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Di Costanzo G, Ascione R, Ponsiglione A, Tucci AG, Dell’Aversana S, Iasiello F, Cavaglià E. Artificial intelligence and radiomics in magnetic resonance imaging of rectal cancer: a review. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2023; 4:406-421. [PMID: 37455833 PMCID: PMC10344900 DOI: 10.37349/etat.2023.00142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 03/01/2023] [Indexed: 07/18/2023] Open
Abstract
Rectal cancer (RC) is one of the most common tumours worldwide in both males and females, with significant morbidity and mortality rates, and it accounts for approximately one-third of colorectal cancers (CRCs). Magnetic resonance imaging (MRI) has been demonstrated to be accurate in evaluating the tumour location and stage, mucin content, invasion depth, lymph node (LN) metastasis, extramural vascular invasion (EMVI), and involvement of the mesorectal fascia (MRF). However, these features alone remain insufficient to precisely guide treatment decisions. Therefore, new imaging biomarkers are necessary to define tumour characteristics for staging and restaging patients with RC. During the last decades, RC evaluation via MRI-based radiomics and artificial intelligence (AI) tools has been a research hotspot. The aim of this review was to summarise the achievement of MRI-based radiomics and AI for the evaluation of staging, response to therapy, genotyping, prediction of high-risk factors, and prognosis in the field of RC. Moreover, future challenges and limitations of these tools that need to be solved to favour the transition from academic research to the clinical setting will be discussed.
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Affiliation(s)
- Giuseppe Di Costanzo
- Department of Radiology, Santa Maria delle Grazie Hospital, ASL Napoli 2 Nord, 80078 Pozzuoli, Italy
| | - Raffaele Ascione
- Department of Radiology, Santa Maria delle Grazie Hospital, ASL Napoli 2 Nord, 80078 Pozzuoli, Italy
| | - Andrea Ponsiglione
- Department of Advanced Biomedical Sciences, University of Naples Federico II, 80131 Naples, Italy
| | - Anna Giacoma Tucci
- Department of Radiology, Santa Maria delle Grazie Hospital, ASL Napoli 2 Nord, 80078 Pozzuoli, Italy
| | - Serena Dell’Aversana
- Department of Radiology, Santa Maria delle Grazie Hospital, ASL Napoli 2 Nord, 80078 Pozzuoli, Italy
| | - Francesca Iasiello
- Department of Radiology, Santa Maria delle Grazie Hospital, ASL Napoli 2 Nord, 80078 Pozzuoli, Italy
| | - Enrico Cavaglià
- Department of Radiology, Santa Maria delle Grazie Hospital, ASL Napoli 2 Nord, 80078 Pozzuoli, Italy
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Dias Carvalho P, Martins F, Mendonça S, Ribeiro A, Machado AL, Carvalho J, Oliveira MJ, Velho S. Mutant KRAS modulates colorectal cancer cells invasive response to fibroblast‐secreted factors through the HGF/C‐MET axis. Int J Cancer 2022; 151:1810-1823. [DOI: 10.1002/ijc.34225] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 07/07/2022] [Accepted: 07/19/2022] [Indexed: 11/06/2022]
Affiliation(s)
- Patrícia Dias Carvalho
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
- ICBAS ‐ Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto Porto Portugal
| | - Flávia Martins
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
- Department of Pathology FMUP – Faculty of Medicine of the University of Porto Porto Portugal
| | - Susana Mendonça
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
- Department of Pathology FMUP – Faculty of Medicine of the University of Porto Porto Portugal
| | - Andreia Ribeiro
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
| | - Ana Luísa Machado
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
- Department of Pathology FMUP – Faculty of Medicine of the University of Porto Porto Portugal
- Ciências Químicas e das Biomoléculas, Centro de Investigação em Saúde e Ambiente, Escola Superior de Saúde do Porto, Instituto Politécnico do Porto Porto Portugal
| | - Joana Carvalho
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
| | - Maria José Oliveira
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- INEB – Institute of Biomedical Engineering, University of Porto Porto Portugal
| | - Sérgia Velho
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
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Stanzione A, Verde F, Romeo V, Boccadifuoco F, Mainenti PP, Maurea S. Radiomics and machine learning applications in rectal cancer: Current update and future perspectives. World J Gastroenterol 2021; 27:5306-5321. [PMID: 34539134 PMCID: PMC8409167 DOI: 10.3748/wjg.v27.i32.5306] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/13/2021] [Accepted: 07/22/2021] [Indexed: 02/06/2023] Open
