|
1
|
Soltysova A, Dvorska D, Ficek A, Pecimonova M, Samec M, Kasubova I, Horvathova Kajabova V, Demkova L, Babal P, Valaskova J, Dankova Z, Smolkova B, Furdova A. Clinical Value of MLPA for Prognostic Assessment of Chromosomal Rearrangements and DNA Methylation in Uveal Melanoma. Invest Ophthalmol Vis Sci 2025; 66:51. [PMID: 40131297 PMCID: PMC11951064 DOI: 10.1167/iovs.66.3.51] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 02/28/2025] [Indexed: 03/26/2025] Open
Abstract
Purpose Uveal melanoma (UM) is the most prevalent primary intraocular malignancy in adults, with prognosis significantly influenced by genetic and epigenetic factors. Reliable and cost-effective methods to detect chromosomal aberrations and DNA methylation changes are essential for improving prognostication and informing treatment strategies in UM. This study evaluated the effectiveness of multiplex ligation-dependent probe amplification (MLPA) in detecting UM-specific copy number variations (CNVs) and promoter methylation changes across 25 tumor suppressor genes (TSGs). Methods DNA from 58 UM tissues was analyzed with the SALSA MLPA Probemix P027 Uveal melanoma kit, and a subset of 18 samples was further assessed using the SALSA MLPA Probemix ME002-C1 Tumour suppressor mix 2 kit to identify key CNVs and methylation alterations linked to poor prognosis. Validation was carried out with a high-resolution comparative genomic hybridization (CGH) array on 10 samples and the Illumina Infinium Methylation EPIC v1.0 BeadChip array on 25 samples. Results Our findings indicate that MLPA is a versatile and robust method for detecting CNVs, showing strong correlations with CGH data and highlighting specific CNV patterns linked to clinical outcomes in UM. However, the ME002-C1 kit showed limited utility for comprehensive methylation analysis, as differential methylation was not observed in the studied TSG loci. Conclusions Although MLPA effectively identifies CNVs relevant to UM prognosis, integrating additional methylation-specific approaches could broaden the scope of DNA methylation analysis, offering a more comprehensive molecular understanding of UM that may enhance prognostication and personalized treatment.
Collapse
Affiliation(s)
- Andrea Soltysova
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, Slovakia
- Institute for Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Dana Dvorska
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Andrej Ficek
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, Slovakia
| | - Martina Pecimonova
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, Slovakia
| | - Marek Samec
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
- Department of Medical Biology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Ivana Kasubova
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Viera Horvathova Kajabova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia
| | - Lucia Demkova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia
| | - Pavel Babal
- Institute of Pathological Anatomy, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
| | - Jela Valaskova
- Department of Ophthalmology, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
| | - Zuzana Dankova
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
- Biobank for Cancer and Rare Diseases, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Bozena Smolkova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia
| | - Alena Furdova
- Department of Ophthalmology, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
| |
Collapse
|
|
2
|
Li JS, Riggins K, Yang L, Chen C, Castro P, Alfarkh W, Zarrin-Khameh N, Scheurer ME, Creighton CJ, Musher B, Li W, Shen L. DNA methylation profiling at base-pair resolution reveals unique epigenetic features of early-onset colorectal cancer in underrepresented populations. Clin Epigenetics 2025; 17:11. [PMID: 39844333 PMCID: PMC11753045 DOI: 10.1186/s13148-025-01817-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 01/10/2025] [Indexed: 01/24/2025] Open
Abstract
BACKGROUND The incidence of early-onset colorectal cancer (EOCRC) has been rising at an alarming rate in the USA, and EOCRC disproportionately affects racial/ethnic minorities. Here, we construct comprehensive profiles of EOCRC DNA methylomes at base-pair resolution for a cohort of Hispanic and African American patients. RESULTS We show the epigenetic landscape of these EOCRC patients differs from that of late-onset colorectal cancer patients, and methylation canyons in EOCRC tumor tissue preferentially overlapped genes in cancer-related pathways. Furthermore, we identify epigenetic alterations in metabolic genes that are specific to our racial/ethnic minority EOCRC cohort but not Caucasian patients from TCGA. Top genes differentially methylated between these cohorts included the obesity-protective MFAP2 gene as well as cancer risk susceptibility genes APOL3 and RNASEL. CONCLUSIONS In this study, we provide to the scientific community high-resolution DNA methylomes for a cohort of EOCRC patients from underrepresented populations. Our exploratory findings in this cohort highlight epigenetic mechanisms underlying the pathogenesis of EOCRC and nominate novel biomarkers for EOCRC in underrepresented populations.
Collapse
Affiliation(s)
- Jason Sheng Li
- Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, 92697, USA
| | - Karen Riggins
- Department of Medicine, Hematology and Oncology, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Li Yang
- Department of Pediatrics, USDA Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Chaorong Chen
- Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, 92697, USA
| | - Patricia Castro
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Wedad Alfarkh
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Neda Zarrin-Khameh
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, 77030, USA
- Department of Pathology, Ben Taub Hospital, 1504 Taub Loop, Houston, TX, 77030, USA
| | - Michael E Scheurer
- Department of Pediatrics, Center for Epidemiology and Population Health, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Chad J Creighton
- Department of Medicine and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Benjamin Musher
- Department of Medicine, Gastrointestinal Medical Oncology, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
| | - Wei Li
- Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, 92697, USA.
| | - Lanlan Shen
- Department of Pediatrics, USDA Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, 77030, USA.
| |
Collapse
|
|
3
|
Zinkeng A, Taylor FL, Cheong SH, Song H, Merchant JL. Early Onset Colorectal Cancer: Molecular Underpinnings Accelerating Occurrence. Cell Mol Gastroenterol Hepatol 2024; 19:101425. [PMID: 39510499 PMCID: PMC11731505 DOI: 10.1016/j.jcmgh.2024.101425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 10/28/2024] [Accepted: 10/28/2024] [Indexed: 11/15/2024]
Abstract
The onset of colorectal cancer (CRC) in patients younger than 50 continues to rapidly increase. This study highlights the epidemiologic changes, risk factors, clinical characteristics, and molecular profiles prevalent in early onset CRC patients, and identifies key areas for future research. It has been noted that only a small fraction of early onset CRC cases is attributed to known hereditary mutations and fit the canonical pathway of late-onset colorectal cancer development. To highlight this, we review the genetic and epigenetic modifications specific to early onset CRC. We also discuss the synergetic effect of single-nucleotide polymorphisms and environmental factors on the early onset of CRC. Additionally, we discuss the potential of noninvasive biomarker assays to enhance early detection, screening, diagnosis, and prognostic outcome predictions.
Collapse
Affiliation(s)
- Atehkeng Zinkeng
- Medical Scientist Training Program, University of Arizona College of Medicine, Tucson, Arizona
| | | | | | | | - Juanita L Merchant
- Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona.
| |
Collapse
|
|
4
|
Ullah F, Pillai AB, Omar N, Dima D, Harichand S. Early-Onset Colorectal Cancer: Current Insights. Cancers (Basel) 2023; 15:3202. [PMID: 37370811 DOI: 10.3390/cancers15123202] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 06/01/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
Over the past decade, the incidence of colorectal cancer has increased in individuals under the age of 50 years. Meanwhile, the incidence has gradually decreased in the older population. As described herein, we reviewed the available literature to summarize the current landscape of early-onset colorectal cancer, including risk factors, clinicopathological presentation, genetic makeup of patients, and management. Currently, early-onset colorectal cancer is treated similarly as late-onset colorectal cancer, yet the available literature shows that early-onset colorectal cancer is more aggressive and different, and this remains a significant unmet need. A detailed understanding of early-onset colorectal cancer is needed to identify risk factors for the increased incidence and tailor treatments accordingly.
