A Comprehensive Survey of Ras Mutations in Cancer

TLDR

Ras proteins H‑Ras, K‑Ras, and N‑Ras drive oncogenesis when mutated at codons 12, 13, or 61, with K‑Ras mutations occurring far more frequently and each isoform preferentially linked to specific cancer types. The study aims to explore genetic, epigenetic, and isoform‑specific structural and signaling factors that could explain these distinct mutation patterns and their cancer‑type associations. Researchers analyzed mutational spectra of Ras isoforms from large‑scale tumor profiling, revealing distinctive codon and amino‑acid substitution biases for each isoform. These biases were unexpected given the 100 % sequence identity among isoforms, persisted across cancer types, and were not attributable to mutagen exposure. Published in Cancer Research 72(10):2457–67; ©2012 AACR.

Abstract

Abstract All mammalian cells express 3 closely related Ras proteins, termed H-Ras, K-Ras, and N-Ras, that promote oncogenesis when they are mutationally activated at codon 12, 13, or 61. Although there is a high degree of similarity among the isoforms, K-Ras mutations are far more frequently observed in cancer, and each isoform displays preferential coupling to particular cancer types. We examined the mutational spectra of Ras isoforms curated from large-scale tumor profiling and found that each isoform exhibits surprisingly distinctive codon mutation and amino-acid substitution biases. These findings were unexpected given that these mutations occur in regions that share 100% amino-acid sequence identity among the 3 isoforms. Of importance, many of these mutational biases were not due to differences in exposure to mutagens, because the patterns were still evident when compared within specific cancer types. We discuss potential genetic and epigenetic mechanisms, as well as isoform-specific differences in protein structure and signaling, that may promote these distinct mutation patterns and differential coupling to specific cancers. Cancer Res; 72(10); 2457–67. ©2012 AACR.