Allelic imbalance of the mutant and wild-type RET allele in MEN 2A-associated medullary thyroid carcinoma

Germline mutations of the RET proto-oncogene are responsible for the famili al tumor syndrome called multiple endocrine neoplasia type 2 (MEN 2) that i ncludes medullary thyroid carcinoma (MTC). Although inherited mutations of RET lead to tumor formation in patients with MEN 2, it is not understood wh y only selected cells develop into tumors. We have recently shown that dupl ication of the mutated RET allele or loss of the wild-type allele might rep resent mechanisms of tumorigenesis in patients with MEN 2A-related pheochro mocytoma. We now analysed 19 DNA samples of MTC (15 of which were non-micro dissected, four of which were microdissected) from patients with MEN 2A. Us ing polymorphic marker and phosphorimage densitometry analyses, we found al lelic imbalance of the mutated and wild-type RET allele in six of 19 DNA MT C samples. Of note, two of the four microdissected tumor DNA samples showed allelic imbalance of RET, whereas only four of the 15 non-microdissected M TC samples did. These results underscore the significance of microdissectio n in the analysis of tumor DNA. In our study, some of the non-microdissecte d tumor DNA samples may have failed to display allelic imbalance of RET, be cause of contamination of tumor DNA with nonneoplastic. DNA or noninformati ve microsatellite marker analysis. Taken together, our results suggest alle lic imbalance between mutated and wild-type RET as a possible mechanism for tumor formation in some patients with MEN 2A-related MTC.