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K‐ Ras V14I ‐induced Noonan syndrome predisposes to tumour development in mice
Author(s) -
HernándezPorras Isabel,
Schuhmacher Alberto J,
GarciaMedina Raquel,
Jiménez Beatriz,
Cañamero Marta,
de Martino Alba,
Guerra Carmen
Publication year - 2016
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4719
Subject(s) - noonan syndrome , kras , mutation , oncogene , cancer research , short stature , juvenile myelomonocytic leukemia , genetic predisposition , cancer , carcinogenesis , medicine , genetics , endocrinology , biology , cell cycle , gene , disease , stem cell , haematopoiesis
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.