Estimation of risk of inherited medullary thyroid carcinoma in apparent sporadic patients

Purpose: The study was undertaken to evaluate the frequency of inherited me dullary thyroid carcinoma (MTC) among patients with apparent sporadic disea se. A stepwise algorithm was used depending on clinical indices and the age of patient at MTC diagnosis. Patients and Methods: One hundred sixteen patients with MTC verified by pos toperative pathologic examination were subjected to genetic analysis of RET exons 10, 11, 13, 14, and 16 by means of polymerase chain reaction, restri ction endonuclease digestion, and DNA sequencing. Results: Among 116 apparent sporadic MTC patients, we identified eleven (9. 5%) RET germline mutation carriers. Seven of these (6.0%) were found by rou tine analysis (exons 10 and 11). The frequency of inherited disease among p atients younger than 45 years at diagnosis wets 10.2% by analysis of typica l mutations in exons 10 and 11. Extended genetic analysis (sequencing of ex ons 11, 13, 14, and 16) yielded 6.1% additional diagnoses, giving a risk of 16.3% in this age group. One previously unreported mutation in exon 11 aff ected codon 649 (TCG>TTG, Ser>Leu). In the true sporadic MTC patients young er than 30 years at diagnosis, frequencies of 36% and 4.5% in polymorphic v ariants L769L and S836S, respectively, were observed. The frequency for L76 9L wars higher than in older patients (P < .05). Conclusion: The frequency of inherited disease among apparent sporadic medu llary thyroid carcinoma patients is close to 10% in the Polish population o f MTC patients. The extended analysis of all known RET proto-oncogene mutat ion sites is obligatory in patients younger than 45 years at diagnosis, but we also see she need to analyze the impact of rarer mutations in alder pat ients. J Clin Oncol 19:1374-1380. (C) 2001 by American Society of Clinical Oncology.