Cancer-driving mutations are enriched in genic regions intolerant to germline variation

• DOI: 10.1126/sciadv.abo6371
• Publication Date: 2022-08-26T17:57:15Z
• Authors: Dimitrios Vitsios; Ryan S. Dhindsa; Dorota Matelska; Jonathan Mitchell; Xuequing Zou; Joshua Armenia; Fengyuan Hu; Quanli Wang; Ben Sidders; Andrew R. Harper; Slavé Petrovski
• Keywords: Exome

Large reference datasets of protein-coding variation in human populations have allowed us to determine which genes and genic subregions are intolerant germline genetic variation. There is also a growing number implicated severe Mendelian diseases that overlap with cancer. We hypothesized cancer-driving mutations might be enriched depleted relative somatic introduce new metric, OncMTR (oncology missense tolerance ratio), uses 125,748 exomes the Genome Aggregation Database (gnomAD) identify these subregions. demonstrate can significantly predict driver hematologic malignancies. Divergent regions were for cancer-relevant protein domains, overlaying scores on structures identified functionally important residues. Last, we performed rare variant, gene-based collapsing analysis an independent set 394,694 from UK Biobank find markedly improves signals