Abstract
The high incidence of rectal cancer in both sexes makes it one of the most common tumors, with significant morbidity and mortality rates. To define the best treatment option and optimize patient outcome, several rectal cancer biological variables must be evaluated. Currently, medical imaging plays a crucial role in the characterization of this disease, and it often requires a multimodal approach. Magnetic resonance imaging is the first-choice imaging modality for local staging and restaging and can be used to detect high-risk prognostic factors. Computed tomography is widely adopted for the detection of distant metastases. However, conventional imaging has recognized limitations, and many rectal cancer characteristics remain assessable only after surgery and histopathology evaluation. There is a growing interest in artificial intelligence applications in medicine, and imaging is by no means an exception. The introduction of radiomics, which allows the extraction of quantitative features that reflect tumor heterogeneity, allows the mining of data in medical images and paved the way for the identification of potential new imaging biomarkers. To manage such a huge amount of data, the use of machine learning algorithms has been proposed. Indeed, without prior explicit programming, they can be employed to build prediction models to support clinical decision making. In this review, current applications and future perspectives of artificial intelligence in medical imaging of rectal cancer are presented, with an imaging modality-based approach and a keen eye on unsolved issues. The results are promising, but the road ahead for translation in clinical practice is rather long.
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Affiliation(s)
- Arnaldo Stanzione
- Department of Advanced Biomedical Sciences, University of Naples "Federico II", Naples 80131, Italy
| | - Francesco Verde
- Department of Advanced Biomedical Sciences, University of Naples "Federico II", Naples 80131, Italy
| | - Valeria Romeo
- Department of Advanced Biomedical Sciences, University of Naples "Federico II", Naples 80131, Italy
| | - Francesca Boccadifuoco
- Department of Advanced Biomedical Sciences, University of Naples "Federico II", Naples 80131, Italy
| | - Pier Paolo Mainenti
- Institute of Biostructures and Bioimaging, National Council of Research, Napoli 80131, Italy
| | - Simone Maurea
- Department of Advanced Biomedical Sciences, University of Naples "Federico II", Naples 80131, Italy
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Tabibzadeh A, Tameshkel FS, Moradi Y, Soltani S, Moradi-Lakeh M, Ashrafi GH, Motamed N, Zamani F, Motevalian SA, Panahi M, Esghaei M, Ajdarkosh H, Mousavi-Jarrahi A, Niya MHK. Signal transduction pathway mutations in gastrointestinal (GI) cancers: a systematic review and meta-analysis. Sci Rep 2020; 10:18713. [PMID: 33127962 PMCID: PMC7599243 DOI: 10.1038/s41598-020-73770-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 09/02/2020] [Indexed: 02/07/2023] Open
Abstract
The present study was conducted to evaluate the prevalence of the signaling pathways mutation rate in the Gastrointestinal (GI) tract cancers in a systematic review and meta-analysis study. The study was performed based on the PRISMA criteria. Random models by confidence interval (CI: 95%) were used to calculate the pooled estimate of prevalence via Metaprop command. The pooled prevalence indices of signal transduction pathway mutations in gastric cancer, liver cancer, colorectal cancer, and pancreatic cancer were 5% (95% CI: 3-8%), 12% (95% CI: 8-18%), 17% (95% CI: 14-20%), and 20% (95% CI: 5-41%), respectively. Also, the mutation rates for Wnt pathway and MAPK pathway were calculated to be 23% (95% CI, 14-33%) and 20% (95% CI, 17-24%), respectively. Moreover, the most popular genes were APC (in Wnt pathway), KRAS (in MAPK pathway) and PIK3CA (in PI3K pathway) in the colorectal cancer, pancreatic cancer, and gastric cancer while they were beta-catenin and CTNNB1 in liver cancer. The most altered pathway was Wnt pathway followed by the MAPK pathway. In addition, pancreatic cancer was found to be higher under the pressure of mutation compared with others based on pooled prevalence analysis. Finally, APC mutations in colorectal cancer, KRAS in gastric cancer, and pancreatic cancer were mostly associated gene alterations.
