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A novel deletion in the RET proto-oncogene found in sporadic medullary thyroid carcinoma
M Alemi1, S D Lucas, J F Sällström
1Department of Pathology, University of Uppsala, University Hospital, Sweden.
Abstract:
Germ line point mutations in the RET proto-oncogene have been implicated in four inherited disorders: multiple endocrine neoplasia 2A (MEN 2A) and 2B (MEN 2B); familial medullary thyroid carcinoma (FMTC); and Hirschprung's disease, a congenital lack of enteric plexus neurons. Oncogenically activated RET has also been demonstrated in some sporadic medullary thyroid tumors, which show somatic missense mutations in the same regions as those found in MEN 2B. Upon screening archival sporadic MTC tumor tissue by nonradioactive single-strand conformational polymorphism analysis (SSCP), a markedly divergent exon 11 pattern was found in an unusually aggressive neoplasm. Sequencing of PCR amplified DNA revealed the deletion of nine bases encompassing a key cysteine codon at position 1831-3, often altered in MEN 2A. Normal thyroid tissue from the same patient showed a normal SSCP pattern and sequence for this exon. This novel somatic mutation further implicates the RET proto-oncogene in the development of MTC.
Insights
This study identified a novel RET proto-oncogene mutation in sporadic medullary thyroid carcinoma. This finding further implicates RET in the development of aggressive thyroid tumors.
Area of Science:
- Oncology
- Genetics
- Endocrinology
Background:
- Germ line mutations in the RET proto-oncogene are linked to inherited endocrine disorders like MEN 2A, MEN 2B, FMTC, and Hirschsprung's disease.
- Somatic RET mutations are found in sporadic medullary thyroid tumors, often in regions associated with MEN 2B.
Purpose of the Study:
- To investigate the role of the RET proto-oncogene in sporadic medullary thyroid carcinoma (MTC).
- To identify novel mutations in sporadic MTC tumors.
Main Methods:
- Screening of archival sporadic MTC tumor tissue using nonradioactive single-strand conformational polymorphism analysis (SSCP).
- DNA sequencing of PCR amplified DNA from tumor and normal thyroid tissue.
Main Results:
- A divergent exon 11 SSCP pattern was identified in an aggressive sporadic MTC neoplasm.
- Sequencing revealed a novel nine-base deletion in exon 11 of the RET proto-oncogene, affecting a key cysteine codon.
- The same patient's normal thyroid tissue showed a normal sequence for this exon.
Conclusions:
- This novel somatic mutation in the RET proto-oncogene provides further evidence for its role in the pathogenesis of medullary thyroid carcinoma.
- The findings highlight the importance of RET mutations in both inherited and sporadic forms of MTC.