Does genetic screening increase detection of familial medullary thyroid cancer in apparently sporadic cases?

BACKGROUND Around 25% of all cases of medullary thyroid cancer (MTC) arise as part of the hereditary multiple endocrine neoplasia type 2 (MEN2) syndrome, which is characterized by activating point mutations in the RET proto-oncogene. The remaining 75% of cases are sporadic. OBJECTIVE To report the results of genetic screening for RET mutations performed at a single Italian center over a 13 year period. DESIGN AND INTERVENTION This study enrolled individuals who presented with sporadic or hereditary MTC between 1993 and 2006. First-degree relatives of patients with hereditary disease were also invited to enroll. Genomic DNA was isolated from peripheral blood lymphocytes and subjected to genetic screening for RET mutations. Exons 10, 11, 13, 14, 15, and 16 were analyzed by polymerase chain reaction and DNA sequencing. Patients with MTC and individuals found to be RET mutation carriers were screened annually for clinical and biochemical signs for thyroid, parathyroid and adrenal gland involvement. MTC was confirmed by histological appearance and the presence of cells that stained positive for calcitonin and chromogranin. OUTCOME MEASURES The main outcome measures were the identification of germline RET mutations and the genotype-phenotype correlation. RESULTS Genetic screening was performed in 481 patients with sporadic MTC (60% female; median age 51 years), 37 patients with hereditary MTC (59% female; median age 31 years), and 289 first-degree relatives (50% female; median age 31 years). Clinical follow-up was for 1-25 years. Germline RET mutations were identified in 35 patients who presented with sporadic MTC (7.3%). Mutations in these patients were distributed across several exons; however, non-cysteine-encoding codons were affected in 23 cases (65.7%). In 34 of these patients, MTC was the only endocrine tumor detected (mean followup 8.1 years). Pheochromocytoma was detected 6 years after the initial diagnosis of MTC in the remaining case. By contrast, RET mutations were identified in 36 patients who presented with hereditary MTC (97%). Of these, only 12.9% were detected in non-cysteine-encoding codons. The prevalence of mutations in non-cysteine-encoding codons was, therefore, significantly greater in cases of familial MTC originally diagnosed as sporadic disease than in cases that originally presented as familial MTC (P<0.0001). When all cases of hereditary MTC with mutations in non-cysteine-encoding codons were considered together, the most common mutation was at codon 804 (14 of 27 cases [51.8%]), which results in a substitution of valine to methionine. When genotype was correlated with phenotype, the 72 families with hereditary disease analyzed in this study were characterized as follows: familial MTC (45 families [62.5%]), MEN2A (22 families [30.5%]) and MEN2B (5 families [7.0%]). CONCLUSION Hereditary disease was identified in 7.3% of the apparently sporadic cases of MTC. A strong association between familial MTC previously diagnosed as sporadic disease and RET mutations in non-cysteine-encoding codons was reported. [ABSTRACT FROM AUTHOR]