of miRNAs in cancer has been widely reported and it has often been shown to be specific, sensitive and stable, suggesting miRNAs could be a potential specific biomarker for the disease. Previously, we identified four miRNAs that are significantly upregulated in plasma from PCa patients when compared to healthy controls: miR-98-5p, miR-152-3p, miR-326 and miR-4289. This panel showed high specificity and sensitivity in detecting PCa (area under the curve (AUC) = 0.88). To investigate the specificity of these miRNAs as biomarkers for PCa, we undertook an in depth analysis on these miRNAs in cancer from the existing literature and data. Additionally, we explored their prognostic value found in the literature when available. Most studies showed these miRNAs are downregulated in cancer and this is often associated with cancer progression and poorer overall survival rate. These results suggest our four miRNA signatures could potentially become a specific PCa diagnostic tool of which prognostic potential should also be explored.
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Affiliation(s)
- Leire Moya
- Australian Prostate Cancer Research Centre-Queensland, Translational Research Institute, 37 Kent St, Brisbane, Queensland 4102, Australia.
- Cancer Program, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Brisbane, Queensland 4059, Australia.
| | - Jonelle Meijer
- Australian Prostate Cancer Research Centre-Queensland, Translational Research Institute, 37 Kent St, Brisbane, Queensland 4102, Australia.
- Cancer Program, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Brisbane, Queensland 4059, Australia.
| | - Sarah Schubert
- Australian Prostate Cancer Research Centre-Queensland, Translational Research Institute, 37 Kent St, Brisbane, Queensland 4102, Australia.
- Cancer Program, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Brisbane, Queensland 4059, Australia.
| | - Farhana Matin
- Australian Prostate Cancer Research Centre-Queensland, Translational Research Institute, 37 Kent St, Brisbane, Queensland 4102, Australia.
- Cancer Program, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Brisbane, Queensland 4059, Australia.
| | - Jyotsna Batra
- Australian Prostate Cancer Research Centre-Queensland, Translational Research Institute, 37 Kent St, Brisbane, Queensland 4102, Australia.
- Cancer Program, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Brisbane, Queensland 4059, Australia.
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44
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Toraih EA, Abdallah HY, Rashed EA, El-Wazir A, Tantawy MA, Fawzy MS. Comprehensive data analysis for development of custom qRT-PCR miRNA assay for glioblastoma: a prevalidation study. Epigenomics 2019; 11:367-380. [DOI: 10.2217/epi-2018-0134] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Aim: Glioblastoma (GB) is one notable example of miRNA-modulated neoplasms. Given its unique expression signature, proper miRNA profiling can help discriminate between GB and other types of brain tumors. The current work aimed to develop a more GB-specific and applicable custom designed quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) miRNA assay. Materials & methods: A comprehensive data analysis of bioinformatics databases, previous literature and commercially available pre-designed miRNA PCR arrays within the market. Results: A highly enriched panel of 84 deregulated and GB-specific miRNAs has been developed. Conclusion: After validation of this newly developed array, it can not only save the researcher's time and effort, but can also have a potential diagnostic and/or prognostic role in GB, paving the road toward personalized medicine.
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Affiliation(s)
- Eman A Toraih
- Department of Histology & Cell Biology, Genetics Unit, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
- Center of Excellence of Molecular & Cellular Medicine, Suez Canal University, Ismailia, Egypt
| | - Hoda Y Abdallah
- Department of Histology & Cell Biology, Genetics Unit, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
- Center of Excellence of Molecular & Cellular Medicine, Suez Canal University, Ismailia, Egypt
| | - Essam A Rashed
- Department of Mathematics, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
- Department of Computer Science, Faculty of Informatics and Computer Science, The British University in Egypt, Cairo 11837, Egypt
| | - Aya El-Wazir
- Department of Histology & Cell Biology, Genetics Unit, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
- Center of Excellence of Molecular & Cellular Medicine, Suez Canal University, Ismailia, Egypt
| | - Mohamed A Tantawy
- Hormones Department, Medical Research Division, National Research Center, Cairo, Egypt
| | - Manal S Fawzy
- Department of Medical Biochemistry & Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
- Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia
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45
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Laprovitera N, Grzes M, Porcellini E, Ferracin M. Cancer Site-Specific Multiple microRNA Quantification by Droplet Digital PCR. Front Oncol 2018; 8:447. [PMID: 30374423 PMCID: PMC6196277 DOI: 10.3389/fonc.2018.00447] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 09/24/2018] [Indexed: 01/04/2023] Open
Abstract
Archival formalin-fixed paraffin-embedded (FFPE) tissues represent an extraordinary source of smallRNAs, including microRNAs (miRNAs). Contrary to other RNA molecules, miRNAs are stable, nuclease-resistant and quantifiable even in low quality samples. The accurate assessment of miRNA levels in archival samples is of great interest for many pathological conditions, including cancer. In human tumors, microRNA expression is type-specific and can be used as diagnostic, prognostic or response-to-treatment biomarker. In this study, we provide a method for multiple miRNA quantification in 96-well plates, using EvaGreen-based droplet digital PCR technology and miRCURY LNA miRNA assays. This approach allows the absolute quantification of a customizable panel of miRNAs at the same time and under identical experimental conditions, to be used for diagnostic or prognostic applications.
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Affiliation(s)
- Noemi Laprovitera
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Maria Grzes
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.,Department of Molecular Biology, Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Lesznowola, Poland
| | - Elisa Porcellini
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Manuela Ferracin
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
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46
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Binder C, Matthes KL, Korol D, Rohrmann S, Moch H. Cancer of unknown primary-Epidemiological trends and relevance of comprehensive genomic profiling. Cancer Med 2018; 7:4814-4824. [PMID: 30019510 PMCID: PMC6144156 DOI: 10.1002/cam4.1689] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 06/21/2018] [Indexed: 01/08/2023] Open
Abstract
Background Cancer of unknown primary (CUP) is a distinct clinicopathological entity with poor prognosis, frequently resistant to chemotherapy. Comprehensive genomic profiling (CGP) by next‐generation sequencing potentially identifies novel treatment options for CUP patients. The objective of this study was to determine incidence and survival trends and to discuss the value of CGP in CUP patients. Methods Age‐standardized incidence rates (ASR) per 100 000 were calculated for 2935 CUP patients from 1981 to 2014 using cancer registry data of the canton of Zurich, Switzerland. Kaplan–Meier survival curves were estimated for sex, age, and histological groups. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (HR). A literature review was conducted to assess the current use of CGP in CUP patients. Results ASR of CUP increased from 10.3 to 17.6 between 1981 and 1997 and decreased to 5.8/100 000 in 2014. Mean overall survival remained stable. Mortality was significantly lower for patients with squamous cell carcinoma (HR 0.48 [95% CI, 0.41‐0.57]) and neuroendocrine carcinoma (0.75 [0.63‐0.88]) and higher for unclassified neoplasms (1.25 [1.13‐1.66]) compared to adenocarcinomas. The literature review identified 10 studies using CGP of CUP tissue. Clinically relevant mutations were identified in up to 85% of CUP patients, of which 13%‐64% may benefit from currently available drugs. Conclusions CUP incidence decreased probably due to improved diagnostics, but mortality did not improve over the last 34 years. CGP testing may help to identify molecular signatures in CUP patients and enable targeted treatment.
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Affiliation(s)
- Carmen Binder
- Division of Chronic Disease Epidemiology, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland.,Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Katarina Luise Matthes
- Division of Chronic Disease Epidemiology, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland.,Cancer Registry Zurich and Zug, University Hospital Zurich, Zurich, Switzerland
| | - Dimitri Korol
- Cancer Registry Zurich and Zug, University Hospital Zurich, Zurich, Switzerland
| | - Sabine Rohrmann
- Division of Chronic Disease Epidemiology, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland.,Cancer Registry Zurich and Zug, University Hospital Zurich, Zurich, Switzerland
| | - Holger Moch
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
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47
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The Challenges and Opportunities in the Clinical Application of Noncoding RNAs: The Road Map for miRNAs and piRNAs in Cancer Diagnostics and Prognostics. Int J Genomics 2018; 2018:5848046. [PMID: 29854719 PMCID: PMC5952559 DOI: 10.1155/2018/5848046] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 03/13/2018] [Accepted: 03/25/2018] [Indexed: 12/11/2022] Open
Abstract
Discoveries on nonprotein-coding RNAs have induced a paradigm shift in our overall understanding of gene expression and regulation. We now understand that coding and noncoding RNA machinery work in concert to maintain overall homeostasis. Based on their length, noncoding RNAs are broadly classified into two groups—long (>200 nt) and small noncoding RNAs (<200 nt). These RNAs perform diverse functions—gene regulation, splicing, translation, and posttranscriptional modifications. MicroRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs) are two classes of small noncoding RNAs that are now classified as master regulators of gene expression. They have also demonstrated clinical significance as potential biomarkers and therapeutic targets for several diseases, including cancer. Despite these similarities, both these RNAs are generated through contrasting mechanisms, and one of the aims of this review is to cover the distance travelled since their discovery and compare and contrast the various facets of these RNAs. Although these RNAs show tremendous promise as biomarkers, translating the findings from bench to bedside is often met with roadblocks. The second aim of this review therefore is to highlight some of the challenges that hinder application of miRNA and piRNA as in guiding treatment decisions.
