Different mutations to the same gene lead to different clinical outcomes

Richard Heywood, University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0SP

Since the identification of the first oncogenes in the 1970s, thousands of genes have been identified that drive tumour formation when mutated. For many of these the cellular effects on signalling pathways have been carefully elucidated, and for most of these oncogenes the effect of mutations is always the same. However, for some oncogenes, the site of the mutation affects the biological function of the gene, but until now it was not clear whether this was clinically significant. Ihle et al. report in the Journal of the National Cancer Institute that different mutations to the KRAS gene contribute to different clinical outcomes.

The KRAS gene is a GTPase which is involved in several pro-proliferation and pro-survival pathways, including the PI3K-Akt pathway and the MAPK-Erk pathway. Mutations to KRAS have previously been shown to be prognostically unfavourable in colorectal cancer, predicting a poor response to therapy. The authors obtained biopsies from 268 patients with non-small cell lung cancer (NSCLC), and sequenced the KRAS gene to identify mutations. Of this sample, 48 patients had mutations to KRAS, the majority of which (88%) were in codon 12; of the patients with codon 12 mutations, just over half involved glycine to valine or cysteine substitutions (Gly12Val or Gly12Cys).

The authors found that patients with the Gly12Val or Gly12Cys substitutions had significantly poorer outcome than those with wild type KRAS or other mutations (e.g. codon 13 or 61 mutations). Transcriptomic analysis demonstrated that patients with Gly12Cys or Gly12Val mutations had higher transcript levels of several cell-cycle genes such as PLK1 and CCNB1. They found that patients with Gly12Cys or Gly12Val had lower levels of Akt, but higher levels of RalA and RalB. This suggests that different mutations lead to different downstream signalling pathway activation, leading to different outcomes.

These findings add another layer of complexity to the genetics of NSCLC, but provide evidence that different mutations to KRAS can affect the behaviour of tumour cells, which in turn lead to clinical effects. This could be of value in calculating prognosis, and may also allow future studies to stratify on the basis of mutations status to see if different groups benefit from therapies.

References: 

1. Ihle NT, Byers LA, Kim ES, Saintigny P, Lee JJ, Blumenschein GR, Tsao A, Liu S, Larsen JE, Wang J,Diao L, Coombes KR, Chen L, Zhang S, Abdelmelek MF, Tang X, Papadimitrakopoulou V, Minna JD,Lippman SM, Hong WK, Herbst RS, Wistuba II, Heymach JV, Powis G. Effect of KRAS Oncogene Substitutions on Protein Behavior: Implications for Signaling and Clinical Outcome. Journal of the National Cancer Institute. 2012 Feb 8;104(3):228-39.
doi: 10.1093/jnci/djr523

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