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A pan-cancer landscape of somatic mutations in non-unique regions of the human genome

par Tarabichi, Maxime ;Demeulemeester, Jonas;Verfaillie, Annelien;Flanagan, Adrienne Margaret;Van Loo, Peter;Konopka, Tomasz
Référence Nature biotechnology
Publication Publié, 2021-01-01

Article révisé par les pairs

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Résumé :

A substantial fraction of the human genome displays high sequence similarity with at least one other genomic sequence, posing a challenge for the identification of somatic mutations from short-read sequencing data. Here we annotate genomic variants in 2,658 cancers from the Pan-Cancer Analysis of Whole Genomes (PCAWG) cohort with links to similar sites across the human genome. We train a machine learning model to use signals distributed over multiple genomic sites to call somatic events in non-unique regions and validate the data against linked-read sequencing in an independent dataset. Using this approach, we uncover previously hidden mutations in ~1,700 coding sequences and in thousands of regulatory elements, including in known cancer genes, immunoglobulins and highly mutated gene families. Mutations in non-unique regions are consistent with mutations in unique regions in terms of mutation burden and substitution profiles. The analysis provides a systematic summary of the mutation events in non-unique regions at a genome-wide scale across multiple human cancers.