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Affiliation(s)
- Alireza Tabibzadeh
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fahimeh Safarnezhad Tameshkel
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Yousef Moradi
- Social Determinants of Health Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Saber Soltani
- Department of Virology, Tehran University of Medical Sciences, Tehran, Iran
| | - Maziar Moradi-Lakeh
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
- Preventive Medicine and Public Health Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - G Hossein Ashrafi
- Cancer Theme SEC Faculty, Kingston University, Penrhyn Road, London, KT1 2EE, UK
| | - Nima Motamed
- Department of Social Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Farhad Zamani
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Abbas Motevalian
- Department of Epidemiology, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Mahshid Panahi
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Esghaei
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Ajdarkosh
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
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Jin J, Shi Y, Zhang S, Yang S. PIK3CA mutation and clinicopathological features of colorectal cancer: a systematic review and Meta-Analysis. Acta Oncol 2020; 59:66-74. [PMID: 31545109 DOI: 10.1080/0284186x.2019.1664764] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Background: There is conflicting evidence regarding the association between PIK3CA mutations and clinicopathological features of colorectal cancer (CRC). We performed a comprehensive meta-analysis investigating the association between PIK3CA mutations and clinicopathological features in CRC, including subgroup analysis of mutations in exons 9 and 20, to elucidate the role of PIK3CA mutations in CRC.Materials and Methods: A detailed literature search was performed within the PubMed, Web of Science, and Embase databases, examining the associations between PIK3CA mutations and demographic characteristics, clinicopathologic parameters, and molecular features in patients with CRC. The odds ratios with 95% confidence intervals were used to estimate the effect of PIK3CA mutations on outcome parameters.Results: Forty-four studies enrolling 17621 patients were eligible for inclusion. PIK3CA mutations were associated with proximal tumor location, mucinous differentiation, KRAS mutations, and microsatellite instability (MSI). Subgroup analysis demonstrated that PIK3CA exon 9 mutations were positively associated with proximal tumor location and KRAS mutations, and negatively associated with BRAF mutations and MSI; exon 20 mutations were associated with proximal tumor location, KRAS mutations, BRAF mutations and MSI.Conclusions: Our findings suggest that overall or exon-specific PIK3CA mutations showed null associations with key clinicopathological parameters, including disease stage and tumor differentiation, indicating that PIK3CA mutations do not predict aggressive clinicopathological characteristics in CRC. As PIK3CA mutations were found to be closely associated with KRAS mutations, their relationship warrants further investigation. Since PIK3CA exon 9 and 20 mutations showed different tendencies with regard to BRAF mutation and MSI status, they may have distinct molecular impacts on CRC.
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Affiliation(s)
- Juan Jin
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yaqin Shi
- Department of Medical Oncology, the First Hospital Affiliated to Soochow University, Suzhou, China
| | - Shu Zhang
- Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Shuofei Yang
- Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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Ding X, Yin K, Chen J, Wang K, Liu C. A ribonuclease-dependent cleavable beacon primer triggering DNA amplification for single nucleotide mutation detection with ultrahigh sensitivity and selectivity. Chem Commun (Camb) 2019; 55:12623-12626. [PMID: 31580354 DOI: 10.1039/c9cc06296c] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
We described a ribonuclease-dependent cleavable beacon primer, an energy-transfer-tagged oligonucleotide inserted with a ribonucleotide, which can be cleaved by ribonuclease to generate enhanced fluorescence signals and initiate DNA amplification for single nucleotide mutation detection with ultrahigh sensitivity and selectivity.
