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RET Exon 11 (G691S) Polymorphism Is Significantly More Frequent in Sporadic Medullary Thyroid Carcinoma Than in the General Population

Departments of Endocrinology and Metabolism (R.E., B.C., C.R., V.B., M.S., A.P.), and Human and Environmental Sciences (R.B.), University of Pisa, 56100 Pisa, Italy; Section of Endocrinology (R.L.), Ospedale F. Lotti, 56025 Pontedera, Pisa, Italy; Department of Internal Medicine, Endocrinology, and Metabolism and Biochemistry (F.P.), University of Siena, 53100 Siena, Italy; and AMBISEN Center (R.B., A.P.), High Technology Center for the Study of the Environmental Damage of the Endocrine and Nervous Systems, University of Pisa, 56124 Pisa, Italy

Address all correspondence and requests for reprints to: R. Elisei, M.D., Department of Endocrinology, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy. E-mail: relisei{at}endoc.med.unipi.it.

The RET protooncogene is constitutively activated by point mutations in hereditary medullary thyroid carcinomas (MTCs). RET somatic point mutations have also been reported in 40–50% of sporadic MTCs. Several single nucleotide polymorphisms of the RET gene have been described in the general population as well as in patients with MTC. These allelic variants do not seem to confer any transforming activity to the tyrosine kinase domain of the RET gene. Because the exon 11 RET polymorphism determines an important aminoacidic variation (G691S), we studied its frequency in 212 subjects, 106 sporadic MTC patients and 106 normal age-, sex-, race-, and geographic origin-matched controls. In 46 cases of sporadic MTCs, we also studied the cosegregation of somatic RET gene mutation and G691S polymorphism as well as the linkage of the polymorphism with RET germline mutation in 60 members of eight multiple endocrine neoplasia type 2 families. The influence of this polymorphism on the RET gene transcription has also been studied. In parallel we analyzed the frequencies of another three neutral polymorphisms (L769L, S836S, S904S). We found a statistically significant (P = 0.029) higher allelic frequency of G691S polymorphism in MTCs (27.83%) than that found in normal controls (18.86%), at variance with the three neutral polymorphisms whose frequencies were not different in patients and controls. With this study we excluded the influence of the G691S polymorphism on RET mRNA expression, the development of the somatic RET mutation, the linkage with the germline RET mutation, the younger onset of the MTCs, and the clinical outcome of the disease. A putative role of the G691S polymorphism as genetic modifier in the normal subjects remains to be established.

This work was supported in part by grants from Ministero dell’Istruzione dell’Università e della Ricerca (ex 40%) 2002 and Associazione Italiana per la Ricerca sul Cancro.

Abbreviations: GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; MTC, medullary thyroid carcinoma.

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