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Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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Article / Publication DetailsFirst-Page Preview
Received: December 21, 2020
Accepted: August 30, 2021
Published online: October 29, 2021
Number of Print Pages: 10
Number of Figures: 2
Number of Tables: 3
ISSN: 0001-5652 (Print)
eISSN: 1423-0062 (Online)
For additional information: https://www.karger.com/HHE
AbstractBackground: Many cancer types show considerable heritability, and extensive research has been done to identify germline susceptibility variants. Linkage studies have discovered many rare high-risk variants, and genome-wide association studies (GWAS) have discovered many common low-risk variants. However, it is believed that a considerable proportion of the heritability of cancer remains unexplained by known susceptibility variants. The “rare variant hypothesis” proposes that much of the missing heritability lies in rare variants that cannot reliably be detected by linkage analysis or GWAS. Until recently, high sequencing costs have precluded extensive surveys of rare variants, but technological advances have now made it possible to analyze rare variants on a much greater scale. Objectives: In this study, we investigated associations between rare variants and 14 cancer types. Methods: We ran association tests using whole-exome sequencing data from The Cancer Genome Atlas (TCGA) and validated the findings using data from the Pan-Cancer Analysis of Whole Genomes Consortium (PCAWG). Results: We identified four significant associations in TCGA, only one of which was replicated in PCAWG (BRCA1 and ovarian cancer). Conclusions: Our results provide little evidence in favor of the rare variant hypothesis. Much larger sample sizes may be needed to detect undiscovered rare cancer variants.
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Received: December 21, 2020
Accepted: August 30, 2021
Published online: October 29, 2021
Number of Print Pages: 10
Number of Figures: 2
Number of Tables: 3
ISSN: 0001-5652 (Print)
eISSN: 1423-0062 (Online)
For additional information: https://www.karger.com/HHE
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