Collapse
Affiliation(s)
- Fauzia Ullah
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Ashwathy Balachandran Pillai
- Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Najiullah Omar
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Danai Dima
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
- Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Seema Harichand
- Department of Internal Medicine, Mission Cancer + Blood, University of Iowa, Des Moines, IA 50309, USA
| |
Collapse
|
|
5
|
Marx O, Mankarious M, Yochum G. Molecular genetics of early-onset colorectal cancer. World J Biol Chem 2023; 14:13-27. [PMID: 37034132 PMCID: PMC10080548 DOI: 10.4331/wjbc.v14.i2.13] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/20/2022] [Accepted: 02/13/2023] [Indexed: 03/24/2023] Open
Abstract
Early-onset colorectal cancer (EOCRC) has been rising in global prevalence and incidence over the past several decades. Environmental influences, including generational lifestyle changes and rising obesity, contribute to these increased rates. While the rise in EOCRC is best documented in western countries, it is seen throughout the world, although EOCRC may have distinct genetic mutations in patients of different ethnic backgrounds. Pathological and molecular characterizations show that EOCRC has a distinct presentation compared with later-onset colorectal cancer (LOCRC). Recent studies have identified DNA, RNA, and protein-level alterations unique to EOCRC, revealing much-needed biomarkers and potential novel therapeutic targets. Many molecular EOCRC studies have been performed with Caucasian and Asian EOCRC cohorts, however, studies of other ethnic backgrounds are limited. In addition, certain molecular characterizations that have been conducted for LOCRC have not yet been repeated in EOCRC, including high-throughput analyses of histone modifications, mRNA splicing, and proteomics on large cohorts. We propose that the complex relationship between cancer and aging should be considered when studying the molecular underpinnings of EOCRC. In this review, we summarize current EOCRC literature, focusing on sporadic molecular alterations in tumors, and their clinical implications. We conclude by discussing current challenges and future directions of EOCRC research efforts.
Collapse
Affiliation(s)
- Olivia Marx
- Department of Biochemistry & Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States
| | - Marc Mankarious
- Department of Surgery, Division of Colon & Rectal Surgery, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA 17033, United States
| | - Gregory Yochum
- Department of Biochemistry & Molecular Biology & Surgery, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States
| |
Collapse
|
|
6
|
Hamilton AC, Bannon FJ, Dunne PD, James J, McQuaid S, Gray RT, Salto-Tellez M, Cardwell CR, Loughrey MB, Coleman HG. Distinct Molecular Profiles of Sporadic Early-Onset Colorectal Cancer: A Population-Based Cohort and Systematic Review. GASTRO HEP ADVANCES 2022; 2:347-359. [PMID: 39132649 PMCID: PMC11307521 DOI: 10.1016/j.gastha.2022.11.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 11/02/2022] [Indexed: 08/13/2024]
Abstract
BACKGROUND AND AIMS The observed increase in the incidence of early-onset colorectal cancer (EOCRC) is being driven by sporadic cases, but the molecular characteristics of these tumors are not fully understood. Our objective was to investigate the prevalence of microsatellite instability (MSI) and selected mutations in sporadic EOCRC, and their association with survival. METHODS Firstly, we compared the prevalence of molecular characteristics and survival within a population-based cohort study of 652 stage II and III colon cancer patients in Northern Ireland, comparing sporadic early-onset (<50 years, n = 35) with older (60-69 years, n = 179) patients. Secondly, a systematic review for studies reporting the prevalence of MSI, mismatch repair deficiency (dMMR), or BRAF, KRAS, NRAS, PIK3CA, and TP53 mutations in sporadic EOCRC was conducted. A meta-analysis was performed to calculate pooled estimates of the prevalence of molecular features in sporadic EOCRC. RESULTS Firstly, within the cohort study, EOCRC patients did not have a significantly increased risk of colorectal cancer-specific death (adjusted hazard ratio 1.20; 95% confidence interval [CI] 0.61-2.39) compared with 60- to 69-year-olds. Second, 32 studies were included in the systematic review. The pooled analysis estimated a prevalence of 10% (95% CI 7%-14%) for MSI high/dMMR in sporadic EOCRC. BRAF and KRAS mutations had a prevalence of 1% (95% CI 0%-3%) and 32% (95% CI 23%-40%), respectively. CONCLUSION The molecular characteristics of sporadic EOCRC differ from those of cancers in older adults, particularly regarding reduced prevalence of BRAF mutations. Ten percent of sporadic EOCRC display MSI high/dMMR. Further studies are needed to address survival in sporadic EOCRC cases and whether molecular profiles influence EOCRC outcomes in this patient group.
Collapse
Affiliation(s)
| | - Finian J. Bannon
- Centre for Public Health, Queen’s University Belfast, Northern Ireland, UK
| | - Philip D. Dunne
- Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Northern Ireland, UK
- CRUK Beatson Institute, Glasgow, UK
| | - Jacqueline James
- Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Northern Ireland, UK
- Northern Ireland Biobank, Belfast, Northern Ireland, UK
- Precision Medicine Centre of Excellence, Queen’s University Belfast, Northern Ireland, UK
| | - Stephen McQuaid
- Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Northern Ireland, UK
- Northern Ireland Biobank, Belfast, Northern Ireland, UK
| | - Ronan T. Gray
- Centre for Public Health, Queen’s University Belfast, Northern Ireland, UK
- South Eastern Health and Social Care Trust, Northern Ireland, UK
| | - Manuel Salto-Tellez
- Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Northern Ireland, UK
- Precision Medicine Centre of Excellence, Queen’s University Belfast, Northern Ireland, UK
| | - Chris R. Cardwell
- Centre for Public Health, Queen’s University Belfast, Northern Ireland, UK
| | - Maurice B. Loughrey
- Centre for Public Health, Queen’s University Belfast, Northern Ireland, UK
- Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Northern Ireland, UK
- Department of Cellular Pathology, Belfast Health and Social Care Trust, Northern Ireland, UK
| | - Helen G. Coleman
- Centre for Public Health, Queen’s University Belfast, Northern Ireland, UK
- Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Northern Ireland, UK
| |
Collapse
|
|
7
|
The potential of liquid biopsy in the management of cancer patients. Semin Cancer Biol 2022; 84:69-79. [PMID: 35331850 DOI: 10.1016/j.semcancer.2022.03.013] [Citation(s) in RCA: 75] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 03/06/2022] [Accepted: 03/17/2022] [Indexed: 02/07/2023]
|
|
8
|
Wu CWK, Lui RN. Early-onset colorectal cancer: Current insights and future directions. World J Gastrointest Oncol 2022; 14:230-241. [PMID: 35116113 PMCID: PMC8790420 DOI: 10.4251/wjgo.v14.i1.230] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 08/02/2021] [Accepted: 11/24/2021] [Indexed: 02/06/2023] Open
Abstract
Early-onset colorectal cancer (EOCRC) has seen an alarming rise worldwide over the past two decades. The reason for this global trend is poorly understood. EOCRC appears to have its own unique clinical and molecular features when compared with late-onset colorectal cancer. Younger patients appear to have more distal or rectal disease, a more advanced stage of disease at presentation, and more unfavorable histological features. Identifying risk factors for EOCRC is the first step in mitigating the rising burden of this disease. Here we summarize several noteworthy biological factors and environmental exposures that are postulated to be responsible culprits. This can hopefully translate in clinical practice to the development of better risk stratification tool for identifying high-risk individuals for early colorectal cancer screening, and identifying areas needed for further research to curb this rising trend.
