Detection Of RET Proto-oncogene Mutation In Chinese Families With Hereditary Medullary Thyroid Carcinoma And Its Clinical Significance

Background:Medullary thyroid carcinoma (MTC) arises from parafollicular or C cells that produce calcitonin, and accounts for4-8%of all thyroid cancers. MTC presents worldwide as an autosomal dominant inherited disorder in about25%of cases and as a sporadic tumor in the remainder. Multiple foci, early metastasis, and not sensitive to chemoradiotherapy are biological characteristics of MTC, and prognosis is worse than differentiated thyroid cancer. Early diagnosis and surgical treatment is considered to be the key to its treatment. In recent years, the important role of the RET proto-oncogene mutations in MTC development was well demonstrated, and nearly90%of gene carriers will develop MTC. Genetic screening of RET proto-oncogene has been a powerful tool for the early identification of hereditary MTC. However, the genetic screening of RET in Chinese MTC patients have been reported rarely.Objective:The aim of this study was to investigate the spectrum of predominant germline mutations in seven key exons of RET proto-oncogene and relationship between the phenotype and genotype by detection of RET proto-oncogene germline mutation in Chinese families with hereditary medullary thyroid carcinoma. The mutation carriers will undergo further clinical examination to to determine whether they have affected. Base on the spectrum of predominant germline mutations, we will try to develop the gene screening strategy in China and establish the evidence-based medicine basis of the early molecular diagnosis of hereditary medullary thyroid carcinoma and prophylactic thyroid surgery in our country.Methods:73patients with MTC and39members of their families were recruited voluntarily. Genomic DNA was extracted from peripheral blood leucocytes and the exons8,10,11,13,14,15and16was amplified using polymerase chain reaction. The products were directly sequenced, and then germline mutations of RET proto-oncogene in the exons was analyzed.Results:In73MTC patients, the germline mutations of RET proto-oncogene were detected in10individuals from different families, and23family members were found carrying same mutations with their proband. A total of seven different mutations identified among all of the families studied, distributed in exons10,11, and13. The most of mutations were located at codon634of exonll. The most prevalent mutation was C634R among the afflicted families. The phenotype associated to the mutations on codon634was MEN2A. The incidences of MTC, pheochromocytoma and hyperparathyroidism in MEN2A patients were100%,33.3%and9.5%respectively. The phenotype of family with L790F mutation was categorized as familial MTC. Other families were categorized as unclassified MEN2. Hereditary MTC patients have an earlier age of diagnosis than the sporadic cases (34.7±13.8vs.44.8±10.9yr, P-0.003). Multivariate Logistic regression analysis showed that the risk rank of RET mutation was the only independent risk factors for hereditary MTC stages.Conclusions:The detected mutations of RET proto-oncogene among Chinese hereditary MTC patients and their family members were located in codon606,618of exon10, codon634of exon11and codon790of exon13. The most mutations of RET proto-oncogene were located at codon634. The phenotype associated to the mutations on codon634was MEN2A. The risk rank of RET mutation was the only independent risk factors for hereditary MTC stages. Molecular scanning of the RET gene in Chinese patients with hereditary MTC probably should be limited to exons10,11,13,15and16initially to be cost-effective.