Allele-Specific Genomics is an Orthogonal Feature in the Landscape of Primary Tumors Phenotypes

Pan-cancer studies sketched the genomic landscape of a spectrum of tumor types. We posit that the allele-specific characterization of genomes would nominate yet uncovered biological features relevant to the understanding of human tumors. We herein delineated the allele-specific profiles of 4,950 patients across 27 tumor types. We observed more than 18M allelic imbalance somatic events at the gene level and re-classified as loss of heterozygosity (LOH) 9% and 7% of apparent copy number wild-type and gain, respectively. The allele informed data allowed for the definition of a novel cellularity corrected continuous ploidy score faithfully reflecting the tumor cell DNA amount and revealed novel associations between driver mutations and copy number events. Integrating allele-specific genomics and matched transcriptomics, we disclosed a pervasive haploinsufficiency signal across tumor types and associations with disease progression strongly contributed by copy neutral LOH condition. Our results indicate a previously unappreciated role of allele-specific features in cancer genomes that may contribute to oncogenesis and tumor progression.