Mutation analysis of NTRK2 and NTRK3, encoding 2 tyrosine kinase receptors, in sporadic human medullary thyroid carcinoma reveals novel sequence variants

Somatic mutations in the proto-oncogene RET are found in 25% to 80% of spor adic medullary thyroid carcinomas (MTCs), The significance of somatic RET m utation in MTC initiation and progression, however, remains unknown. Like R ET, TRK is a neurotrophic receptor tyrosine kinase, Immunostaining has show n that only a subset of normal C cells expresses Trk family receptors, but in C-cell hyperplasia, they consistently express NTRK2, with variable expre ssion of NTRK1 and NTRK3, In later stages of MTC, NTRK2 expression was redu ced while NTRK3 expression was increased. In the context of these data, we sought to determine whether sequence variants in NTRK2 and NTRK3 are respon sible for these differences in protein expression. We determined the genomi c structure of NTRK2 and found that it consists of at least 17 exons varyin g in size from 36 to 306 bp, Mutation analysis of sporadic MTC did not reve al any sequence variants in NTRK2 but did reveal 3 variants in NTRK3, c.573 C>T (N 191N, exon 5), c.678T>C (N226N, exon 6) and c.1488C>G (A496A, exon 1 2) occurring among 19 chromosomes (31%), 1 chromosome (2%) and 24 chromosom es (39%), respectively. Corresponding germline also harbored these variants . There was a trend toward excess association of the NTRK3 variant c.1488C> G (A496A) in cases (24/62 chromosomes, 39%) compared to controls (18/62, 29 %), but this difference did not reach significance (p > 0.05), The remainin g 2 NTRK3 variants occurred with similar frequencies between MTC cases and population-matched controls(19 vs. 17 and 1 vs. 0, p > 0.05), We conclude t hat sequence variants in NTRK2 and NTRK3 are not likely to be responsible f or large differences in expression at the protein level, but we cannot excl ude very low penetrance effects. (C) 2001 Wiley-Liss, Inc.