Dataset Information

Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes.

ABSTRACT:

Background

Mutations in several genes predispose to colorectal cancer. Genetic testing for hereditary colorectal cancer syndromes was previously limited to single gene tests; thus, only a very limited number of genes were tested, and rarely those infrequently mutated in colorectal cancer. Next-generation sequencing technologies have made it possible to sequencing panels of genes known and suspected to influence colorectal cancer susceptibility.

Methods

Targeted sequencing of 36 known or putative CRC susceptibility genes was conducted for 1231 CRC cases from five subsets: (1) Familial Colorectal Cancer Type X (n = 153); (2) CRC unselected by tumor immunohistochemical or microsatellite stability testing (n = 548); (3) young onset (age <50 years) (n = 333); (4) proficient mismatch repair (MMR) in cases diagnosed at ≥50 years (n = 68); and (5) deficient MMR CRCs with no germline mutations in MLH1, MSH2, MSH6, or PMS2 (n = 129). Ninety-three unaffected controls were also sequenced.

Results

Overall, 29 nonsense, 43 frame-shift, 13 splice site, six initiator codon variants, one stop codon, 12 exonic deletions, 658 missense, and 17 indels were identified. Missense variants were reviewed by genetic counselors to determine pathogenicity; 13 were pathogenic, 61 were not pathogenic, and 584 were variants of uncertain significance. Overall, we identified 92 cases with pathogenic mutations in APC,MLH1,MSH2,MSH6, or multiple pathogenic MUTYH mutations (7.5%). Four cases with intact MMR protein expression by immunohistochemistry carried pathogenic MMR mutations.

Conclusions

Results across case subsets may help prioritize genes for inclusion in clinical gene panel tests and underscore the issue of variants of uncertain significance both in well-characterized genes and those for which limited experience has accumulated.

SUBMITTER: DeRycke MS

PROVIDER: S-EPMC5606870 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Publications

Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes.

DeRycke Melissa S MS Gunawardena Shanaka S Balcom Jessica R JR Pickart Angela M AM Waltman Lindsey A LA French Amy J AJ McDonnell Shannon S Riska Shaun M SM Fogarty Zachary C ZC Larson Melissa C MC Middha Sumit S Eckloff Bruce W BW Asmann Yan W YW Ferber Matthew J MJ Haile Robert W RW Gallinger Steven S Clendenning Mark M Rosty Christophe C Win Aung K AK Buchanan Daniel D DD Hopper John L JL Newcomb Polly A PA Le Marchand Loic L Goode Ellen L EL Lindor Noralane M NM Thibodeau Stephen N SN

Molecular genetics & genomic medicine 20170723 5

<h4>Background</h4>Mutations in several genes predispose to colorectal cancer. Genetic testing for hereditary colorectal cancer syndromes was previously limited to single gene tests; thus, only a very limited number of genes were tested, and rarely those infrequently mutated in colorectal cancer. Next-generation sequencing technologies have made it possible to sequencing panels of genes known and suspected to influence colorectal cancer susceptibility.<h4>Methods</h4>Targeted sequencing of 36 kn ...[more]

PMID: 28944238

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Dataset Information

Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes.

Background

Methods

Results

Conclusions

Publications

Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes.

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