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Affiliation(s)
- Xiong Ding
- Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
| | - Kun Yin
- Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
| | - Ju Chen
- Department of Immunology, School of Medicine, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030, USA
| | - Kepeng Wang
- Department of Immunology, School of Medicine, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030, USA
| | - Changchun Liu
- Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
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Xu Y, Xu Q, Ma Y, Duan J, Zhang H, Liu T, Li L, Sun H, Shi K, Xie S, Wang W. Characterizing MRI features of rectal cancers with different KRAS status. BMC Cancer 2019; 19:1111. [PMID: 31727020 PMCID: PMC6857233 DOI: 10.1186/s12885-019-6341-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 11/06/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND To investigate whether MRI findings, including texture analysis, can differentiate KRAS mutation status in rectal cancer. METHODS Totally, 158 patients with pathologically proved rectal cancers and preoperative pelvic MRI examinations were enrolled. Patients were stratified into two groups: KRAS wild-type group (KRASwt group) and KRAS mutation group (KRASmt group) according to genomic DNA extraction analysis. MRI findings of rectal cancers (including texture features) and relevant clinical characteristics were statistically evaluated to identify the differences between the two groups. The independent samples t test or Mann-Whitney U test were used for continuous variables. The differences of the remaining categorical polytomous variables were analyzed using the Chi-square test or Fisher exact test. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the discriminatory power of MRI features. The area under the ROC curve (AUC) and the optimal cut-off values were calculated using histopathology diagnosis as a reference; meanwhile, sensitivity and specificity were determined. RESULTS Mean values of six texture parameters (Mean, Variance, Skewness, Entropy, gray-level nonuniformity, run-length nonuniformity) were significantly higher in KRASmt group compared to KRASwt group (p < 0.0001, respectively). The AUC values of texture features ranged from 0.703~0.813. In addition, higher T stage and lower ADC values were observed in the KRASmt group compared to KRASwt group (t = 7.086, p = 0.029; t = - 2.708, p = 0.008). CONCLUSION The MRI findings of rectal cancer, especially texture features, showed an encouraging value for identifying KRAS status.
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Affiliation(s)
- Yanyan Xu
- Department of Radiology, China-Japan Friendship Hospital, No.2 Yinghua East Street, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Qiaoyu Xu
- Department of Radiology, China-Japan Friendship Hospital, No.2 Yinghua East Street, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Yanhui Ma
- Department of Radiology, China-Japan Friendship Hospital, No.2 Yinghua East Street, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Jianghui Duan
- Department of Radiology, China-Japan Friendship Hospital, No.2 Yinghua East Street, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Haibo Zhang
- Department of Radiology, China-Japan Friendship Hospital, No.2 Yinghua East Street, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Tongxi Liu
- Department of Radiology, China-Japan Friendship Hospital, No.2 Yinghua East Street, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Lu Li
- Department of Radiology, China-Japan Friendship Hospital, No.2 Yinghua East Street, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Hongliang Sun
- Department of Radiology, China-Japan Friendship Hospital, No.2 Yinghua East Street, Chaoyang District, Beijing, 100029, People's Republic of China.
| | - Kaining Shi
- Philips Healthcare, Beijing, 100001, People's Republic of China
| | - Sheng Xie
- Department of Radiology, China-Japan Friendship Hospital, No.2 Yinghua East Street, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Wu Wang
- Department of Radiology, China-Japan Friendship Hospital, No.2 Yinghua East Street, Chaoyang District, Beijing, 100029, People's Republic of China
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Fu Y, Duan X, Huang J, Huang L, Zhang L, Cheng W, Ding S, Min X. Detection of KRAS mutation via ligation-initiated LAMP reaction. Sci Rep 2019; 9:5955. [PMID: 30976068 PMCID: PMC6459849 DOI: 10.1038/s41598-019-42542-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Accepted: 04/03/2019] [Indexed: 02/06/2023] Open
Abstract
KRAS mutations are abnormalities widely found in genomic DNA and circulating tumor DNA (ctDNA) of various types of cancers. Thus, highly sensitive detection of KRAS mutations in genomic DNA is of great significance in disease diagnosis and personalized medicine. Here, we developed a ligation-initiated loop-mediated isothermal amplification (LAMP) assaying method for ultrasensitive detection of KRAS mutation. In the presence of mutant KRAS DNA (mutDNA), the dumbbell-shaped structure (DSS) is formed by the specific ligation of two substrates (SLS1 and SLS2), which act as a template to initiate the following LAMP amplification. Making use of the outstanding specificity of ligation reaction and superior amplification of LAMP, 10 aM mutDNA can be accurately determined. In addition, as low as 0.1% mutDNA can be detected in the presence of a large excess of wild-type KRAS DNA (wtDNA), indicating the high sensitivity and specificity of the method. Furthermore, this strategy has been successfully applied for detection of a KRAS mutation from tissue samples of colorectal cancer patients. Thus, the developed ligation-initiated LAMP fluorescence assaying strategy presents a promising prospect for ultrasensitive detection of mutations.
