title: K-Ras(V14I) -induced Noonan syndrome predisposes to tumour development in mice.
abstract: 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.
authors.affiliation: Molecular Oncology, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Hernández-Porras
authors.affiliation: Molecular Oncology, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Schuhmacher
authors.affiliation: Molecular Oncology, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Garcia-Medina
authors.affiliation: Molecular Oncology, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Jiménez
authors.affiliation: Biotechnology Programs, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.affiliation: Biotechnology Programs, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: de Martino
authors.affiliation: Molecular Oncology, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Guerra
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D006580:Genetic Carrier Screening; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D009634:Noonan Syndrome / Q000235:genetics* / Q000473:pathology; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism
chemical_list: D015513:Oncogene Proteins; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: K-Ras; Noonan syndrome; RASopathies; cancer