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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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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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Project description:ImportanceMolecular diagnosis is difficult to achieve in disease groups with a highly heterogeneous genetic background, such as cerebellar ataxia (CA). In many patients, candidate gene sequencing or focused resequencing arrays do not allow investigators to reach a genetic conclusion.ObjectivesTo assess the efficacy of exome-targeted capture sequencing to detect mutations in genes broadly linked to CA in a large cohort of undiagnosed patients and to investigate their prevalence.Design, setting, and participantsThree hundred nineteen index patients with CA and without a history of dominant transmission were included in the this cohort study by the Spastic Paraplegia and Ataxia Network. Centralized storage was in the DNA and cell bank of the Brain and Spine Institute, Salpetriere Hospital, Paris, France. Patients were classified into 6 clinical groups, with the largest being those with spastic ataxia (ie, CA with pyramidal signs [n = 100]). Sequencing was performed from January 1, 2014, through December 31, 2016. Detected variants were classified as very probably or definitely causative, possibly causative, or of unknown significance based on genetic evidence and genotype-phenotype considerations.Main outcomes and measuresIdentification of variants in genes broadly linked to CA, classified in pathogenicity groups.ResultsThe 319 included patients had equal sex distribution (160 female [50.2%] and 159 male patients [49.8%]; mean [SD] age at onset, 27.9 [18.6] years). The age at onset was younger than 25 years for 131 of 298 patients (44.0%) with complete clinical information. Consanguinity was present in 101 of 298 (33.9%). Very probable or definite diagnoses were achieved for 72 patients (22.6%), with an additional 19 (6.0%) harboring possibly pathogenic variants. The most frequently mutated genes were SPG7 (n = 14), SACS (n = 8), SETX (n = 7), SYNE1 (n = 6), and CACNA1A (n = 6). The highest diagnostic rate was obtained for patients with an autosomal recessive CA with oculomotor apraxia-like phenotype (6 of 17 [35.3%]) or spastic ataxia (35 of 100 [35.0%]) and patients with onset before 25 years of age (41 of 131 [31.3%]). Peculiar phenotypes were reported for patients carrying KCND3 or ERCC5 variants.Conclusions and relevanceExome capture followed by targeted analysis allows the molecular diagnosis in patients with highly heterogeneous mendelian disorders, such as CA, without prior assumption of the inheritance mode or causative gene. Being commonly available without specific design need, this procedure allows testing of a broader range of genes, consequently describing less classic phenotype-genotype correlations, and post hoc reanalysis of data as new genes are implicated in the disease.

Dataset Information

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

Publications

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

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