Frequent somatic gene conversion as a mechanism for loss of heterozygosity in tumor suppressor genes
- 1SOKENDAI, The Graduate University for Advanced Studies, Hayama, Kanagawa 240–0193, Japan;
- 2Laboratory of Plant Genetics, Graduate School of Agriculture, Kyoto University, Kyoto 606–8502, Japan;
- 3Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108–8639, Japan
Abstract
The major processes in carcinogenesis include the inactivation of tumor-suppressor genes (TSGs). Although Knudson's two-hit model requires two independent inactivating mutations, perhaps more frequently, a TSG inactivation can occur through a loss of heterozygosity (LOH) of an inactivating mutation. Deletion and uniparental disomy (UPD) have been well documented as LOH mechanisms, but the role of gene conversion is poorly understood. Here, we developed a simple algorithm to detect somatic gene conversion from short-read sequencing data. We applied it to 6285 cancer patient samples, from which 4978 somatic mutations that underwent gene conversion to achieve LOH were found. This number accounted for 14.8% of the total LOH mutations. We further showed that LOH by gene conversion was enriched in TSGs compared with non-TSG genes, showing a significant contribution of gene conversion to carcinogenesis.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.276617.122.
- Received January 18, 2022.
- Accepted May 18, 2022.
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