Abstract 5011: Potential tumor suppressor role of PHD2 : functional study of mutations identified in germline DNA of patients with congenital polycythemia with or without paraganglioma

The Hypoxia Inducible Factor (HIF) plays a major role in tissue response to hypoxia. HIF induces expression of many genes involved in anaerobic glycolysis, angiogenesis, erythropoiesis and cell proliferation. HIF-alpha subunit is tightly regulated by a family of specific hydroxylases in normoxia. PHD (prolyl-hydroxylase domain) proteins hydroxylate HIF-alpha, thereby allowing its attachment to the VHL protein, a component of an E3 ubiquitin ligase complex involved in protein ubiquitination and degradation. Mutations in HIF regulators have been described and lead to the stabilization of HIF, activation of target genes and development of either tumors or polycythemia. Heterozygous germline mutations in the VHL gene predispose to the von Hippel-Lindau disease characterized by a panel of highly vascularized tumors (central nervous system and retinal hemangioblastomas, pheochromocytomas, renal cell carcinoma, pancreatic endocrine tumors) whereas homozygous or compound heterozygous VHL mutations are responsible for isolated polycythemia (”Chuvash polycythemia”) with high circulating erythropoietin levels. Recently, heterozygous germline mutations in the PHD2 gene have been described in few patients with such congenital polycythemia and a particular mutation (H374R) has been identified in a patient with a polycythemia and a recurrent paraganglioma1. This observation raised the question of a possible role of PHD2 loss of function in the genesis of tumors usually seen in the VHL disease. We report here four new heterozygous PHD2 germline mutations in patients with familial or apparently sporadic polycythemia. We performed a functional study of these mutants compared to the H374R mutant and we showed differences in the capacity of the PHD2 mutants to downregulate HIF-alpha. These differences, tested in various conditions, are highly reproducible and suggest that there may be a genotype/phenotype correlation for the PHD2 mutants like the VHL mutants with their different ability to regulate HIF associated with different phenotypes in the VHL disease. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 5011.