Accelerating Discovery of Functional Mutant Alleles in Cancer.

ABSTRACT: Most mutations in cancer are rare, which complicates the identification of therapeutically significant mutations and thus limits the clinical impact of genomic profiling in patients with cancer. Here, we analyzed 24,592 cancers including 10,336 prospectively sequenced patients with advanced disease to identify mutant residues arising more frequently than expected in the absence of selection. We identified 1,165 statistically significant hotspot mutations of which 80% arose in 1 in 1,000 or fewer patients. Of 55 recurrent in-frame indels, we validated that novel AKT1 duplications induced pathway hyperactivation and conferred AKT inhibitor sensitivity. Cancer genes exhibit different rates of hotspot discovery with increasing sample size, with few approaching saturation. Consequently,

SUBMITTER: Chang MT 

PROVIDER: S-EPMC5809279 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature