Multiple Endocrine Neoplasia Type 2 in Taiwan: Genetic Diagnosis and Genetic Counseling Procedures

• Main Authors: Chin-Feng Chang, 張金鳳
• Other Authors: 楊偉勛
• Format: Others
• Language: zh-TW
• Published: 2006
• Online Access: http://ndltd.ncl.edu.tw/handle/41319495945285163114

碩士 === 國立臺灣大學 === 分子醫學研究所 === 94 === Multiple endocrine neoplasia type 2 (MEN 2) is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene which has a high penetrance for medullary thyroid carcinoma (MTC). So far, the associations between specific RET mutations (genotype) and the aggressiveness of MTC and variations of other endocrine neoplasia (phenotype) are well expounded. Hot spot mutations in six exons (10, 11, 13, 14, 15, and 16) located in either cysteine-rich or tyrosine kinase domains of RET cause one of three distinctive clinical subtypes: MEN 2A, MEN 2B, and familial MTC. In this study, we propose to elucidate the germ-line RET proto-oncogene mutations and subtypes in Taiwanese subjects with MTC, and evaluate the value of appropriate medical interventions and genetic counseling in afflicted patients and asymptomatic gene carriers. DNA was extracted from the peripheral blood leukocytes of 61 members of 20 unrelated families as having individuals affected by MTC. The suspected carriers and apparently sporadic MTC cases were tested for MEN 2-associated germ-line mutations by polymerase chain reaction (PCR)-based sequencing of the RET gene exons, including 8, 10, 11, 13, 14, 15, and 16. Ten family members in the three MEN 2A kindreds had mutations in codon 634 of exon 11, 1 C > R and 2 C > F. Two family members of one unclassified kindred had the C620F mutation of exon 10. An index case had the C634W germ-line mutation but her family refused the test, could not be defined as hereditary or de novo MEN 2A. Additionally we found 3 de novo cases, including 2 MEN 2B and 1 MEN 2A, with the M918T and C634R mutations, respectively. These mutations were not detected in either of their parents or siblings. The other 12 MTC cases were defined as sporadic MTC whose DNA did not carry any non-synonymous mutations in the 7 exons. We found that all MTC patient with family history or with the other phenotypes of MEN 2 had RET germ-line mutations. For patients with isolated MTC without family history and other endocrine syndromes, we did not find any non-synonymous RET germ-line mutations among the 7 exons. Our findings suggest that all patients with MTC should be screened for the RET proto-oncogene by molecular analysis in order to detect occult or de novo MEN 2 or familial MTC. To date, germ-line genetic testing has become the basis for therapeutic decisions in MEN 2 affected patients and can facilitate the early presymptomatic detections of gene carriers. MEN 2 gives a unique model for early prevention and cure of cancer and for risk stratification of carriers by genetic diagnosis. This provides important insight into the prominent benefits of genetic counseling in cancer therapy.