Endocrine Abstracts (2014) 34 P425 | DOI: 10.1530/endoabs.34.P425

RET mutation negative familial medullary thyroid carcinoma: four families and literature review

Donato Iacovazzo1,4, Patrick Morrison2, William Foulkes3, Douglas Ross6, Francesca Lugli4, Plamena Gabrovska1, Emanuela Lucci-Cordisco5, Giovanni Neri5, Laura De Marinis4 & Marta Korbonits1

1Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK; 2Regional Medical Genetics Centre, Belfast City Hospital, Belfast, UK; 3Departments of Medicine, Human Genetics and Oncology, McGill University, Montreal, Quebec, Canada; 4Division of Endocrinology, Universita’ Cattolica del Sacro Cuore, Rome, Italy; 5Institute of Medical Genetics, Universita’ Cattolica del Sacro Cuore, Rome, Italy; 6Department of Endocrinology, Harvard Medical School, Boston, Massachusetts, USA.

Approximately 25% of the reported cases of MTC are familial. Familial MTC can occur as part of MEN2-syndrome or as familial MTC alone (fMTC) defined as more than ten carriers in the kindred, or multiple carriers or affected members over the age of 50 with an adequate medical history excluding pheochromocytoma. The vast majority of MEN2 families (98%), as well as fMTC kindreds (88%) harbour a RET mutation. In MEN2A, mutations at codon-634 (exon-11) account for 85% of all mutations so far identified; mutations at codons-609, 611, 618, 620 (within exon-10) account for further cases. In MEN2B, about 95% of patients carry the M918T (exon-16). The 39 RET germline mutations identified in fMTC patients are all missense changes in exons-5, 8, 10, 11, 13, 14, 15, 16, except for a 9-bp duplication after codon-531. About 7% of sporadic MTC cases carry a RET mutation. Somatic RET mutations in sporadic MTC tumour samples have been identified in 40–50% of cases, the most common being M918T. There are very few reports on RET mutation-negative fMTC. An Italian study analysed 250 families with hereditary MTC and six families (2.4%) were RET mutation negative. Here, we report four families with RET negative fMTC: an Italian family with 11 members, a family from Northern Ireland with five affected members, an Italian-Argentinian family with two affected subjects and a Greek family with five affected. Several affected members in these families underwent genetic testing, but no RET mutations have been found at direct sequencing of the whole-coding sequence. An autosomal dominant inheritance pattern was observed together with high penetrance. In the Italian family the mean age at diagnosis is 25.8 years (S.D. 7.8) and interestingly none of the patients have distant metastasis, suggesting a possibly better prognosis compared to RET-related fMTC. Identification of the disease causing mutations in these families might reveal a novel pathway and drug target in MTC.