Dataset Information

Prevalence of pathogenic germline cancer risk variants in high-risk urothelial carcinoma.

ABSTRACT:

Purpose

To date, there has not been a large, systematic evaluation of the prevalence of germline risk variants in urothelial carcinoma (UC).

Methods

We evaluated the frequency of germline pathogenic and likely pathogenic variants in 1038 patients with high-risk UC who underwent targeted clinical germline testing. Case-control enrichment analysis was performed to screen for pathogenic variant enrichment in 17 DNA repair genes in 1038 UC patients relative to cancer-free individuals.

Results

Among 1038 patients with UC, the cumulative frequency of patients with pathogenic variants was 24%; 18.6% of patients harbored ≥1 actionable germline variant with preventive or therapeutic utility. MSH2 (34/969, 3.5%) and BRCA1/2 (38/867, 4.4%) germline variants had the highest frequency. Germline variants in DNA damage repair genes accounted for 78% of pathogenic germline variants. Compared to the cancer-free cohort, UC patients had significant variant enrichment in MSH2 (odds ratio [OR]: 15.4, 95% confidence interval [CI]: 7.1-32.7, p < 0.0001), MLH1 (OR: 15.9, 95% CI: 4.4-67.7, p < 0.0001), BRCA2 (OR: 5.7, 95% CI: 3.2-9.6, p < 0.0001), and ATM (OR: 3.8, 95% CI: 1.8-8.3, p = 0.02).

Conclusion

In this study, 24% of UC patients harbored pathogenic germline variants and 18.6% had clinically actionable variants. MLH1 and MSH2 were validated as UC risk genes while ATM and BRCA2 were highlighted as potential UC predisposition genes. This work emphasizes the utility of germline testing in selected high-risk UC cohorts.

SUBMITTER: Nassar AH

PROVIDER: S-EPMC7118025 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Publications

Prevalence of pathogenic germline cancer risk variants in high-risk urothelial carcinoma.

Nassar Amin H AH Abou Alaiwi Sarah S AlDubayan Saud H SH Moore Nicholas N Mouw Kent W KW Kwiatkowski David J DJ Choueiri Toni K TK Curran Catherine C Berchuck Jacob E JE Harshman Lauren C LC Nuzzo Pier V PV Chanza Nieves Martinez NM Van Allen Eliezer E Esplin Edward D ED Yang Shan S Callis Thomas T Garber Judy E JE Rana Huma Q HQ Sonpavde Guru G

Genetics in medicine : official journal of the American College of Medical Genetics 20191217 4

<h4>Purpose</h4>To date, there has not been a large, systematic evaluation of the prevalence of germline risk variants in urothelial carcinoma (UC).<h4>Methods</h4>We evaluated the frequency of germline pathogenic and likely pathogenic variants in 1038 patients with high-risk UC who underwent targeted clinical germline testing. Case-control enrichment analysis was performed to screen for pathogenic variant enrichment in 17 DNA repair genes in 1038 UC patients relative to cancer-free individuals. ...[more]

PMID: 31844177

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Project description:PurposeGenomic ascertainment of electronic health record-linked exome data in two large biobanks was used to quantify germline pathogenic/likely pathogenic (P/LP) variant prevalence, cancer prevalence, and survival in adults with non-NF1 RAS/mitogen-activated protein kinase genes (RASopathies).Patients and methodsGermline RASopathy variants were examined from adult participants in UK Biobank (UKBB; n=469,802), Geisinger MyCode (n=167,050) and Mount Sinai BioMe (n=30,470). Variants were classified as per American College of Medical Genetics/Association for Molecular Pathology criteria and reviewed by a RASopathy variant expert. Heterozygotes harbored a RASopathy pathogenic/likely pathogenic variant; controls harbored wild type or benign/likely benign RASopathy variation. To distinguish germline variants from clonal hematopoiesis, benign tissues were Sanger sequenced. Tumor phenotype and demographic data were retrieved from MyCode and UKBB.ResultsPathogenic variants in Noonan syndrome-associated genes (excluding known Noonan syndrome with multiple lentigines variants) were the most common with an estimated prevalence that ranged between 1:1,772-1:3,330 in the three cohorts. Pathogenic variants in cardiofaciocutaneous syndrome-associated genes had an estimated prevalence of 1:41,762-1:55,683 in two cohorts. Pathogenic variants in SPRED1 (Legius syndrome) were more frequent in UKBB (1:19,567 [95%CI: 1:13,150-1:29,116]) compared to MyCode (1:41,762 [95%CI: 1:15,185-1:130,367]). In SPRED1-heterozygotes, cancer prevalence was significantly increased in UKBB (OR:3.8 [95% CI: 2.48-8.64]; p=1.2×10-3) but not in the MyCode cohort. Pathogenic variants in HRAS (Costello syndrome) were not identified. In MyCode and UKBB cohorts, there was no significant increase in cancer prevalence in individuals with Noonan-, CBL- and CFC syndrome-associated pathogenic variants.ConclusionGenomic ascertainment from two large biobanks did not show evidence of elevated cancer risk in adult Noonan syndrome heterozygotes. There may be an increased cancer risk for adult SPRED1 heterozygotes.

Dataset Information

Prevalence of pathogenic germline cancer risk variants in high-risk urothelial carcinoma.

Purpose

Methods

Results

Conclusion

Publications

Prevalence of pathogenic germline cancer risk variants in high-risk urothelial carcinoma.

Similar Datasets

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