Four Families with RET-Mutation Negative Familial Medullary Thyroid Carcinoma: What Lies Beyond RET?

Presentation Number: PP39-1
Date of Presentation: June 23rd, 2014

Donato Iacovazzo*1, Patrick J. Morrison2, William Foulkes3, Douglas S Ross4, Francesca Lugli5, Plamena Gabrovska1, Emanuela Lucci-Cordisco6, Laura De Marinis5 and Márta Korbonits7
1Barts and The London School of Medicine, London, United Kingdom, 2Belfast City Hospital, Belfast, United Kingdom, 3McGill University, Montreal, Canada, 4Mass General Hospital, Boston, MA, 5Università Cattolica del Sacro Cuore, Rome, Italy, 6Catholic University, Rome, Italy, 7William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom


Familial medullary thyroid carcinoma (MTC) accounts for approximately 25% of MTC cases, and can occur either as part of MEN2-syndrome or as isolated familial MTC (fMTC), defined as more than 10 carriers in the kindred, or multiple carriers or affected members over the age of 50 with an adequate medical history excluding pheochromocytoma. Most MEN2 families (98%), as well as fMTC kindreds (88%), harbour a mutation in the proto-oncogene RET. Moreover, about 7% of apparently sporadic MTC cases carry a RET mutation. Somatic RET mutations in sporadic MTC tumour samples have been identified in 40-50% of cases, while more recently somatic RAS mutations have been identified in 13% of cases from different studies. There are very few reports about RET mutation-negative fMTC. An Italian study analysed 250 families with hereditary MTC and 6 families (2.4%) were RET mutation-negative (Romei C. et al, EJE 2010).

Here we report 4 families with RET mutation-negative fMTC-like phenotype: an Italian family with 11 affected members, a Greek family with 5 affected, a family from Northern Ireland with 3 affected and an Italian-Argentinian family with 2 affected subjects. Several affected members in these families underwent genetic testing, but no mutations have been found of germline DNA at direct sequencing of the whole-coding sequence of RET. Moreover, somatic hotspot RET (M918T, C634, A883F) and RAS mutations (HRAS, KRAS, NRAS – codons 12, 13, 61) have been searched in an MTC tissue sample from the Italian family, but no mutations have been identified. In these families an autosomal dominant inheritance pattern was observed together with high penetrance. The mean age at diagnosis in these patients is 37 yrs (SD 16.4), and interestingly only 2 out of 21 patients presented with distant metastasis at diagnosis, 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.


Disclosure: DSR: Consultant, Novo Nordisk, Consultant, Bayer, Inc.. MK: Advisory Group Member, Pfizer, Inc., Investigator, Pfizer, Inc., Investigator, Novartis Pharmaceuticals. Nothing to Disclose: DI, PJM, WF, FL, PG, EL, LD