Widespread Epistasis between Cancer Driver Mutations and Allele-Specific Copy Number Variations.

ABSTRACT: Cancer driver mutations alone are often insufficient to fully explain tumorigenesis. We demonstrate that these mutations cooperate with somatic copy number variations (CNVs) in a tissue-specific pattern of genomic epistasis. Analyzing 93,462 tumors, we identified 54 gene-cancer type pairs with significant co-occurrence of somatic mutations and CNVs. Our new Binoculars algorithm, which resolved phased DNA/RNA reads, revealed frequent preferential amplification in oncogenic mutation alleles, including AKT1 p.E17K, BRAF p.V600E, KRAS p.G12C/D/V, NRAS p.Q61K, and a fraction of gain-of-function TP53 p.R175H. Conversely, deletions selectively targeted the reference alleles, leading to loss of heterozygosity of IDH1 p.R132H and tumor suppressor mutations, including CDKN2A and TP53 t

SUBMITTER: Merzliakov S 

PROVIDER: S-EPMC12710650 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature