Allelic loss of susceptibility loci and the occurrence of BRAF and RAS mutations in patients with familial non-medullary thyroid cancer

Objectives : Approximately 5% of non-medullary thyroid cancer (NMTC) diagnoses are made against a background of familial predisposition and, in such instances, the disease is termed familial non-medullary thyroid cancer (FNMTC). To date, neither genetic alterations causing FNMTC nor genes predisposing to the condition have been described. The objective of the present study was to evaluate loss of heterozygosity (LOH) at the four known susceptibility loci (fPTC/PRN, NMTC1, MNG1, and TCO1) and to compare the mutation rates of RAS/RAF genes in patients with FNMTC and sporadic NMTC. Methods : Fourteen FNMTCs in patients from seven families were analyzed in terms of involvement of the four susceptibility loci, and 63 thyroid cancer tumors [FNMTC (29) and NMTC (34)] were evaluated for the occurrence of mutations in BRAF, and H-, N-, and K-RAS, using polymerase chain reaction, single-strand conformation polymorphism (PCR-SSCP) analysis, and direct sequencing. Results : Only five (35.7%) tumors showed loss of LOH at the three susceptibility loci (NMTC1, MNG1, or TCO1). These allelic losses did not show a specific pattern. Four (13.8%) FNMTCs and one (2.9%) NMTC had H-RAS (codon 12) mutations. Further, mutation of BRAF V600E was observed in 12 (41.4%) FNMTCs and 29 (85.3%) NMTCs. Conclusion : Four known susceptibility loci are infrequently involved in FNMTC. Although further studies are needed, the present findings additionally suggest that somatic activation of oncogenes via BRAF and RAS mutation plays a role in FNMTC tumorigenesis.restrictio