ESPE Abstracts (2018) 89 RFC5.5

Evidence for a Founder Effect in Multiple Endocrine Neoplasia 2

Pavlos Fanisa, Nicos Skordisa,b,c, Savvas Frangosd, George Christopoulose, Elena Spanou-Aristidouf, Elena Andreoug, Panayiotis Manolih, Michalis Mavrommatise, Stella Nicolaoui, Marina Kleanthouse, Marios A Cariolouh,j, Violetta Christophidou-Anastasiadouk,f, George A Tantelesf, Leonidas A Phylactoua,j & Vassos Neocleousa

aDepartment of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; bDivision of Pediatric Endocrinology, Paedi Center for Specialized Pediatrics, Nicosia, Cyprus; cSt George’s, University of London Medical School at the University of Nicosia, Nicosia, Cyprus; dNuclear Medicine Department, Bank of Cyprus Oncology Center, Nicosia, Cyprus; eMolecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; fDepartment of Clinical Genetics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; gDasoupolis Endocrinology Center, Andrea Dimitriou Street Dasoupolis, Nicosia, Cyprus; hDepartment of Cardiovascular Genetics and the Laboratory of Forensic Genetics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; iDivision of Pediatric Endocrinology, Makarios III Hospital, Nicosia, Cyprus; jCyprus School of Molecular Medicine, Nicosia, Cyprus; kDepartment of Clinical Genetics, Makarios III Hospital, Nicosia, Cyprus

Purpose: Multiple Endocrine Neoplasia type 2 (MEN2) affects patients with RET proto-oncogene mutations. This cohort study refer to patients who were diagnosed with familial medullary thyroid carcinoma (MTC) and underwent RET genetic testing in Cyprus between years 2002 and 2017.

Methods and Patients: Forty patients underwent RET testing by Sanger sequencing of exons 10–11 and 13–16. Genotyping with STR genetic markers flanking the RET gene along with Y-chromosome genotyping and haplogroup assignment was also performed.

Results: RET mutations were identified in 40 patients from 11 apparently unrelated Cypriot families and two non-familial sporadic cases. Nine probands (69.2%) were heterozygous for p.Cys618Arg, one (7.7%) for p.Cys634Phe, one (7.7%) for the somatic delE632-L633 and two (15.4%) for p.Met918Thr mutations. The mean age at MTC diagnosis of patients carrying p.Cys618Arg was 36.8±14.2 years. The age of pheo diagnosis ranged from 26-43 years and appeared simultaneously with MTC in 5/36 (13.9%) cases. The high frequency of the p.Cys618Arg mutation suggested a possible ancestral mutational event. Haplotype analysis was performed in families with and without p.Cys618Arg. Six microsatellite markers covering the RET gene and neighbouring regions, identified one core haplotype associated with all patients carrying p.Cys618Arg.

Conclusions: The mutation p.Cys618Arg is by far the most prevalent mutation in Cyprus followed by other reported mutations of variable clinical significance. The provided molecular evidence speculates p.Cys618Arg mutation as an ancestral mutation that has spread in Cyprus due to a possible founder effect.