Collapse
Affiliation(s)
- Claudia Wing-Kwan Wu
- Division of Gastroenterology and Hepatology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Rashid N Lui
- Division of Gastroenterology and Hepatology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
- Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China
| |
Collapse
|
|
9
|
Chen J, Lin M, Che Y, Guo J, Lin W. Key genes in youth colorectal cancer based on data mining and verification by reverse transcription-quantitative PCR. Oncol Lett 2021; 21:194. [PMID: 33574933 PMCID: PMC7816307 DOI: 10.3892/ol.2021.12455] [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: 07/10/2020] [Accepted: 12/07/2020] [Indexed: 12/24/2022] Open
Abstract
In recent years, among all patients with colorectal cancer, the proportion of young patients has been gradually increasing. However, the molecular mechanisms involved in colorectal cancer in the young are largely unknown. In the present study the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas datasets were integrated to elucidate the key gene biomarkers in these patients. The GSE41657 and GSE41258 datasets were downloaded from the GEO database. By screening for differentially expressed genes, Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, protein-protein interaction analysis, hub gene screening and survival analysis, two key genes, CXCL8 and VEGFA, which were enriched in cancer pathways, were obtained. Reverse transcription-quantitative (RT-q)PCR was performed to verify the outcome obtained by bioinformatics analysis. In conclusion, the present study identified two key genes using bioinformatics analysis and RT-qPCR validation. These results indicated that the candidate genes may be involved in the progression of colorectal cancer in young people, and these two genes may act as ideal prognostic indicators or therapeutic targets for colorectal cancer in the youth.
Collapse
Affiliation(s)
- Jianxin Chen
- The First Department of Gastrointestinal Surgery, The Affiliated Hospital of Putian University, Putian, Fujian 351100, P.R. China.,Gastrointestinal Surgery Research Institute, The Affiliated Hospital of Putian University, Putian, Fujian 351100, P.R. China
| | - Min Lin
- College of Information Engineering, Putian University, Putian, Fujian 351100, P.R. China
| | - Yan Che
- College of Information Engineering, Putian University, Putian, Fujian 351100, P.R. China.,Engineering Research Center of Big Data Application in Private Health Medicine, Fujian Province University, Putian, Fujian 351100, P.R. China
| | - Jian Guo
- The First Department of Gastrointestinal Surgery, The Affiliated Hospital of Putian University, Putian, Fujian 351100, P.R. China.,Gastrointestinal Surgery Research Institute, The Affiliated Hospital of Putian University, Putian, Fujian 351100, P.R. China
| | - Wei Lin
- The First Department of Gastrointestinal Surgery, The Affiliated Hospital of Putian University, Putian, Fujian 351100, P.R. China.,Gastrointestinal Surgery Research Institute, The Affiliated Hospital of Putian University, Putian, Fujian 351100, P.R. China
| |
Collapse
|
|
10
|
Maugeri A, Barchitta M, Magnano San Lio R, Li Destri G, Agodi A, Basile G. Epigenetic Aging and Colorectal Cancer: State of the Art and Perspectives for Future Research. Int J Mol Sci 2020; 22:ijms22010200. [PMID: 33379143 PMCID: PMC7795459 DOI: 10.3390/ijms22010200] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 12/22/2020] [Accepted: 12/24/2020] [Indexed: 12/13/2022] Open
Abstract
Although translational research has identified a large number of potential biomarkers involved in colorectal cancer (CRC) carcinogenesis, a better understanding of the molecular pathways associated with biological aging in colorectal cells and tissues is needed. Here, we aim to summarize the state of the art about the role of age acceleration, defined as the difference between epigenetic age and chronological age, in the development and progression of CRC. Some studies have shown that accelerated biological aging is positively associated with the risk of cancer and death in general. In line with these findings, other studies have shown how the assessment of epigenetic age in people at risk for CRC could be helpful for monitoring the molecular response to preventive interventions. Moreover, it would be interesting to investigate whether aberrant epigenetic aging could help identify CRC patients with a high risk of recurrence and a worst prognosis, as well as those who respond poorly to treatment. Yet, the application of this novel concept is still in its infancy, and further research should be encouraged in anticipation of future applications in clinical practice.
Collapse
Affiliation(s)
- Andrea Maugeri
- Department of Medical and Surgical Sciences and Advanced Technologies “GF Ingrassia”, University of Catania, via S. Sofia, 87, 95123 Catania, Italy; (A.M.); (R.M.S.L.); (G.L.D.); (A.A.)
| | - Martina Barchitta
- Department of Medical and Surgical Sciences and Advanced Technologies “GF Ingrassia”, University of Catania, via S. Sofia, 87, 95123 Catania, Italy; (A.M.); (R.M.S.L.); (G.L.D.); (A.A.)
- Correspondence:
| | - Roberta Magnano San Lio
- Department of Medical and Surgical Sciences and Advanced Technologies “GF Ingrassia”, University of Catania, via S. Sofia, 87, 95123 Catania, Italy; (A.M.); (R.M.S.L.); (G.L.D.); (A.A.)
| | - Giovanni Li Destri
- Department of Medical and Surgical Sciences and Advanced Technologies “GF Ingrassia”, University of Catania, via S. Sofia, 87, 95123 Catania, Italy; (A.M.); (R.M.S.L.); (G.L.D.); (A.A.)
| | - Antonella Agodi
- Department of Medical and Surgical Sciences and Advanced Technologies “GF Ingrassia”, University of Catania, via S. Sofia, 87, 95123 Catania, Italy; (A.M.); (R.M.S.L.); (G.L.D.); (A.A.)
| | - Guido Basile
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, via S. Sofia, 78, 95123 Catania, Italy;
| |
Collapse
|
|
11
|
Xu T, Zhang Y, Zhang J, Qi C, Liu D, Wang Z, Li Y, Ji C, Li J, Lin X, Hou T, Liu H, Zhang L, Han-Zhang H, Shen L, Wang X. Germline Profiling and Molecular Characterization of Early Onset Metastatic Colorectal Cancer. Front Oncol 2020; 10:568911. [PMID: 33194656 PMCID: PMC7604404 DOI: 10.3389/fonc.2020.568911] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 09/23/2020] [Indexed: 12/12/2022] Open
Abstract
Background Early onset colorectal cancer (EO CRC) is a heterogeneous colorectal cancer subtype with obvious hereditary tendencies and increasing incidence. We sought to determine the susceptibility genes and molecular characteristics of EO CRC. Methods 330 EO metastatic CRC (mCRC) (≤55 years) and 110 average-onset (AO) mCRC patients (>55 years) were enrolled. Capture-based targeted sequencing was performed on tumor tissue and paired white blood cells using a sequencing panel of 520 genes. The association between molecular alterations and overall survival (OS) was analyzed. Results Of the 330 EO mCRC patients, 31 carried pathogenic or likely pathogenic germline mutations, with 16 of them diagnosed with lynch syndrome. Fifteen patients had germline mutations in non-mismatch repair genes, including four in MUTHY, three in RAD50, one in TP53, and eight in other genes. Twenty-nine genes were recurrently mutated in EO mCRC, including TP53, APC, KRAS, SMAD4, and BRCA2. The majority of genomic alterations were comparable between EO and AO mCRC. EO mCRC patients were more likely to have a high tumor mutation burden (p < 0.05). RNF43, RBM10, TSC, and BRAF V600E mutations were more commonly observed in EO mCRC, while APC, ASXL1, DNMT3B, and MET genes were more commonly altered in AO patients. At the pathway level, the WNT pathway was the only differentially mutated pathway between EO and AO mCRC (p < 0.0001). The wild-type WNT pathway (p = 0.0017) and mutated TGF-β pathway (p = 0.023) were associated with unfavorable OS in EO mCRC. Conclusions Approximately one in 10 EO mCRC was associated with hereditary tumors. The spectrum of somatic alterations was largely comparable between EO and AO mCRC with several notable differences.
