The RET proto-oncogene and cancer

Area of Science:

• Genetics
• Oncology
• Endocrinology

Background:

• The RET proto-oncogene, a receptor tyrosine kinase, is implicated in endocrine neoplasias.
• Understanding RET gene mutations is crucial for diagnosing and managing multiple endocrine neoplasia types 2A and 2B (MEN 2A and MEN 2B), familial medullary thyroid carcinoma (FMTC), and sporadic medullary thyroid carcinoma (MTC) and pheochromocytomas.

Purpose of the Study:

• To determine the genomic structure of RET.
• To identify sequence variants in RET associated with MEN 2, FMTC, MTC, and pheochromocytomas.
• To propose a model for RET's action as a dominant oncogene.

Main Methods:

• Genomic DNA analysis using single-strand conformational polymorphism (SSCP).
• Examination of paired tumor and lymphocyte DNA.
• Polymerase chain reaction (PCR) amplification and restriction endonuclease cleavage for mutation detection.

Main Results:

• 21 missense mutations in RET exons 10 and 11 were found in MEN 2A and FMTC families.
• A specific point mutation in RET exon 16 (codon 918) causes all MEN 2B cases.
• Two missense mutations and a deletion were identified in MTC tumors; no mutations found in pheochromocytoma tumors.

Conclusions:

• RET mutations are key drivers for MEN 2A, MEN 2B, FMTC, and some sporadic MTC.
• A predictive DNA test for MEN 2A-associated RET mutations has been developed.
• The RET gene product likely acts as a dominant oncogene in these endocrine tumor syndromes.