Comprehensive Analysis of Hypermutation in Human Cancer
A partir de données portant sur plus de 81 000 échantillons tumoraux prélevés sur des patients pédiatriques et adultes atteints d'un cancer, cette étude identifie la présence d'un nombre élevé de mutations dans différentes localisations tumorales et, notamment, suggère que ces tumeurs affectées d'une hypermutation suivent des trajectoires évolutionnistes similaires
We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors? tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design.