Collapse
Affiliation(s)
- Ting Xu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Yinjie Zhang
- Sichuan Cancer Center, School of Medicine, Sichuan Cancer Hospital and Institute, University of Electronic Science and Technology of China, Chengdu, China
| | - Jing Zhang
- Department of Radiation Oncology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Changsong Qi
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Dan Liu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhenghang Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Yanyan Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Congcong Ji
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jian Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Xuan Lin
- Burning Rock Biotech, Guangzhou, China
| | - Ting Hou
- Burning Rock Biotech, Guangzhou, China
| | - Hao Liu
- Burning Rock Biotech, Guangzhou, China
| | - Lu Zhang
- Burning Rock Biotech, Guangzhou, China
| | | | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Xicheng Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| |
Collapse
|
|
12
|
Salem ME, Battaglin F, Goldberg RM, Puccini A, Shields AF, Arguello D, Korn WM, Marshall JL, Grothey A, Lenz H. Molecular Analyses of Left- and Right-Sided Tumors in Adolescents and Young Adults with Colorectal Cancer. Oncologist 2020; 25:404-413. [PMID: 31848314 PMCID: PMC7216442 DOI: 10.1634/theoncologist.2019-0552] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 09/13/2019] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND The incidence of colorectal cancer (CRC), particularly left-sided tumors (LT), in adolescents and young adults (AYA) is rising. Epigenetic events appear to play an important role in tumorigenesis and cancer progression, especially in younger patients. We compared molecular features of LT to right-sided tumors (RT) in AYA. MATERIALS AND METHODS A total of 246 LT and 56 RT were identified in a cohort of 612 AYA with primary CRC. Tumors were examined by next-generation sequencing (NGS), protein expression, and gene amplification. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined based on NGS data. RESULTS RT showed higher mutation rates compared with LT in several genes including BRAF (10.3% vs. 2.8%), KRAS (64.1% vs. 45.5%), PIK3CA (27% vs. 11.2%), and RNF43 (24.2% vs. 2.9%). Notably, additional mutations in distinct genes involved in histone modification and chromatin remodeling, as well as genes associated with DNA repair and cancer-predisposing syndromes, were characteristic of RT; most frequently KMT2D (27.8% vs. 3.4%), ARID1A (53.3% vs. 21.4%), MSH6 (11.1% vs. 2.3%), MLH1 (10.5% vs. 2.3%), MSH2 (10.5% vs. 1.2%), POLE (5.9% vs. 0.6%), PTEN (10.8% vs. 2.3%), and BRCA1 (5.4% vs. 0.6%). MSI was seen in 20.8% of RT versus 4.8% of LT. RT had a higher frequency of TMB-high regardless of MSI status. CONCLUSION Molecular profiling of AYA CRC revealed different molecular characteristics in RT versus LT. Epigenetic mechanisms and alteration in DNA repair genes warrant further investigation and may be a promising treatment target for CRC in AYA. IMPLICATIONS FOR PRACTICE Colorectal cancer (CRC) in adolescents and young adults (AYA) comprises a distinct entity with different clinicopathologic features and prognosis compared with older patients. Molecular profiling of right- and left-sided tumors in AYA is needed to gain novel insight into CRC biology and to tailor targeted treatment in this age group. This study found that right- and left-sided CRC show distinct molecular features in AYA, overall and in subgroups based on microsatellite instability status. Alterations in DNA double-strand break repair and homologous recombination repair, as well as epigenetic mechanisms, appear to play a critical role. The present molecular profiling data may support the development of personalized treatment strategies in the AYA population.
Collapse
Affiliation(s)
- Mohamed E. Salem
- Department of Medical Oncology, Levine Cancer Institute, Atrium HealthCharlotteNorth CarolinaUSA
| | - Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern CaliforniaLos AngelesCaliforniaUSA
| | | | - Alberto Puccini
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern CaliforniaLos AngelesCaliforniaUSA
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, University of GenoaItaly
| | - Anthony F. Shields
- Department of Oncology, Karmanos Cancer Institute, Wayne State UniversityDetroitMichiganUSA
| | | | - W. Michael Korn
- Caris Life SciencesPhoenixArizonaUSA
- University of California at San FranciscoSan FranciscoCaliforniaUSA
| | - John L. Marshall
- The Ruesch Center and Georgetown Lombardi Comprehensive Cancer CenterWashingtonDCUSA
| | | | - Heinz‐Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern CaliforniaLos AngelesCaliforniaUSA
| |
Collapse
|
|
13
|
Tapial S, Olmedillas-López S, Rueda D, Arriba M, García JL, Vivas A, Pérez J, Pena-Couso L, Olivera R, Rodríguez Y, García-Arranz M, García-Olmo D, González-Sarmiento R, Urioste M, Goel A, Perea J. Cimp-Positive Status is More Representative in Multiple Colorectal Cancers than in Unique Primary Colorectal Cancers. Sci Rep 2019; 9:10516. [PMID: 31324877 PMCID: PMC6642151 DOI: 10.1038/s41598-019-47014-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 07/09/2019] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) with CpG island methylator phenotype (CIMP) is recognized as a subgroup of CRC that shows association with particular genetic defects and patient outcomes. We analyzed CIMP status of 229 individuals with CRC using an eight-marker panel (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1); CIMP-(+) tumors were defined as having ≥ 5 methylated markers. Patients were divided into individuals who developed a "unique" CRC, which were subclassified into early-onset CRC (EOCRC) and late-onset CRC (LOCRC), and patients with multiple primary CRCs subclassified into synchronous CRC (SCRC) and metachronous CRC (MCRC). We found 9 (15.2%) CIMP-(+) EOCRC patients related with the proximal colon (p = 0.008), and 19 (26.8%) CIMP-(+) LOCRC patients associated with tumor differentiation (p = 0.045), MSI status (p = 0.021) and BRAF mutation (p = 0.001). Thirty-five (64.8%) SCRC patients had at least one CIMP-(+) tumor and 20 (44.4%) MCRC patients presented their first tumor as CIMP-(+). Thirty-nine (72.2%) SCRC patients showed concordant CIMP status in their simultaneous tumors. The differences in CIMP-(+) frequency between groups may reflect the importance of taking into account several criteria for the development of multiple primary neoplasms. Additionally, the concordance between synchronous tumors suggests CIMP status is generally maintained in SCRC patients.
Collapse
Affiliation(s)
- Sandra Tapial
- Digestive Cancer Research Group, 12 de Octubre Research Institute, Madrid, Spain
- Hereditary Cancer Laboratory, 12 de Octubre University Hospital, Madrid, Spain
| | - Susana Olmedillas-López
- New Therapies Laboratory, Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid, Spain
| | - Daniel Rueda
- Digestive Cancer Research Group, 12 de Octubre Research Institute, Madrid, Spain
- Hereditary Cancer Laboratory, 12 de Octubre University Hospital, Madrid, Spain
| | - María Arriba
- Department of Biochemistry, Gregorio Marañón University Hospital, Madrid, Spain
| | - Juan L García
- Biomedical Research Institute of Salamanca (IBSAL), University Hospital of Salamanca-USAL-CSIC, Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain
| | - Alfredo Vivas
- Surgery Department, University Hospital 12 de Octubre, Madrid, Spain
| | - Jessica Pérez
- Biomedical Research Institute of Salamanca (IBSAL), University Hospital of Salamanca-USAL-CSIC, Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain
| | - Laura Pena-Couso
- Familial Cancer Clinical Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Rocío Olivera
- New Therapies Laboratory, Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid, Spain
| | - Yolanda Rodríguez
- Pathology Department, University Hospital 12 de Octubre, Madrid, Spain
| | - Mariano García-Arranz
- New Therapies Laboratory, Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid, Spain
| | - Damián García-Olmo
- New Therapies Laboratory, Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid, Spain
- Surgery Department, Fundación Jiménez Díaz University Hospital, Madrid, Spain
| | - Rogelio González-Sarmiento
- Biomedical Research Institute of Salamanca (IBSAL), University Hospital of Salamanca-USAL-CSIC, Salamanca, Spain.
- Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain.
| | - Miguel Urioste
- Familial Cancer Clinical Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER). Institute of Health Carlos III, Madrid, Spain
| | - Ajay Goel
- Beckman Research Institute at City of Hope Comprehensive Cancer Center 1218S, Fifth Avenue, Monrovia, CA, 91016, USA.
| | - José Perea
- Surgery Department, Fundación Jiménez Díaz University Hospital, Madrid, Spain.
| |
Collapse
|
|
14
|
Puccini A, Lenz HJ, Marshall JL, Arguello D, Raghavan D, Korn WM, Weinberg BA, Poorman K, Heeke AL, Philip PA, Shields AF, Goldberg RM, Salem ME. Impact of Patient Age on Molecular Alterations of Left-Sided Colorectal Tumors. Oncologist 2019; 24:319-326. [PMID: 30018131 PMCID: PMC6519749 DOI: 10.1634/theoncologist.2018-0117] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 04/27/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The incidence of colorectal cancer (CRC) in younger patients is rising, mostly due to tumors in the descending colon and rectum. Therefore, we aimed to explore the molecular differences of left-sided CRC between younger (≤45 years) and older patients (≥65). SUBJECTS, MATERIALS, AND METHODS In total, 1,126 CRC tumor samples from the splenic flexure to (and including) the rectum were examined by next-generation sequencing (NGS), immunohistochemistry, and in situ hybridization. Microsatellite instability (MSI) and tumor mutational burden (TMB) were assessed by NGS. RESULTS Younger patients (n = 350), when compared with older patients (n = 776), showed higher mutation rates in genes associated with cancer-predisposing syndromes (e.g., Lynch syndrome), such as MSH6 (4.8% vs. 1.2%, p = .005), MSH2 (2.7% vs. 0.0%, p = .004), POLE (1.6% vs. 0.0%, p = .008), NF1 (5.9% vs. 0.5%, p < .001), SMAD4 (14.3% vs. 8.3%, p = .024), and BRCA2 (3.7% vs. 0.5%, p = .002). Genes involved in histone modification were also significantly more mutated: KDM5C (1.9% vs. 0%, p = .036), KMT2A (1.1% vs. 0%, p = .033), KMT2C (1.6% vs. 0%, p = .031), KMT2D (3.8% vs. 0.7%, p = .005), and SETD2 (3.2% vs. 0.9%, p = .039). Finally, TMB-high (9.7% vs. 2.8%, p < .001) and MSI-high (MSI-H; 8.1% vs. 1.9%, p = .009) were more frequent in younger patients. CONCLUSION Our findings highlight the importance of genetic counseling and screening in younger CRC patients. MSI-H and TMB-high tumors could benefit from immune-checkpoint inhibitors, now approved for the treatment of MSI-H/deficient mismatch repair metastatic CRC patients. Finally, histone modifiers could serve as a new promising therapeutic target. With confirmatory studies, these results may influence our approach to younger adults with CRC. IMPLICATIONS FOR PRACTICE The increasing rate of colorectal cancers (CRC), primarily distal tumors, among young adults poses a global health issue. This study investigates the molecular differences between younger (≤45 years old) and older (≥65) adults with left-sided CRCs. Younger patients more frequently harbor mutations in genes associated with cancer-predisposing syndromes. Higher rates of microsatellite instability-high and tumor mutational burden-high tumors occur in younger patients, who could benefit from immune-checkpoint inhibitors. Finally, histone modifiers are more frequently mutated in younger patients and could serve as a new promising therapeutic target. This study provides new insights into mutations that may guide development of novel tailored therapy in younger CRC patients.
Collapse
Affiliation(s)
- Alberto Puccini
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
- Department of Medical Oncology, Ospedale Policlinico San Martino, Genova, Italy
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - John L Marshall
- Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | | | - Derek Raghavan
- Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, USA
| | | | - Benjamin A Weinberg
- Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | | | - Arielle L Heeke
- Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Philip A Philip
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA
| | - Anthony F Shields
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA
| | - Richard M Goldberg
- West Virginia University Cancer Institute, Morgantown, West Virginia, USA
| | - Mohamed E Salem
- Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina, USA
| |
Collapse
|
|
15
|
Mauri G, Sartore-Bianchi A, Russo AG, Marsoni S, Bardelli A, Siena S. Early-onset colorectal cancer in young individuals. Mol Oncol 2018; 13:109-131. [PMID: 30520562 PMCID: PMC6360363 DOI: 10.1002/1878-0261.12417] [Citation(s) in RCA: 394] [Impact Index Per Article: 56.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 11/01/2018] [Accepted: 11/20/2018] [Indexed: 12/15/2022] Open
Abstract
Treatment of young adults with colorectal cancer (CRC) represents an unmet clinical need, especially as diagnosis in this population might lead to the greatest loss of years of life. Since 1994, CRC incidence in individuals younger than 50 years has been increasing by 2% per year. The surge in CRC incidence in young adults is particularly alarming as the overall CRC frequency has been decreasing. Early-onset CRC are characterized by a more advanced stage at diagnosis, poorer cell differentiation, higher prevalence of signet ring cell histology, and left colon-sided location of the primary tumor. Among EO-CRC, approximately 30% of patients are affected by tumors harboring mutations causing hereditary cancer predisposing syndromes, and 20% have familial CRC. Most notably, the remaining 50% of EO-CRC patients have neither hereditary syndromes nor familial CRC, thus representing a formidable challenge for research. In this review article we summarize epidemiology, clinical and molecular features, heredity and outcome of treatments of EO-CRC, and provide considerations for future perspectives.
Collapse
Affiliation(s)
- Gianluca Mauri
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Dipartimento di Oncologia e Emato-Oncologia, Università degli Studi di Milano (La Statale), Milan, Italy
| | - Andrea Sartore-Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Dipartimento di Oncologia e Emato-Oncologia, Università degli Studi di Milano (La Statale), Milan, Italy
| | | | - Silvia Marsoni
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Dipartimento di Oncologia e Emato-Oncologia, Università degli Studi di Milano (La Statale), Milan, Italy.,FIRC Institute of Molecular Oncology (IFOM), Milan, Italy
| | - Alberto Bardelli
- Department of Oncology, University of Turin, Italy.,Candiolo Cancer Institute - FPO, IRCCS, Turin, Italy
| | - Salvatore Siena
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Dipartimento di Oncologia e Emato-Oncologia, Università degli Studi di Milano (La Statale), Milan, Italy
| |
Collapse
|
|
16
|
Palomo L, Malinverni R, Cabezón M, Xicoy B, Arnan M, Coll R, Pomares H, García O, Fuster-Tormo F, Grau J, Feliu E, Solé F, Buschbeck M, Zamora L. DNA methylation profile in chronic myelomonocytic leukemia associates with distinct clinical, biological and genetic features. Epigenetics 2018; 13:8-18. [PMID: 29160764 DOI: 10.1080/15592294.2017.1405199] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Chromosomal abnormalities are detected in 20-30% of patients with chronic myelomonocytic leukemia (CMML) and correlate with prognosis. On the mutation level, disruptive alterations are particularly frequent in chromatin regulatory genes. However, little is known about the consequential alterations in the epigenetic marking of the genome. Here, we report the analysis of genomic DNA methylation patterns of 64 CMML patients and 10 healthy controls, using a DNA methylation microarray focused on promoter regions. Differential methylation analysis between patients and controls allowed us to identify abnormalities in DNA methylation, including hypermethylation of specific genes and large genome regions with aberrant DNA methylation. Unsupervised hierarchical cluster analysis identified two main clusters that associated with the clinical, biological, and genetic features of patients. Group 1 was enriched in patients with adverse clinical and biological characteristics and poorer overall and progression-free survival. In addition, significant differences in DNA methylation were observed between patients with low risk and intermediate/high risk karyotypes and between TET2 mutant and wild type patients. Taken together, our results demonstrate that altered DNA methylation patterns reflect the CMML disease state and allow to identify patient groups with distinct clinical features.
