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.
Highlights
MyCode Community Health initiative is a precision medicine initiative by Geisinger Health System [1]
All patients diagnosed with any type of cancer were retrieved from the cancer registry and a subset of patients with international classification of diseases for oncology (ICD-O) site codes relevant to endometrial cancer, C54.0: Isthmus uteri, C54.1: Endometrium, C54.3: Fundus uteri, and C54.9: Corpus uteri were selected
The results from this study illustrate that a population from a single hospital system can be used to identify rare germline variants associated with endometrial cancer diagnosis
Summary
MyCode Community Health initiative is a precision medicine initiative by Geisinger Health System [1]. As part of the initiative, blood and other samples are collected from the patients who have consented to participate in the MyCode Community Health initiative. The genetic data from DiscovEHR has been successfully used to detect various diseasecausing variants, which confer increased risk to develop one or more of 21 conditions including hereditary breast and ovarian cancer, familial hypercholesterolemia, cardiomyopathy, Marfan syndrome, and Lynch syndrome [2]. The clinically actionable pathogenic variants identified are delivered to the patients through the return of results program at Geisinger Health System and their EHR is updated with the information, which can be readily accessed by their provider [1]. Among Lynch syndrome patients, endometrial cancer is the second most diagnosed condition [3]. The germline abnormalities associated with Lynch syndrome only explain a small fraction of heritability of endometrial cancer, which suggests there are other rare germline variants that can help explain the heritability of the disease
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