Frequent somatic gene conversion as a mechanism for loss of heterozygosity in tumor suppressor genes
Abstract
The major processes to carcinogenesis include inactivation of tumor suppressor genes (TSGs). While Knudson's two-hit model requires two independent inactivating mutations, perhaps more frequently, inactivation of a TSG can occur through loss of heterozygosity (LOH) of one inactivating mutation. Deletion and uniparental disomy (UPD) have been well documented as the mechanisms of LOH, but the role of gene conversion is poorly understood. We here developed a simple algorithm to detect somatic gene conversion from short-read sequencing data. We applied it to 6,285 cancer patient samples, from which we found in total 4,978 somatic mutations that underwent gene conversion to achieve LOH. This number accounted for 14.8% of the total LOH mutations. We further demonstrated that LOH by gene conversion was enriched in TSGs, in comparison with non-TSG genes, demonstrating a significant contribution of gene conversion to carcinogenesis.
- Received January 18, 2022.
- Accepted May 18, 2022.
- Published by Cold Spring Harbor Laboratory Press
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see https://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
