Genetic analysis of functional rare germline variants across 9 cancer types from the DiscovEHR study

MedRxiv : the Preprint Server for Health Sciences
Manu ShivakumarDokyoon Kim


Rare variants play an essential role in the etiology of cancer and characterizing rare germline variants that impact the risk of cancer is an ongoing challenge. We performed a genome-wide rare variant analysis using germline whole exome sequencing (WES) data derived from the Geisinger MyCode initiative to discover cancer predisposition variants. The analysis was conducted using 5,538 cancer patients and 7,286 matched controls in a discovery set and 1,991 cancer patients and 2,504 matched controls in a validation set across nine cancer types. The variants in the WES data were annotated and filtered for pathogenic and likely pathogenic variants using ClinVar and Variant Effect Predictor (VEP). After filtering, case-control association tests were conducted on each cancer type separately by binning the pathogenic and likely pathogenic rare variants into genes and pathways using SKAT-O. We discovered 87 genes and 106 pathways significantly associated with cancer (Bonferroni-corrected P < 0.05) out of which seven genes and 26 pathways replicated from the validation set (suggestive threshold P < 0.05). Further, four genes and 21 pathways were discovered to be associated with multiple cancers (Bonferroni-corrected P < 0.05). Additional...Continue Reading

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