Protein Domain Hotspots Reveal Functional Mutations across Genes in Cancer

Abstract

In cancer genomics, frequent recurrence of mutations in independent tumor samples is a strong indication of functional impact. However, rare functional mutations can escape detection by recurrence analysis for lack of statistical power. We address this problem by extending the notion of recurrence of mutations from single genes to gene families that share homologous protein domains. In addition to lowering the threshold of detection, this sharpens the functional interpretation of the impact of mutations, as protein domains more succinctly embody function than entire genes. Mapping mutations in 22 different tumor types to equivalent positions in multiple sequence alignments of protein domains, we confirm well-known functional mutation hotspots and make two types of discoveries: 1) identification and functional interpretation of uncharacterized rare variants in one gene that are equivalent to well-characterized mutations in canonical cancer genes, such as uncharacterized ERBB4 (S303F) mutations that are analogous to canonical ERRB2 (S310F) mutations in the furin-like domain, and 2) detection of previously unknown mutation hotspots with novel functional implications. With the rapid expansion of cancer genomics projects, protein domain hotspot analysis is likely to provide many more leads linking mutations in proteins to the cancer phenotype.