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48
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Inada K, Okoshi Y, Cho-Isoda Y, Ishiguro S, Suzuki H, Oki A, Tamaki Y, Shimazui T, Saito H, Hori M, Iijima T, Kojima H. Endogenous reference RNAs for microRNA quantitation in formalin-fixed, paraffin-embedded lymph node tissue. Sci Rep 2018; 8:5918. [PMID: 29651113 PMCID: PMC5897550 DOI: 10.1038/s41598-018-24338-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 03/28/2018] [Indexed: 12/18/2022] Open
Abstract
Lymph node metastasis is one of the most important factors for tumor dissemination. Quantifying microRNA (miRNA) expression using real-time PCR in formalin-fixed, paraffin-embedded (FFPE) lymph node can provide valuable information regarding the biological research for cancer metastasis. However, a universal endogenous reference gene has not been identified in FFPE lymph node. This study aimed to identify suitable endogenous reference genes for miRNA expression analysis in FFPE lymph node. FFPE lymph nodes were obtained from 41 metastatic cancer and from 16 non-cancerous tissues. We selected 10 miRNAs as endogenous reference gene candidates using the global mean method. The stability of candidate genes was assessed by the following four statistical tools: BestKeeper, geNorm, NormFinder, and the comparative ΔCt method. miR-103a was the most stable gene among candidate genes. However, the use of a single miR-103a was not recommended because its stability value exceeded the reference value. Thus, we combined stable genes and investigated the stability and the effect of gene normalization. The combination of miR-24, miR-103a, and let-7a was identified as one of the most stable sets of endogenous reference genes for normalization in FFPE lymph node. This study may provide a basis for miRNA expression analysis in FFPE lymph node tissue.
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Affiliation(s)
- Katsushige Inada
- Department of Hematology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan.
| | - Yasushi Okoshi
- Department of Hematology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan.,Ibaraki Clinical Education and Training Center, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Yukiko Cho-Isoda
- Department of Medical Oncology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan
| | - Shingo Ishiguro
- Department of Medical Oncology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan
| | - Hisashi Suzuki
- Ibaraki Clinical Education and Training Center, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.,Department of Thoracic Surgery, Ibaraki Prefectural Central Hospital, Ibaraki, Japan
| | - Akinori Oki
- Ibaraki Clinical Education and Training Center, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.,Department of Obstetrics and Gynecology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan
| | - Yoshio Tamaki
- Ibaraki Clinical Education and Training Center, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.,Department of Radiation Oncology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan
| | - Toru Shimazui
- Ibaraki Clinical Education and Training Center, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.,Department of Urology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan
| | - Hitoaki Saito
- Department of Pathology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan
| | - Mitsuo Hori
- Department of Hematology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan
| | - Tatsuo Iijima
- Department of Pathology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan
| | - Hiroshi Kojima
- Ibaraki Clinical Education and Training Center, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.,Department of Medical Oncology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan
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49
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Schrijver WAME, van Diest PJ, Moelans CB. Unravelling site-specific breast cancer metastasis: a microRNA expression profiling study. Oncotarget 2018; 8:3111-3123. [PMID: 27902972 PMCID: PMC5356868 DOI: 10.18632/oncotarget.13623] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 10/21/2016] [Indexed: 01/07/2023] Open
Abstract
