A comprehensive survey of Ras mutations in cancer

By I. Prior, P. Lewis, Carla Mattos. Cancer Research, 2012

1,826 citations recorded by the source corpus.

All mammalian cells express three closely related Ras proteins: H-Ras, K-Ras and N-Ras that promote oncogenesis when mutationally activated at codons 12, 13 or 61. Despite a high degree of similarity between the isoforms, K-Ras mutations are far more frequently observed in cancer and each isoform displays preferential coupling to particular cancer types. We have examined the mutation spectra of Ras isoforms curated from large-scale tumour profiling and found that each isoform exhibits surprisingly distinctive codon mutation and amino acid substitution biases. These were unexpected given that these mutations occur in regions that share 100% amino acid sequence identity between the three isoforms. Importantly, many of the 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 together with isoform-specific differences in protein structure and signalling that may promote these distinct mutation patterns and differential coupling to specific cancers.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/30705f36018150c285de28890141197fe0cf971e

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. K. Rossman
2. C. Der

In Oncology

1. K. Rossman
2. G. A. Hobbs
3. C. Der

Citations in the corpus

• Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations (2015, background): “The forces driving these differences have been explored and are likely a combination of the nature of the genotoxic stress causing the mutations (12, 13) and biologic selection with influence from many factors ranging from genomic topology, (14, 15) to protein expression levels (16, 17), and cellula”
• The frequency of Ras mutations in cancer (2020, background): “The frequency of individual mutations in patients also varies across tissue types and between isoforms, suggesting contextual influences that determine which isoform–mutation combinations have a selective advantage in different cancer types (5).”
• Neutron Crystal Structure of RAS GTPase Puts in Question the Protonation State of the GTP γ-Phosphate* (2015, background): “RAS GTPase is at the hub of numerous signaling pathways thatregulatecellproliferation,differentiation, survival, andapoptosis (1) and is mutated in about 20% of all human cancers (2).”
• KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer (2018, background): “1A) However, they are differentially expressed and mutated with different frequencies in cancer (Prior et al. 2012; Cox et al. 2014).”
• RAS isoforms and mutations in cancer at a glance (2016, background): “Further, there are striking cancer-type-specific and isoformdistinct differences in the observed frequencies of specific RAS missense mutations at the three hotspots (Cox et al., 2014; Prior et al., 2012).”
• The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes (2016, neutral): “These classical activating mutations are characteristic in other cancer types 18,19 and are actionable mutations in those settings 20 .”