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Affiliation(s)
- Yixin Fu
- Department of Laboratory Medicine, The Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, P.R. China.,School of Laboratory Medicine, Zunyi Medical University, Zunyi, 563003, P.R. China
| | - Xiaolei Duan
- School of Laboratory Medicine, Zunyi Medical University, Zunyi, 563003, P.R. China.,Key Laboratory of Clinical Laboratory Diagnostics (Ministry of education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400010, P.R. China
| | - Jian Huang
- Department of Laboratory Medicine, The Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, P.R. China.,School of Laboratory Medicine, Zunyi Medical University, Zunyi, 563003, P.R. China
| | - Lizhen Huang
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P.R. China
| | - Lutan Zhang
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P.R. China
| | - Wei Cheng
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P.R. China
| | - Shijia Ding
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400010, P.R. China
| | - Xun Min
- Department of Laboratory Medicine, The Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, P.R. China. .,School of Laboratory Medicine, Zunyi Medical University, Zunyi, 563003, P.R. China.
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9
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Huang D, Sun W, Zhou Y, Li P, Chen F, Chen H, Xia D, Xu E, Lai M, Wu Y, Zhang H. Mutations of key driver genes in colorectal cancer progression and metastasis. Cancer Metastasis Rev 2019; 37:173-187. [PMID: 29322354 DOI: 10.1007/s10555-017-9726-5] [Citation(s) in RCA: 205] [Impact Index Per Article: 34.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The association between mutations of key driver genes and colorectal cancer (CRC) metastasis has been investigated by many studies. However, the results of these studies have been contradictory. Here, we perform a comprehensive analysis to screen key driver genes from the TCGA database and validate the roles of these mutations in CRC metastasis. Using bioinformatics analysis, we identified six key driver genes, namely APC, KRAS, BRAF, PIK3CA, SMAD4 and p53. Through a systematic search, 120 articles published by November 30, 2017, were included, which all showed roles for these gene mutations in CRC metastasis. A meta-analysis showed that KRAS mutations (combined OR 1.18, 95% CI 1.05-1.33) and p53 mutations (combined OR 1.49, 95% CI 1.23-1.80) were associated with CRC metastasis, including lymphatic and distant metastases. Moreover, CRC patients with a KRAS mutation (combined OR 1.29, 95% CI 1.13-1.47), p53 mutation (combined OR 1.35, 95% CI 1.06-1.72) or SMAD4 mutation (combined OR 2.04, 95% CI 1.41-2.95) were at a higher risk of distant metastasis. Subgroup analysis stratified by ethnic populations indicated that the BRAF mutation was related to CRC metastasis (combined OR 1.42, 95% CI 1.18-1.71) and distant metastasis (combined OR 1.51, 95% CI 1.20-1.91) in an Asian population. No significant association was found between mutations of APC or PIK3CA and CRC metastasis. In conclusion, mutations of KRAS, p53, SMAD4 and BRAF play significant roles in CRC metastasis and may be both potential biomarkers of CRC metastasis as well as therapeutic targets.
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Affiliation(s)
- Dongdong Huang
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Wenjie Sun
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Yuwei Zhou
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Peiwei Li
- Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, 310058, China
- Department of Gastroenterology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - Fang Chen
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Hanwen Chen
- Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, 310058, China
| | - Dajing Xia
- Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, 310058, China
| | - Enping Xu
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Maode Lai
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Yihua Wu
- Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, 310058, China.
| | - Honghe Zhang
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
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Lohinai Z, Klikovits T, Moldvay J, Ostoros G, Raso E, Timar J, Fabian K, Kovalszky I, Kenessey I, Aigner C, Renyi-Vamos F, Klepetko W, Dome B, Hegedus B. KRAS-mutation incidence and prognostic value are metastatic site-specific in lung adenocarcinoma: poor prognosis in patients with KRAS mutation and bone metastasis. Sci Rep 2017; 7:39721. [PMID: 28051122 PMCID: PMC5209707 DOI: 10.1038/srep39721] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 11/21/2016] [Indexed: 01/08/2023] Open
Abstract
Current guidelines lack comprehensive information on the metastatic site-specific role of KRAS mutation in lung adenocarcinoma (LADC). We investigated the effect of KRAS mutation on overall survival (OS) in this setting. In our retrospective study, 500 consecutive Caucasian metastatic LADC patients with known KRAS mutational status were analyzed after excluding 32 patients with EGFR mutations. KRAS mutation incidence was 28.6%. The most frequent metastatic sites were lung (45.6%), bone (26.2%), adrenal gland (17.4%), brain (16.8%), pleura (15.6%) and liver (11%). Patients with intrapulmonary metastasis had significantly increased KRAS mutation frequency compared to those with extrapulmonary metastases (35% vs 26.5%, p = 0.0125). In contrast, pleural dissemination and liver involvement were associated with significantly decreased KRAS mutation incidence (vs all other metastatic sites; 17% (p < 0.001) and 16% (p = 0.02) vs 33%, respectively). Strikingly, we found a significant prognostic effect of KRAS status only in the bone metastatic subcohort (KRAS-wild-type vs KRAS-mutant; median OS 9.7 v 3.7 months; HR, 0.49; 95% CI, 0.31 to 0.79; p = 0.003). Our study suggests that KRAS mutation frequency in LADC patients shows a metastatic site dependent variation and, moreover, that the presence of KRAS mutation is associated with significantly worse outcome in bone metastatic cases.
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Affiliation(s)
- Zoltan Lohinai
- National Koranyi Institute of Pulmonology, Budapest, Hungary
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria
| | - Thomas Klikovits
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria
| | - Judit Moldvay
- National Koranyi Institute of Pulmonology, Budapest, Hungary
| | - Gyula Ostoros
- National Koranyi Institute of Pulmonology, Budapest, Hungary
| | - Erzsebet Raso
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Jozsef Timar
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
- Molecular Oncology Research Group, Hungarian Academy of Sciences-Semmelweis University, Budapest, Hungary
| | - Katalin Fabian
- Department of Pulmonology, Semmelweis University, Budapest, Hungary
| | - Ilona Kovalszky
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - István Kenessey
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Clemens Aigner
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria
- Department of Thoracic Surgery, Ruhrlandklinik Essen, University Hospital of University Duisburg-Essen, Essen, Germany
| | - Ferenc Renyi-Vamos
- Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Budapest, Hungary
| | - Walter Klepetko
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria
| | - Balazs Dome
- National Koranyi Institute of Pulmonology, Budapest, Hungary
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria
- Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Budapest, Hungary
- Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Balazs Hegedus
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria
- Molecular Oncology Research Group, Hungarian Academy of Sciences-Semmelweis University, Budapest, Hungary
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11
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Mei ZB, Duan CY, Li CB, Cui L, Ogino S. Prognostic role of tumor PIK3CA mutation in colorectal cancer: a systematic review and meta-analysis. Ann Oncol 2016; 27:1836-1848. [PMID: 27436848 PMCID: PMC5035784 DOI: 10.1093/annonc/mdw264] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 06/28/2016] [Accepted: 06/28/2016] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Somatic mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT pathway play a vital role in carcinogenesis. Approximately 15%-20% of colorectal cancers (CRCs) harbor activating mutations in PIK3CA, making it one of the most frequently mutated genes in CRC. We thus carried out a systematic review and meta-analysis investigating the prognostic significance of PIK3CA mutations in CRC. MATERIALS AND METHODS Electronic databases were searched from inception through May 2015. We extracted the study characteristics and prognostic data of each eligible study. The hazard ratio (HR) and 95% confidence interval (CI) were derived and pooled using the random-effects Mantel-Haenszel model. RESULTS Twenty-eight studies enrolling 12 747 patients were eligible for inclusion. Data on overall survival (OS) and progression-free survival (PFS) were available from 19 and 10 studies, respectively. Comparing PIK3CA-mutated CRC patients with PIK3CA-wild-type CRC patients, the summary HRs for OS and PFS were 0.96 (95% CI 0.83-1.12) and 1.20 (95% CI 0.98-1.46), respectively. The trim-and-fill, Copas model and subgroup analyses stratified by the study characteristics confirmed the robustness of the results. Five studies reported the CRC prognosis for PIK3CA mutations in exons 9 and 20 separately; neither exon 9 mutation nor exon 20 mutation in PIK3CA was significantly associated with patient survival. CONCLUSIONS Our findings suggest that PIK3CA mutation has the neutral prognostic effects on CRC OS and PFS. Evidence was accumulating for the establishment of CRC survival between PIK3CA mutations and patient-specific clinical or molecular profiles.
