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Polymorphisms in RET and Its Coreceptors and Ligands as Genetic Modifiers of Multiple Endocrine Neoplasia Type 2A

¹ Strangeways Research Laboratory, Cancer Research UK Department of Oncology, University of Cambridge; ² EAMGS Molecular Genetics Laboratory, Addenbrooke's Hospital, Cambridge, United Kingdom; ³ Human Cancer Genetics Programme, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain; ⁴ Service d'Endocrinologie, CHU Timone, Marseilles, France; ⁵ Department of Internal Medicine, Ljungby Hospital, Ljungby, Sweden; and ⁶ Laboratoire de Génétique Humaine, Hopital Edouard Herriot, Lyon, France

Requests for reprints: Arancha Cebrian, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, United Kingdom. Phone: 44-1223-740684; Fax: 44-1223-740147; E-mail: arancha{at}srl.cam.ac.uk.

Germ line missense mutations in the RET proto-oncogene are responsible for the inherited cancer syndrome multiple endocrine neoplasia type 2A (MEN2A). The clinical presentation of the disease and the age at onset varies even within families, where patients carry the same mutation. These variations in phenotypes suggest a role for genetic modifiers, and recently, it has been reported that polymorphisms within RET (G691S/S904S) may have such a modifier effect on the age at onset. Here, we investigate whether this observed association could be confirmed in a larger set of 384 individuals from MEN2 families from four different European populations. In addition, we tested as modifiers four other single nucleotide polymorphisms (SNPs), which we have found in a previous association study of RET, its coreceptors, and ligands to be associated with the risk of developing sporadic medullary thyroid carcinoma. We could not replicate the association between G691S/S904S and modifier effects in MEN2A families in any of the four European families analyzed. Of the other SNPs tested, only RET A432A showed a positive weak effect on tumor spectrum within MEN2A, which requires replication in a larger series. (Cancer Res 2006; 66(2): 1177-80)

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