Collapse
Affiliation(s)
- Laura Palomo
- a MDS Group. Josep Carreras Leukaemia Research Institute (IJC), ICO-Hospital Germans Trias i Pujol , Universitat Autònoma de Barcelona , Carretera de Can Ruti, Camí de les Escoles, s/n. 08916, Badalona ( Barcelona ), Spain.,b Departament de Bioquímica i Biologia Molecular , Universitat Autònoma de Barcelona , Campus de la UAB, Plaça Cívica, s/n. 08913, Bellaterra ( Barcelona ), Spain
| | - Roberto Malinverni
- c Chromatin, Metabolism and Cell Fate Group. Josep Carreras Leukaemia Research Institute (IJC), Campus ICO-Hospital Germans Trias i Pujol , Program for Predictive and Personalized Medicine of Cancer at the Institute Germans Trias i Pujol (PMPPC-IGTP) , Carretera de Can Ruti, Camí de les Escoles, s/n. 08916, Badalona ( Barcelona ), Spain
| | - Marta Cabezón
- d Hematology Service, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC) , Universitat Autònoma de Barcelona , Carretera del Canyet, s/n. 08916, Badalona ( Barcelona ), Spain
| | - Blanca Xicoy
- d Hematology Service, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC) , Universitat Autònoma de Barcelona , Carretera del Canyet, s/n. 08916, Badalona ( Barcelona ), Spain
| | - Montserrat Arnan
- e Hematology Service , ICO-Hospital Duran i Reynals , Avinguda de la Gran Via de l'Hospitalet, 199-203, 08908 Hospitalet de Llobregat ( Barcelona ), Spain
| | - Rosa Coll
- f Hematology Service , ICO-Girona Hospital Josep Trueta, Girona, Spain , Avenida França, s/n. 17007 Girona , Spain
| | - Helena Pomares
- e Hematology Service , ICO-Hospital Duran i Reynals , Avinguda de la Gran Via de l'Hospitalet, 199-203, 08908 Hospitalet de Llobregat ( Barcelona ), Spain
| | - Olga García
- d Hematology Service, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC) , Universitat Autònoma de Barcelona , Carretera del Canyet, s/n. 08916, Badalona ( Barcelona ), Spain
| | - Francisco Fuster-Tormo
- a MDS Group. Josep Carreras Leukaemia Research Institute (IJC), ICO-Hospital Germans Trias i Pujol , Universitat Autònoma de Barcelona , Carretera de Can Ruti, Camí de les Escoles, s/n. 08916, Badalona ( Barcelona ), Spain
| | - Javier Grau
- d Hematology Service, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC) , Universitat Autònoma de Barcelona , Carretera del Canyet, s/n. 08916, Badalona ( Barcelona ), Spain
| | - Evarist Feliu
- d Hematology Service, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC) , Universitat Autònoma de Barcelona , Carretera del Canyet, s/n. 08916, Badalona ( Barcelona ), Spain
| | - Francesc Solé
- a MDS Group. Josep Carreras Leukaemia Research Institute (IJC), ICO-Hospital Germans Trias i Pujol , Universitat Autònoma de Barcelona , Carretera de Can Ruti, Camí de les Escoles, s/n. 08916, Badalona ( Barcelona ), Spain
| | - Marcus Buschbeck
- c Chromatin, Metabolism and Cell Fate Group. Josep Carreras Leukaemia Research Institute (IJC), Campus ICO-Hospital Germans Trias i Pujol , Program for Predictive and Personalized Medicine of Cancer at the Institute Germans Trias i Pujol (PMPPC-IGTP) , Carretera de Can Ruti, Camí de les Escoles, s/n. 08916, Badalona ( Barcelona ), Spain
| | - Lurdes Zamora
- d Hematology Service, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC) , Universitat Autònoma de Barcelona , Carretera del Canyet, s/n. 08916, Badalona ( Barcelona ), Spain
| |
Collapse
|
|
17
|
Mastoraki S, Strati A, Tzanikou E, Chimonidou M, Politaki E, Voutsina A, Psyrri A, Georgoulias V, Lianidou E. ESR1 Methylation: A Liquid Biopsy-Based Epigenetic Assay for the Follow-up of Patients with Metastatic Breast Cancer Receiving Endocrine Treatment. Clin Cancer Res 2017; 24:1500-1510. [PMID: 29284708 DOI: 10.1158/1078-0432.ccr-17-1181] [Citation(s) in RCA: 107] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 05/29/2017] [Accepted: 12/21/2017] [Indexed: 11/16/2022]
Abstract
Purpose: Liquid biopsy provides real-time monitoring of tumor evolution and response to therapy through analysis of circulating tumor cells (CTCs) and plasma-circulating tumor DNA (ctDNA). ESR1 epigenetic silencing potentially affects response to endocrine treatment. We evaluated ESR1 methylation in CTCs and paired plasma ctDNA. We evaluated ESR1 methylation in CTCs and paired plasma ctDNA as a potential biomarker for response to everolimus/exemestane treatment.Experimental Design: A highly sensitive and specific real-time MSP assay for ESR1 methylation was developed and validated in (i) 65 primary breast tumors formalin-fixed paraffin-embedded (FFPE), (ii) EpCAM+ CTC fractions (122 patients and 30 healthy donors; HD), (iii) plasma ctDNA (108 patients and 30HD), and (iv) in CTCs (CellSearch) and in paired plasma ctDNA for 58 patients with breast cancer. ESR1 methylation status was investigated in CTCs isolated from serial peripheral blood samples of 19 patients with ER+/HER2- advanced breast cancer receiving everolimus/exemestane.Results:ESR1 methylation was detected in: (i) 25/65 (38.5%) FFPEs, (ii) EpCAM+ CTC fractions: 26/112 (23.3%) patients and 1/30 (3.3%) HD, and (iii) plasma ctDNA: 8/108 (7.4%) patients and 1/30 (3.3%) HD. ESR1 methylation was highly concordant in 58 paired DNA samples, isolated from CTCs (CellSearch) and corresponding plasma. In serial peripheral blood samples of patients treated with everolimus/exemestane, ESR1 methylation was observed in 10/36 (27.8%) CTC-positive samples, and was associated with lack of response to treatment (P = 0.023, Fisher exact test).Conclusions: We report for the first time the detection of ESR1 methylation in CTCs and a high concordance with paired plasma ctDNA. ESR1 methylation in CTCs was associated with lack of response to everolimus/exemestane regimen. ESR1 methylation should be further evaluated as a potential liquid biopsy-based biomarker. Clin Cancer Res; 24(6); 1500-10. ©2017 AACR.
