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Author information:
Fanis P1, Skordis N1,2,3, Frangos S4, Christopoulos G5, Spanou-Aristidou E6, Andreou E7, Manoli P8, Mavrommatis M5,9, Nicolaou S10, Kleanthous M5,9, Cariolou MA8,9, Christophidou-Anastasiadou V6,11, Tanteles GA6, Phylactou LA12,13, Neocleous V14.
Author information
1 Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683, Nicosia, Cyprus.
2 Division of Pediatric Endocrinology, Paedi Center for Specialized Pediatrics, Nicosia, Cyprus.
3 St George’s, University of London Medical School at the University of Nicosia, Nicosia, Cyprus.
4 Nuclear Medicine Department, Bank of Cyprus Oncology Center, Nicosia, Cyprus.
5 Molecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
6 Department of Clinical Genetics, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683, Nicosia, Cyprus.
7 Dasoupolis Endocrinology Center, Andrea Dimitriou Street Dasoupolis, Nicosia, Cyprus.
8 Department of Cardiovascular Genetics and the Laboratory of Forensic Genetics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
9 Cyprus School of Molecular Medicine, Nicosia, Cyprus.
10 Division of Pediatric Endocrinology, Makarios III Hospital, Nicosia, Cyprus.
11 Department of Clinical Genetics, Makarios III Hospital, Nicosia, Cyprus.
12 Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683, Nicosia, Cyprus. laphylac@cing.ac.cy.
13 Cyprus School of Molecular Medicine, Nicosia, Cyprus. laphylac@cing.ac.cy.
14 Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683, Nicosia, Cyprus. vassosn@cing.ac.cy.

Abstract
PURPOSE:
Multiple endocrine neoplasia type 2 (MEN2) affects patients with RET proto-oncogene mutations. This cohort study refers 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 to 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 neighboring regions identified one core haplotype associated with all patients carrying p.Cys618Arg mutation.

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.

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