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Affiliation(s)
- Z B Mei
- Department of Anorectal Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai
| | - C Y Duan
- State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing
| | - C B Li
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - L Cui
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - S Ogino
- Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston Department of Medical Oncology, Dana-Farber Cancer Institute, Boston Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA
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12
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Gleeson FC, Kipp BR, Voss JS, Campion MB, Minot DM, Tu ZJ, Klee EW, Graham RP, Lazaridis KN, Henry MR, Levy MJ. Frequency of mitogen-activated protein kinase and phosphoinositide 3-kinase signaling pathway pathogenic alterations in EUS-FNA sampled malignant lymph nodes in rectal cancer with theranostic potential. Gastrointest Endosc 2015; 82:550-6.e1. [PMID: 25887718 DOI: 10.1016/j.gie.2015.01.050] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2014] [Accepted: 01/24/2015] [Indexed: 12/31/2022]
Abstract
BACKGROUND Targeted next-generation sequencing has the potential to stratify a tumor by molecular subtype and aid the development of a biomarker profile for prognostic risk stratification and theranostic potential. OBJECTIVE To assess the frequency and distribution of pathogenic alterations in malignant lymph node cytology specimens. DESIGN Multigene molecular profiling of archived malignant EUS-FNA lymph node cytology specimens using the Ion Ampliseq Cancer Hotspot Panel v2, which targets at least 2855 possible mutations within 50 cancer-associated genes. SETTING Single tertiary referral center. PATIENTS Sporadic, treatment naive, locally advanced primary rectal cancer by EUS-FNA (n = 76) who subsequently completed neoadjuvant therapy with on-site oncologic surgery. MAIN OUTCOME MEASUREMENTS The frequency and distribution of pathogenic alterations in malignant lymph node cytology specimens by the mitogen-activated protein kinase (MAPK) or phosphoinositide 3-kinase (PI3K) signaling pathways, by KRAS or NRAS wild-type lymph node status, by extramesenteric lymph node status, and by a complete pathologic response status. RESULTS Eleven patients (14.5%) were 50-gene panel wild-type. Sixty-five patients had 139 pathogenic alterations (2 [1-3] per patient) in 13 of 50 evaluated genes. The following represent a spectrum of identified alterations: TP53 (n = 52; 68.4%), APC (n = 36; 47.4%), KRAS (n = 22; 28.9%), FBXW7 (n = 8; 10.5%), NRAS (n = 6; 7.9%), PIK3CA (n = 4; 5.3%), SMAD4 (n = 3; 3.9%), and BRAF (n = 3; 3.9%). Pathogenic alterations were identified in the MAPK and PI3K signaling pathways in 41% and 5% of patients, respectively. LIMITATIONS Findings were limited to a 50 cancer-associated gene analysis. CONCLUSIONS Molecular EUS lymph node assessments using cancer "hotspot" panels can identify pathogenic alteration frequency and distribution and have theranostic potential for individualized patient care.
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Affiliation(s)
- Ferga C Gleeson
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Benjamin R Kipp
- Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Jesse S Voss
- Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Michael B Campion
- Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Douglas M Minot
- Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Zheng J Tu
- Division of Biomedical Statics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Eric W Klee
- Division of Biomedical Statics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Rondell P Graham
- Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Konstantinos N Lazaridis
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Michael R Henry
- Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Michael J Levy
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Colorectal cancer metastatic to the brain: analysis of prognostic factors and impact of KRAS mutations on presentation and outcome. Clin Transl Oncol 2015; 18:88-92. [PMID: 26260912 DOI: 10.1007/s12094-015-1340-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Accepted: 06/26/2015] [Indexed: 02/01/2023]
Abstract
BACKGROUND Treatment concepts for metastatic colorectal cancer continue to evolve. While the presence of RAS mutations impacts systemic therapy, little is known about the influence of such mutations in patients with brain metastases. PATIENTS AND METHODS Pooled retrospective analysis was conducted of 57 patients with brain metastases from colorectal cancer treated in two different institutions (2005-2013). RESULTS The only mutations analyzed in a relatively large subgroup were KRAS mutations (14 wild type, 12 mutated). Mutation status was not associated with baseline characteristics such as number or location of metastases, and did not impact prognosis. Three factors were significantly associated with survival in multivariate analysis: Karnofsky Performance Status (KPS), management strategy, and systemic treatment. Median survival was 0.6 months with best supportive care, 3.0 months with initial whole-brain radiotherapy (WBRT), and 12.7 months if initial treatment included surgery or stereotactic radiosurgery (SRS), p = 0.0001. The survival difference between the WBRT and surgery/SRS groups was largest in patients with KPS 80-100. CONCLUSION Effective local treatment was a prerequisite for improved survival. The only significant prognostic baseline factor was KPS, which forms the basis of the diagnosis-specific graded prognostic assessment (DS-GPA) score. Thus, our results validate the DS-GPA in this patient population. So far, neither this nor other studies suggest a clinically important impact of KRAS mutations beyond their previously reported association with development of brain metastases. Studies focusing on patients who develop brain metastases early during the course of metastatic disease might be warranted, because the influence of different systemic therapies might be larger in this subgroup.
