Allele-specific genomic data elucidate the role of somatic gain and copy-number neutral loss of heterozygosity in cancer

Pan-cancer studies sketched the genomic landscape of the tumor types spectrum. We delineated the purity and ploidy-adjusted allele-specific profiles of 4,950 patients across 27 tumor types from the Cancer Genome Atlas (TCGA). Leveraging allele-specific data, we reclassified as loss of heterozygosity (LOH) 9% and 7% of apparent copy-number wild-type and gain calls, respectively, and overall observed more than 18 million allelic imbalance somatic events at the gene level. Reclassification of copy-number events revealed associations between driver mutations and LOH, pointing out the timings between the occurrence of point mutations and copy-number events. Integrating allele-specific genomics and matched transcriptomics, we observed that allele-specific gene status is relevant in the regulation of TP53 and its targets. Further, we disclosed the role of copy-neutral LOH in the impairment of tumor suppressor genes and in disease progression. Our results highlight the role of LOH in cancer and contribute to the understanding of tumor progression.

Automated summary

Pan-cancer studies have provided insights into the genomic landscape of various tumor types. By analyzing allele-specific data from the Cancer Genome Atlas (TCGA), this study reclassified copy-number variations and revealed associations between driver mutations and loss of heterozygosity (LOH). Integration of allele-specific genomics and transcriptomics highlighted the relevance of allele-specific gene status in the regulation of TP53 and its targets. Furthermore, the study identified the role of copy-neutral LOH in the impairment of tumor suppressor genes and disease progression.