Abstract 256: Distinct roles for gain and loss of function p53 mutations in medullary thyroid cancer

Medullary thyroid carcinoma (MTC) accounts for 5-10% of all thyroid cancers and presents as metastatic diseases in ∼50% of patients. Patients with metastatic MTC are typically incurable because of the poor tumor response to current chemotherapeutics and radiation treatment. MTC occurs as sporadic tumors in ∼75% of cases. The remaining cases are familial and associated with either multiple neuroendocrine neoplasia syndromes or familial MTC syndrome. The Rearranged during Transfection (RET) proto-oncogene plays a key role in MTC development: however, the absence of RET mutations in ∼50% of sporadic cases and the variable clinical manifestations in patients with the same RET mutation provide compelling evidence that other genetic alterations are involved in MTC pathogenesis. Recent studies in human tumors and mouse models suggest that the Rb and p53 pathways cooperate to suppress MTC evolution. Although some p53 mutations cause a loss of function, most p53 mutations detected in human cancers result in expression of a mutant p53 protein which may exhibit gain of function properties. The objective of this study was to identify the function of p53 mutant proteins commonly expressed in human cancers in MTC pathogenesis. A conditional mouse model was generated in which MTC is initiated by Rb inactivation. Using this model, the consequences of p53 mutant protein expression on MTC initiation and progression were compared to p53 deletion. Loss of a single copy of p53 led to accelerated medullary thyroid tumor progression resulting in decreased survival. Loss of both p53 alleles resulted in a markedly more severe phenotype leading to a median survival of 4 months. Expression of the structural p53 R172H mutant, but not the DNA contact p53 R270H mutant, resulted in accelerated death compared with p53 deletion demonstrating that p53 R172H has a gain of function property. Interestingly, mice heterozygous for p53 R172H/+ and p53 R270H/+ showed similar survival as mice with loss of a single p53 allele providing evidence that neither p53 mutant protein functions in a dominant negative fashion to promote MTC initiated by Rb loss. These results clearly demonstrate that p53 suppresses the progression of MTC initiated by Rb loss and indicate that gain of function p53 mutations confer poorer prognosis than p53 loss. Given the critical roles played by the Rb and p53 pathways in tumor response to therapy, identifying key Rb and p53 functions in MTC pathogenesis is important for future design of therapies to combat these currently treatment resistant malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 256.