Germline gain-of-function mutations within genes contributing to the Ras-MAPK pathway have been identified in individuals with the phenotypically overlapping congenital disorders, Noonan syndrome, Costello syndrome, Cardio-facio-cutaneous syndrome, and LEOPARD syndrome, collectively known as neuro-cardio-facial-cutaneous syndromes. The high prevalence of somatic mutations within the human
RAS genes (
KRAS,
NRAS, and
HRAS) and within human
BRAF in adult solid tumor epithelial cancers and melanoma, respectively, suggests that children bearing germline mutations in these genes would be pre-disposed to premature malignancy of epithelial origin or melanoma. In fact, these tumor types are uncommon in children with neuro-cardio-facial-cutaneous syndromes, and the most common tumor types reported are myeloid, myogenic, and neural tumors. Children with Costello syndrome and Noonan syndrome have the highest incidence of malignancies, with a cumulative incidence of cancer by age 20 years being 15% and 4%, respectively (Kratz
et al., 2011). The most common tumor types observed in Costello and Noonan syndromes are rhabdomyosarcoma and neuroblastoma. Bladder cancer of epithelial origin is also observed in adolescents with Costello syndrome. In addition to solid tumors, myeloproliferative disorder (MPD) is observed in children with Noonan syndrome. In the majority of cases, the MPD is transient and benign in nature; however, in some children, it progresses to full-blown juvenile myelomonocytic leukemia. Animal models including knock-in of
HRasG12V , which demonstrates development of squamous papillomas, and knock-ins of
KRasG12D,
Ptpn11D61G, or
Ptpn11D61Y , which demonstrate development of MPD, will be presented to demonstrate their utility in delineating molecular mechanisms underlying malignancies in children bearing these mutations.
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