Collapse
Affiliation(s)
- Sophia Mastoraki
- Analysis of Circulating Tumor Cells, Lab of Analytical Chemistry, Department of Chemistry, University of Athens, Athens, Greece
| | - Areti Strati
- Analysis of Circulating Tumor Cells, Lab of Analytical Chemistry, Department of Chemistry, University of Athens, Athens, Greece
| | - Eleni Tzanikou
- Analysis of Circulating Tumor Cells, Lab of Analytical Chemistry, Department of Chemistry, University of Athens, Athens, Greece
| | - Maria Chimonidou
- Analysis of Circulating Tumor Cells, Lab of Analytical Chemistry, Department of Chemistry, University of Athens, Athens, Greece
| | | | | | - Amanda Psyrri
- Oncology Unit, 2nd Department of Internal Medicine-Propaedeutic, Attikon University Hospital, Haidari, Greece
| | | | - Evi Lianidou
- Analysis of Circulating Tumor Cells, Lab of Analytical Chemistry, Department of Chemistry, University of Athens, Athens, Greece.
| |
Collapse
|
|
18
|
Kozak VN, Kalady MF, Gamaleldin MM, Liang J, Church JM. Colorectal surveillance after segmental resection for young-onset colorectal cancer: is there evidence for extended resection? Colorectal Dis 2017; 19:O386-O392. [PMID: 28865167 DOI: 10.1111/codi.13874] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 08/14/2017] [Indexed: 12/23/2022]
Abstract
AIM Although sporadic colorectal cancer (CRC) usually occurs in patients aged over 50, recent evidence suggests that the incidence is increasing in younger patients. Such patients are theoretically at high risk of metachronous neoplasia and may be candidates for extended prophylactic colectomy. This study aimed to define the risk of metachronous cancer/adenomas during follow-up of younger patients who underwent segmental colectomy for CRC. METHOD A CRC database was used to identify patients aged under 50 who underwent surgery for CRC between 1994 and 2010. Patients diagnosed with hereditary cancer or inflammatory bowel disease were excluded. The primary end-points were frequency of extended resection and the rates of metachronous cancer and high-risk adenomas during follow-up. RESULTS There were 284 young patients with a resectable primary tumour, of whom 280 (98.6%) underwent segmental resection, 3 (1%) extended resection and 1 (0.4%) local resection. Endoscopic follow-up was available for 150 of the patients who had segmental colectomy, with a mean age of 42.6 (±5.8) years at diagnosis and median follow-up time of 68 months (interquartile range 45-105). Out of these 150 patients, 4 (2.7%) developed metachronous colonic adenocarcinoma at 24, 71, 151 and 228 months after index surgery. Thirty additional patients had at least one adenoma identified during surveillance, and three had sessile serrated polyps. Out of the three patients undergoing extended resection, none had metachronous cancer or advanced adenomas at an average follow-up of 17 years. CONCLUSION A segmental colectomy or proctectomy is adequate treatment for patients presenting with CRC under the age of 50.
Collapse
Affiliation(s)
- V N Kozak
- Department of Colorectal Surgery, Digestive Diseases Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - M F Kalady
- Department of Colorectal Surgery, Digestive Diseases Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - M M Gamaleldin
- Department of Colorectal Surgery, Digestive Diseases Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - J Liang
- Department of Colorectal Surgery, Digestive Diseases Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - J M Church
- Department of Colorectal Surgery, Digestive Diseases Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| |
Collapse
|
|
19
|
Liu J, Li H, Sun L, Wang Z, Xing C, Yuan Y. Aberrantly methylated-differentially expressed genes and pathways in colorectal cancer. Cancer Cell Int 2017; 17:75. [PMID: 28794688 PMCID: PMC5545832 DOI: 10.1186/s12935-017-0444-4] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 08/02/2017] [Indexed: 12/12/2022] Open
Abstract
Background Methylation plays an important role in the etiology and pathogenesis of colorectal cancer (CRC). This study aimed to identify aberrantly methylated-differentially expressed genes (DEGs) and pathways in CRC by comprehensive bioinformatics analysis. Methods Data of gene expression microarrays (GSE68468, GSE44076) and gene methylation microarrays (GSE29490, GSE17648) were downloaded from GEO database. Aberrantly methylated-DEGs were obtained by GEO2R. Functional and enrichment analyses of selected genes were performed using DAVID database. Protein–protein interaction (PPI) network was constructed by STRING and visualized in Cytoscape. MCODE was used for module analysis of the PPI network. Results Totally 411 hypomethylation-high expression genes were identified, which were enriched in biological processes of response to wounding or inflammation, cell proliferation and adhesion. Pathway enrichment showed cytokine–cytokine receptor interaction, p53 signaling and cell cycle. The top 5 hub genes of PPI network were CAD, CCND1, ATM, RB1 and MET. Additionally, 239 hypermethylation-low expression genes were identified, which demonstrated enrichment in biological processes including cell–cell signaling, nerve impulse transmission, etc. Pathway analysis indicated enrichment in calcium signaling, maturity onset diabetes of the young, cell adhesion molecules, etc. The top 5 hub genes of PPI network were EGFR, ACTA1, SST, ESR1 and DNM2. After validation in TCGA database, most hub genes still remained significant. Conclusion In summary, our study indicated possible aberrantly methylated-differentially expressed genes and pathways in CRC by bioinformatics analysis, which may provide novel insights for unraveling pathogenesis of CRC. Hub genes including CAD, CCND1, ATM, RB1, MET, EGFR, ACTA1, SST, ESR1 and DNM2 might serve as aberrantly methylation-based biomarkers for precise diagnosis and treatment of CRC in the future.
Collapse
Affiliation(s)
- Jingwei Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, 110001 China
| | - Hao Li
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, 110001 China
| | - Liping Sun
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, 110001 China
| | - Zhenning Wang
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, 110001 China
| | - Chengzhong Xing
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, 110001 China.,Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, 155# North Nanjing Street, Heping District, Shenyang, 110001 Liaoning China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, 110001 China.,Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, 155# North Nanjing Street, Heping District, Shenyang, 110001 Liaoning China
| |
Collapse
|
|
20
|
Chang CC, Lin PC, Lin CC, Lan YT, Lin HH, Lin CH, Yang SH, Liang WY, Chen WS, Jiang JK, Lin JK, Chang SC. Molecular and Clinicopathological Differences by Age at the Diagnosis of Colorectal Cancer. Int J Mol Sci 2017; 18:ijms18071441. [PMID: 28678173 PMCID: PMC5535932 DOI: 10.3390/ijms18071441] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2017] [Revised: 06/27/2017] [Accepted: 06/28/2017] [Indexed: 12/26/2022] Open
Abstract
We compared the clinicopathological and molecular profiles between different age groups of sporadic colorectal cancer (CRC) patients (age <50, 56-60, 60-70, 70-80, and >80); 1475 CRC patients were enrolled after excluding 30 individuals with Lynch syndrome. The mutation spectra for APC, TP53, KRAS, PIK3CA, FBXW7, BRAF, NRAS, HRAS, TGFbR, Akt1, and PTEN were analyzed using polymerase chain reaction (PCR), followed by MassArray and microsatellite (MSI-high) analysis by performing genotyping. Male patients (74.1%) were significantly predominant to females (25.9%) in the older age group (70-80, >80). There was an insignificantly linear trend between TNM staging and age-onset of CRC diagnosis. Patients aged < 50 had 58.7% diseases in the advanced stages (Stage III: 36.5% and IV: 22.2% respectively), while this decreased to 40.2% (Stage III: 26.2% and IV; 14.0% respectively) in patients >80. The distributions of mutation frequency were similar in majority of the genes studied among different age groups. Additionally, patients aged <50 had significantly higher frequency of MSI-high, PTEN, and HRAS mutations than those of other groups. Age-onset at diagnosis significantly affected overall survival (HR = 1.46; 95% CI: 1.35-1.58), but not cancer-specific survival (HR = 1.08; 95% CI: 0.99-1.18) in multivariate analysis. In conclusion, molecular and clinicopathological differences were not as significant among different age groups of CRC patients as previously suspected.
