K‐ Ras V14I ‐induced Noonan syndrome predisposes to tumour development in mice

The Noonan syndrome ( NS ) is an autosomal dominant genetic disorder characterized by short stature, craniofacial dysmorphism, and congenital heart defects. A significant proportion of NS patients may also develop myeloproliferative disorders ( MPDs ), including juvenile myelomonocytic leukaemia ( JMML ). Surprisingly, scarce information is available in relation to other tumour types in these patients. We have previously developed and characterized a knock‐in mouse model that carries one of the most frequent KRAS ‐ NS ‐related mutations, the K ‐Ras V14I substitution, which recapitulates most of the alterations described in NS patients, including MPDs. The K ‐Ras V14I mutation is a mild activating K‐Ras protein; thus, we have used this model to study tumour susceptibility in comparison with mice expressing the classical K‐ Ras G12V oncogene. Interestingly, our studies have shown that these mice display a generalized tumour predisposition and not just MPDs. In fact, we have observed that the K ‐Ras V14I mutation is capable of cooperating with the p16Ink4a/p19Arf and Trp53 tumour suppressors, as well as with other risk factors such as pancreatitis, thereby leading to a higher cancer incidence. In conclusion, our results illustrate that the K‐ Ras V14I activating protein is able to induce cancer, although at a much lower level than the classical K‐ Ras G12V oncogene, and that it can be significantly modulated by both genetic and non‐genetic events. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.