Detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencing

BMC Medical Genomics

Research

Finn Drabløs¹  Wenche Sjursen²  Ashish Kumar Singh²  Alexandre Xavier³  Bente Talseth-Palmer⁴  Rodney J. Scott⁵ 

[1] Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway;Department of Medical Genetics, St. Olavs Hospital, Trondheim, Norway;Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway;School of Biomedical Science and Pharmacy, Faculty of Health and Medicine, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia;School of Biomedical Science and Pharmacy, Faculty of Health and Medicine, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia;Møre and Romsdal Hospital Trust, Research Unit, Ålesund, Norway;NSW Health Pathology, Newcastle, Australia;School of Biomedical Science and Pharmacy, Faculty of Health and Medicine, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia;NSW Health Pathology, Newcastle, Australia;

关键词: Whole exome sequencing (WES);    Colorectal cancer (CRC);    Lynch syndrome (LS);    Familial colorectal cancer Type X (FCCTX);    Mismatch repair (MMR);    Copy number variation (CNV);    Variant annotation;    Variant filtration;   

DOI  :  10.1186/s12920-023-01562-3

 received in 2022-11-24, accepted in 2023-05-30,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundHereditary genetic mutations causing predisposition to colorectal cancer are accountable for approximately 30% of all colorectal cancer cases. However, only a small fraction of these are high penetrant mutations occurring in DNA mismatch repair genes, causing one of several types of familial colorectal cancer (CRC) syndromes. Most of the mutations are low-penetrant variants, contributing to an increased risk of familial colorectal cancer, and they are often found in additional genes and pathways not previously associated with CRC. The aim of this study was to identify such variants, both high-penetrant and low-penetrant ones.MethodsWe performed whole exome sequencing on constitutional DNA extracted from blood of 48 patients suspected of familial colorectal cancer and used multiple in silico prediction tools and available literature-based evidence to detect and investigate genetic variants.ResultsWe identified several causative and some potentially causative germline variants in genes known for their association with colorectal cancer. In addition, we identified several variants in genes not typically included in relevant gene panels for colorectal cancer, including CFTR, PABPC1 and TYRO3, which may be associated with an increased risk for cancer.ConclusionsIdentification of variants in additional genes that potentially can be associated with familial colorectal cancer indicates a larger genetic spectrum of this disease, not limited only to mismatch repair genes. Usage of multiple in silico tools based on different methods and combined through a consensus approach increases the sensitivity of predictions and narrows down a large list of variants to the ones that are most likely to be significant.

【 授权许可】

CC BY   
© The Author(s) 2023

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