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14
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Stec R, Semeniuk-Wojtaś A, Charkiewicz R, Bodnar L, Korniluk J, Smoter M, Chyczewski L, Nikliński J, Szczylik C. Mutation of the PIK3CA gene as a prognostic factor in patients with colorectal cancer. Oncol Lett 2015; 10:1423-1429. [PMID: 26622684 DOI: 10.3892/ol.2015.3398] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 05/28/2015] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide, with ~700,000 mortalities occurring due to CRC in 2012. The treatment options are effective in a small percentage of patients, and it is important to identify specific biomarkers in order to determine patients for whom the available therapies will be beneficial. It has been hypothesised that the PIK3CA gene mutation may affect the response to therapy of patients with metastatic CRC. In the present study, primary tumour specimens were collected from 156 patients with CRC who were treated in the Military Institute of Medicine in Warsaw (Warsaw, Poland). Codons 12 and 13 of exon 1 of KRAS, exons 11 and 15 of BRAF and exons 9 and 20 of PIK3CA were analysed for mutation using direct sequencing. The prognostic value of each mutation and the clinical and pathological variables of these tumours were estimated. The results revealed that PIK3CA mutations were present in 15 patients (9.6%), of whom seven (46.7%) possessed mutations in codon 9 and eight (53.3%) possessed mutations in codon 20. Mutation in the PIK3CA gene was detected in six patients with KRAS gene mutations, which accounted for 40% of PIK3CA-mutated tumours, and in one patient with BRAF mutations, which accounted for 6.6% of PIK3CA-mutated tumours. No significant differences were identified between the overall survival (OS) rates of patients with PIK3CA mutations (median OS, 56.7 months) and those with wild-type PIK3CA genes (median OS, 47.6 months) (P=0.1270). Univariate analysis identified that the following prognostic factors affected the OS rate in the current patient cohort: Gender, female patients survived for 57.5 months compared with 39.3 months for male patients (P=0.0111); and lymph node involvement grade, as survival of patients without lymph node metastases was 61.4 months compared with 45.4 months in patients presenting with metastases (P=0.0122). The findings of the present analysis indicate that PIK3CA mutation status is not a prognostic factor in CRC patients. In addition, no statistically significant association exists between tumours with PIK3CA mutations and clinical or pathological factors.
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Affiliation(s)
- Rafał Stec
- Department of Oncology, Military Institute of Medicine, Warsaw 04-141, Poland
| | | | - Radosław Charkiewicz
- Department of Clinical Molecular Biology, Medical University of Bialystok, Bialystok 15-089, Poland
| | - Lubomir Bodnar
- Department of Oncology, Military Institute of Medicine, Warsaw 04-141, Poland
| | - Jan Korniluk
- Department of Oncology, Military Institute of Medicine, Warsaw 04-141, Poland
| | - Marta Smoter
- Department of Oncology, Military Institute of Medicine, Warsaw 04-141, Poland
| | - Lech Chyczewski
- Department of Clinical Pathology, Medical University of Bialystok, Bialystok 15-089, Poland
| | - Jacek Nikliński
- Department of Clinical Molecular Biology, Medical University of Bialystok, Bialystok 15-089, Poland
| | - Cezary Szczylik
- Department of Oncology, Military Institute of Medicine, Warsaw 04-141, Poland
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