Distant metastasis is still the main cause of death from breast cancer. MicroRNAs (miRs) are important regulators of many physiological and pathological processes, including metastasis. Molecular breast cancer subtypes are known to show a site-specific pattern of metastases formation. In this study, we set out to determine the underlying molecular mechanisms of site-specific breast cancer metastasis by microRNA expression profiling. To identify a miR signature for metastatic breast carcinoma that could predict metastatic localization, we compared global miR expression in 23 primary breast cancer specimens with their corresponding multiple distant metastases to ovary (n=9), skin (n=12), lung (n=10), brain (n=4) and gastrointestinal tract (n=10) by miRCURY microRNA expression arrays. For validation, we performed quantitative real-time (qRT) PCR on the discovery cohort and on an independent validation cohort of 29 primary breast cancer specimens and their matched metastases. miR expression was highly patient specific and miR signatures in the primary tumor were largely retained in the metastases, with the exception of several differentially expressed, location specific miRs. Validation with qPCR demonstrated that hsa-miR-106b-5p was predictive for the development of lung metastases. In time, the second metastasis often showed a miR upregulation compared to the first metastasis. This study discovered a metastatic site-specific miR and found miR expression to be highly patient specific. This may lead to novel biomarkers predicting site of distant metastases, and to adjuvant, personalized targeted therapy strategies that could prevent such metastases from becoming clinically manifest.
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Affiliation(s)
| | - Paul J van Diest
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Cathy B Moelans
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
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50
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Rapado-González Ó, Majem B, Muinelo-Romay L, Álvarez-Castro A, Santamaría A, Gil-Moreno A, López-López R, Suárez-Cunqueiro MM. Human salivary microRNAs in Cancer. J Cancer 2018; 9:638-649. [PMID: 29556321 PMCID: PMC5858485 DOI: 10.7150/jca.21180] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 12/11/2017] [Indexed: 12/25/2022] Open
Abstract
Circulating microRNAs (miRNAs) have emerged as excellent candidates for cancer biomarkers. Several recent studies have highlighted the potential use of saliva for the identification of miRNAs as novel biomarkers, which represents a great opportunity to improve diagnosis and monitor general health and disease. This review summarises the mechanisms of miRNAs deregulation in cancer, the value of targeting them with a therapeutic intention and the evidence of the potential clinical use of miRNAs expressed in saliva for the detection of different cancer types. We also provide a comprehensive review of the different methods for normalising the levels of specific miRNAs present in saliva, as this is a critical step in their analysis, and the challenge to validate salivary miRNAs as a reality to manage cancer patients.
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Affiliation(s)
- Óscar Rapado-González
- Department of Surgery and Medical Surgical Specialties, Medicine and Dentistry School, University of Santiago de Compostela, Spain. Health Research Institute of Santiago (IDIS); Santiago de Compostela, Spain.,Liquid Biopsy Analysis Unit, Translational Medical Oncology, Health Research Institute of Santiago (IDIS), CIBERONC, Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), Santiago de Compostela, Spain
| | - Blanca Majem
- Cell Cycle and Cancer Lab, Biomedical Research Group in Gynecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Laura Muinelo-Romay
- Liquid Biopsy Analysis Unit, Translational Medical Oncology, Health Research Institute of Santiago (IDIS), CIBERONC, Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), Santiago de Compostela, Spain
| | - Ana Álvarez-Castro
- Medical Digestive Service, Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS); Santiago de Compostela, Spain
| | - Anna Santamaría
- Cell Cycle and Cancer Lab, Biomedical Research Group in Gynecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Antonio Gil-Moreno
- Cell Cycle and Cancer Lab, Biomedical Research Group in Gynecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.,Department of Gynecology Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Rafael López-López
- Liquid Biopsy Analysis Unit, Translational Medical Oncology, Health Research Institute of Santiago (IDIS), CIBERONC, Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), Santiago de Compostela, Spain
| | - María Mercedes Suárez-Cunqueiro
- Department of Surgery and Medical Surgical Specialties, Medicine and Dentistry School, University of Santiago de Compostela, Spain. Health Research Institute of Santiago (IDIS); Santiago de Compostela, Spain
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