Collapse
Affiliation(s)
- Chu-Cheng Chang
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
- Department of Surgery, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
| | - Pei-Ching Lin
- Department of Clinical Pathology, Yang-Ming Branch, Taipei City Hospital, Taipei 11146, Taiwan.
| | - Chun-Chi Lin
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
- Department of Surgery, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
| | - Yuan-Tzu Lan
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
- Department of Surgery, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
| | - Hung-Hsin Lin
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
- Department of Surgery, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
| | - Chien-Hsing Lin
- Division of Genomic Medicine, National Health Research Institutes, Zhunan 350, Taiwan.
| | - Shung-Haur Yang
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
- Department of Surgery, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
| | - Wen-Yi Liang
- Department of Pathology, Taipei Veterans General Hospital, Taipei 112, Taiwan.
| | - Wei-Shone Chen
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
- Department of Surgery, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
| | - Jeng-Kai Jiang
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
- Department of Surgery, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
| | - Jen-Kou Lin
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
- Department of Surgery, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
| | - Shih-Ching Chang
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
- Department of Surgery, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
- Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei 112, Taiwan.
| |
Collapse
|
|
21
|
Singh MP, Rai S, Suyal S, Singh SK, Singh NK, Agarwal A, Srivastava S. Genetic and epigenetic markers in colorectal cancer screening: recent advances. Expert Rev Mol Diagn 2017; 17:665-685. [PMID: 28562109 DOI: 10.1080/14737159.2017.1337511] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Colorectal cancer (CRC) is a heterogenous disease which develops from benign intraepithelial lesions known as adenomas to malignant carcinomas. Acquired alterations in Wnt signaling, TGFβ, MAPK pathway genes and clonal propagation of altered cells are responsible for this transformation. Detection of adenomas or early stage cancer in asymptomatic patients and better prognostic and predictive markers is important for improving the clinical management of CRC. Area covered: In this review, the authors have evaluated the potential of genetic and epigenetic alterations as markers for early detection, prognosis and therapeutic predictive potential in the context of CRC. We have discussed molecular heterogeneity present in CRC and its correlation to prognosis and response to therapy. Expert commentary: Molecular marker based CRC screening methods still fail to gain trust of clinicians. Invasive screening methods, molecular heterogeneity, chemoresistance and low quality test samples are some key challenges which need to be addressed in the present context. New sequencing technologies and integrated omics data analysis of individual or population cohort results in GWAS. MPE studies following a GWAS could be future line of research to establish accurate correlations between CRC and its risk factors. This strategy would identify most reliable biomarkers for CRC screening and management.
Collapse
Affiliation(s)
- Manish Pratap Singh
- a Department of Biotechnology , Motilal Nehru National Institute of Technology (MNNIT) Allahabad , India
| | - Sandhya Rai
- a Department of Biotechnology , Motilal Nehru National Institute of Technology (MNNIT) Allahabad , India
| | - Shradha Suyal
- a Department of Biotechnology , Motilal Nehru National Institute of Technology (MNNIT) Allahabad , India
| | - Sunil Kumar Singh
- a Department of Biotechnology , Motilal Nehru National Institute of Technology (MNNIT) Allahabad , India
| | - Nand Kumar Singh
- a Department of Biotechnology , Motilal Nehru National Institute of Technology (MNNIT) Allahabad , India
| | - Akash Agarwal
- b Department of Surgical Oncology , Dr. Ram Manohar Lohia Institute of Medical Sciences (DRMLIMS) , Lucknow , India
| | - Sameer Srivastava
- a Department of Biotechnology , Motilal Nehru National Institute of Technology (MNNIT) Allahabad , India
| |
Collapse
|
|
22
|
Sahnane N, Magnoli F, Bernasconi B, Tibiletti MG, Romualdi C, Pedroni M, Ponz de Leon M, Magnani G, Reggiani-Bonetti L, Bertario L, Signoroni S, Capella C, Sessa F, Furlan D. Aberrant DNA methylation profiles of inherited and sporadic colorectal cancer. Clin Epigenetics 2015; 7:131. [PMID: 26697123 PMCID: PMC4687378 DOI: 10.1186/s13148-015-0165-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 12/16/2015] [Indexed: 12/11/2022] Open
Abstract
Background Aberrant DNA methylation has been widely investigated in sporadic colorectal carcinomas (CRCs), and extensive work has been performed to characterize different methylation profiles of CRC. Less information is available about the role of epigenetics in hereditary CRC and about the possible clinical use of epigenetic biomarkers in CRC, regardless of the etiopathogenesis. Long interspersed nucleotide element 1 (LINE-1) hypomethylation and gene-specific hypermethylation of 38 promoters were analyzed in multicenter series of 220 CRCs including 71 Lynch (Lynch colorectal cancer with microsatellite instability (LS-MSI)), 23 CRCs of patients under 40 years in which the main inherited CRC syndromes had been excluded (early-onset colorectal cancer with microsatellite stability (EO-MSS)), and 126 sporadic CRCs, comprising 28 cases with microsatellite instability (S-MSI) and 98 that were microsatellite stable (S-MSS). All tumor methylation patterns were integrated with clinico-pathological and genetic characteristics, namely chromosomal instability (CIN), TP53 loss, BRAF, and KRAS mutations. Results LS-MSI mainly showed absence of extensive DNA hypo- and hypermethylation. LINE-1 hypomethylation was observed in a subset of LS-MSI that were associated with the worse prognosis. Genetically, they commonly displayed G:A transition in the KRAS gene and absence of a CIN phenotype and of TP53 loss. S-MSI exhibited a specific epigenetic profile showing low rates of LINE-1 hypomethylation and extensive gene hypermethylation. S-MSI were mainly characterized by MLH1 methylation, BRAF mutation, and absence of a CIN phenotype and of TP53 loss. By contrast, S-MSS showed a high frequency of LINE-1 hypomethylation and of CIN, and they were associated with a worse prognosis. EO-MSS were a genetically and epigenetically heterogeneous group of CRCs. Like LS-MSI, some EO-MSS displayed low rates of DNA hypo- or hypermethylation and frequent G:A transitions in the KRAS gene, suggesting that a genetic syndrome might still be unrevealed in these patients. By contrast, some EO-MSS showed similar features to those observed in S-MSS, such as LINE-1 hypomethylation, CIN, and TP53 deletion. In all four classes, hypermethylation of ESR1, GATA5, and WT1 was very common. Conclusions Aberrant DNA methylation analysis allows the identification of different subsets of CRCs. This study confirms the potential utility of methylation tests for early detection of CRC and suggests that LINE-1 hypomethylation may be a useful prognostic marker in both sporadic and inherited CRCs. Electronic supplementary material The online version of this article (doi:10.1186/s13148-015-0165-2) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Nora Sahnane
- Department of Surgical and Morphological Sciences, Section of Anatomic Pathology, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy
| | - Francesca Magnoli
- Department of Surgical and Morphological Sciences, Section of Anatomic Pathology, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy
| | - Barbara Bernasconi
- Department of Surgical and Morphological Sciences, Section of Anatomic Pathology, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy
| | | | - Chiara Romualdi
- CRIBI Biotechnology Center, University of Padova, Padua, Italy
| | - Monica Pedroni
- Department of Diagnostic Medicine, Clinical and Public Health, University of Modena and Reggio Emilia, Modena, Italy
| | - Maurizio Ponz de Leon
- Department of Diagnostic Medicine, Clinical and Public Health, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Magnani
- Department of Diagnostic Medicine, Clinical and Public Health, University of Modena and Reggio Emilia, Modena, Italy
| | | | - Lucio Bertario
- Unit of Hereditary Digestive Tract Tumours, Fondazione IRCCS-Istituto Nazionale dei Tumori Milan, Modena, Italy
| | - Stefano Signoroni
- Unit of Hereditary Digestive Tract Tumours, Fondazione IRCCS-Istituto Nazionale dei Tumori Milan, Modena, Italy
| | - Carlo Capella
- Department of Surgical and Morphological Sciences, Section of Anatomic Pathology, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy
| | - Fausto Sessa
- Department of Surgical and Morphological Sciences, Section of Anatomic Pathology, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy
| | - Daniela Furlan
- Department of Surgical and Morphological Sciences, Section of Anatomic Pathology, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy
| | | |
Collapse
|