Detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencing
Abstract Background Hereditary 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...
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| Format: | Article |
| Language: | English |
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BMC
2023-06-01
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| Series: | BMC Medical Genomics |
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| Online Access: | https://doi.org/10.1186/s12920-023-01562-3 |
| _version_ | 1797806471983923200 |
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| author | Ashish Kumar Singh Bente Talseth-Palmer Alexandre Xavier Rodney J. Scott Finn Drabløs Wenche Sjursen |
| author_facet | Ashish Kumar Singh Bente Talseth-Palmer Alexandre Xavier Rodney J. Scott Finn Drabløs Wenche Sjursen |
| author_sort | Ashish Kumar Singh |
| collection | DOAJ |
| description | Abstract Background Hereditary 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. Methods We 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. Results We 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. Conclusions Identification 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. |
| first_indexed | 2024-03-13T06:07:50Z |
| format | Article |
| id | doaj.art-df653a93103441799041e9df5550660a |
| institution | Directory Open Access Journal |
| issn | 1755-8794 |
| language | English |
| last_indexed | 2024-03-13T06:07:50Z |
| publishDate | 2023-06-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Genomics |
| spelling | doaj.art-df653a93103441799041e9df5550660a2023-06-11T11:27:58ZengBMCBMC Medical Genomics1755-87942023-06-0116111310.1186/s12920-023-01562-3Detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencingAshish Kumar Singh0Bente Talseth-Palmer1Alexandre Xavier2Rodney J. Scott3Finn Drabløs4Wenche Sjursen5Department of Medical Genetics, St. Olavs HospitalSchool of Biomedical Science and Pharmacy, Faculty of Health and Medicine, University of Newcastle and Hunter Medical Research InstituteSchool of Biomedical Science and Pharmacy, Faculty of Health and Medicine, University of Newcastle and Hunter Medical Research InstituteSchool of Biomedical Science and Pharmacy, Faculty of Health and Medicine, University of Newcastle and Hunter Medical Research InstituteDepartment of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and TechnologyDepartment of Medical Genetics, St. Olavs HospitalAbstract Background Hereditary 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. Methods We 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. Results We 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. Conclusions Identification 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.https://doi.org/10.1186/s12920-023-01562-3Whole exome sequencing (WES)Colorectal cancer (CRC)Lynch syndrome (LS)Familial colorectal cancer Type X (FCCTX)Mismatch repair (MMR)Copy number variation (CNV) |
| spellingShingle | Ashish Kumar Singh Bente Talseth-Palmer Alexandre Xavier Rodney J. Scott Finn Drabløs Wenche Sjursen Detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencing BMC Medical Genomics Whole exome sequencing (WES) Colorectal cancer (CRC) Lynch syndrome (LS) Familial colorectal cancer Type X (FCCTX) Mismatch repair (MMR) Copy number variation (CNV) |
| title | Detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencing |
| title_full | Detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencing |
| title_fullStr | Detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencing |
| title_full_unstemmed | Detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencing |
| title_short | Detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencing |
| title_sort | detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencing |
| topic | Whole exome sequencing (WES) Colorectal cancer (CRC) Lynch syndrome (LS) Familial colorectal cancer Type X (FCCTX) Mismatch repair (MMR) Copy number variation (CNV) |
| url | https://doi.org/10.1186/s12920-023-01562-3 |
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