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Novel germline RET proto-oncogene mutations associated with medullary thyroid carcinoma (MTC): mutation analysis in
Y Kitamura1, P J Goodfellow, K Shimizu
1Department of Surgery, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Abstract:
Germ-like and somatic mutations in the RET proto-oncogene are associated with inherited and sporadic medullary thyroid carcinoma (MTC). The majority of patients with multiple endocrine neoplasia type 2A (MEN2A) and familial medullary thyroid carcinoma (FMTC) carry germ-line point mutations that result in the substitution of one of five cysteine residues. We investigated exons 10, 11, 13, 14 and 16 of the RET proto-oncogene in 33 unrelated Japanese patients with MTC. Eleven of the 33 cases (33%) were found to have germ-line mutations. Three previously unreported mutations in exon 10 and 11 were identified: one in codon 620, (TGC-->GGC), resulting in a cysteine to glycine substitution, and two in codon 630, (TGC-->TCC) and (TGC-->TAC), resulting in cysteine to serine and cysteine to tyrosine changes, respectively. The new mutations were present in the germ-line DNA of four unrelated patients for whom a family history of MTC had not been documented. Because the new RET alleles described here involve cysteine residues in a region of protein previously associated with FMTC and MEN2A, it is very likely that they represent mutations that predispose to the development of MTC.
Insights
New RET proto-oncogene mutations predispose to medullary thyroid carcinoma (MTC). Researchers identified three novel germ-line mutations in Japanese MTC patients, suggesting a genetic link to MTC development.
Area of Science:
- Oncology
- Genetics
- Endocrinology
Background:
- Germ-line and somatic mutations in the RET proto-oncogene are linked to medullary thyroid carcinoma (MTC).
- Most Multiple Endocrine Neoplasia type 2A (MEN2A) and Familial Medullary Thyroid Carcinoma (FMTC) patients have germ-line point mutations affecting cysteine residues.
Purpose of the Study:
- To investigate RET proto-oncogene mutations in Japanese MTC patients.
- To identify novel mutations predisposing to MTC.
Main Methods:
- Sequencing of exons 10, 11, 13, 14, and 16 of the RET proto-oncogene.
- Analysis of germ-line DNA from 33 unrelated Japanese MTC patients.
Main Results:
- Germ-line mutations were identified in 11 out of 33 (33%) MTC patients.
- Three novel RET mutations were discovered in exons 10 and 11: Cys620Gly, Cys630Ser, and Cys630Tyr.
- These mutations were found in four unrelated patients without a documented family history of MTC.
Conclusions:
- The newly identified RET mutations involve cysteine residues within a region associated with FMTC and MEN2A.
- These novel RET alleles likely represent predisposing mutations for medullary thyroid carcinoma development.