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Exome-Wide Rare Variant Analysis From the DiscovEHR Study Identifies Novel Candidate Predisposition Genes for Endometrial Cancer.

ABSTRACT: Endometrial cancer is the fourth most commonly diagnosed cancer in women. Family history is a known risk factor for endometrial cancer. The incidence of endometrial cancer in a first-degree relative elevates the relative risk to range between 1.3 and 2.8. It is unclear to what extent or what other novel germline variants are at play in endometrial cancer. We aim to address this question by utilizing whole exome sequencing as a means to identify novel, rare variant associations between exonic regions and endometrial cancer. The MyCode community health initiative is an excellent resource for this study with germline whole exome data for 60,000 patients available in the first phase, and further 30,000 patients independently sequenced in the second phase as part of DiscovEHR study. We conducted exome-wide rare variant association using 472 cases and 4,110 controls in 60,000 patients (discovery cohort); and 261 cases and 1,531 controls from 30,000 patients (replication cohort). After binning rare germline variants into genes, case-control association tests performed using Optimal Unified Approach for Rare-Variant Association, SKAT-O. Seven genes, including RBM12, NDUFB6, ATP6V1A, RECK, SLC35E1, RFX3 (Bonferroni-corrected P < 0.05) and ATP8A1 (suggestive P < 10-5), and one long non-coding RNA, DLGAP4-AS1 (Bonferroni-corrected P < 0.05), were associated with endometrial cancer. Notably, RECK, and ATP8A1 were replicated from the replication cohort (suggestive threshold P < 0.05). Additionally, a pathway-based rare variant analysis, using pathogenic and likely pathogenic variants, identified two significant pathways, pyrimidine metabolism and protein processing in the endoplasmic reticulum (Bonferroni-corrected P < 0.05). In conclusion, our results using the single-source electronic health records (EHR) linked to genomic data highlights candidate genes and pathways associated with endometrial cancer and indicates rare variants involvement in endometrial cancer predisposition, which could help in personalized prognosis and also further our understanding of its genetic etiology.

SUBMITTER: Shivakumar M

PROVIDER: S-EPMC6626914 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Exome-Wide Rare Variant Analysis From the DiscovEHR Study Identifies Novel Candidate Predisposition Genes for Endometrial Cancer.

Shivakumar Manu M Miller Jason E JE Dasari Venkata Ramesh VR Gogoi Radhika R Kim Dokyoon D

Frontiers in oncology 20190705

Endometrial cancer is the fourth most commonly diagnosed cancer in women. Family history is a known risk factor for endometrial cancer. The incidence of endometrial cancer in a first-degree relative elevates the relative risk to range between 1.3 and 2.8. It is unclear to what extent or what other novel germline variants are at play in endometrial cancer. We aim to address this question by utilizing whole exome sequencing as a means to identify novel, rare variant associations between exonic reg ...[more]

PMID: 31338326

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Project description:PurposeTo identify susceptibility genes associated with hereditary predisposition to uveal melanoma (UM) in patients with no detectable germline BAP1 alterations.DesignRetrospective case series from academic referral centers.ParticipantsCohort of 154 UM patients with high risk of hereditary cancer defined as patients with 1 or more of the following: (1) familial UM, (2) young age (<35 years) at diagnosis, (3) personal history of other primary cancers, and (4) family history of 2 or more primary cancers with no detectable mutation or deletion in BAP1 gene.MethodsWhole exome sequencing, a cancer gene panel, or both were carried out. Probands included 27 patients with familial UM, 1 patient with bilateral UM, 1 patient with congenital UM, and 125 UM patients with strong personal or family histories, or both, of cancer. Functional validation of variants was carried out by immunohistochemistry, reverse-transcriptase polymerase chain reaction, and genotyping.Main outcome measuresClinical characterization of UM patients with germline alterations in known cancer genes.ResultsWe identified actionable pathogenic variants in 8 known hereditary cancer predisposition genes (PALB2, MLH1, MSH6, CHEK2, SMARCE1, ATM, BRCA1, and CTNNA1) in 9 patients, including 3 of 27 patients (11%) with familial UM and 6 of 127 patients (4.7%) with a high risk for cancer. Two patients showed pathogenic variants in CHEK2 and PALB2, whereas variants in the other genes each occurred in 1 patient. Biallelic inactivation of PALB2 and MLH1 was observed in tumors from the respective patients. The frequencies of pathogenic variants in PALB2, MLH1, and SMARCE1 in UM patients were significantly higher than the observed frequencies in noncancer controls (PALB2: P = 0.02; odds ratio, 8.9; 95% confidence interval, 1.5-30.6; MLH1: P = 0.04; odds ratio, 25.4; 95% confidence interval, 1.2-143; SMARCE1: P = 0.001; odds ratio, 2047; 95% confidence interval, 52-4.5e15, respectively).ConclusionsThe study provided moderate evidence of gene and disease association of germline mutations in PALB2 and MLH1 with hereditary predisposition to UM. It also identified several other candidate susceptibility genes. The results suggest locus heterogeneity in predisposition to UM. Genetic testing for hereditary predisposition to cancer is warranted in UM patients with strong personal or family history of cancers, or both.

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Dataset Information

Exome-Wide Rare Variant Analysis From the DiscovEHR Study Identifies Novel Candidate Predisposition Genes for Endometrial Cancer.

Publications

Exome-Wide Rare Variant Analysis From the DiscovEHR Study Identifies Novel Candidate Predisposition Genes for Endometrial Cancer.

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