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 familial tumor syndrome called multiple endocrine neoplasia type 2 (MEN 2) that includes medullary thyroid carcinoma (MTC). Although inherited mutations of RET lead to tumor formation in patients with MEN 2, it is not understood why only selected cells develop into tumors. We have recently shown that duplication of the mutated RET allele or loss of the wild-type allele might represent mechanisms of tumorigenesis in patients with MEN 2A-related pheochromocytoma. We now analysed 19 DNA samples of MTC (15 of which were non-microdissected, four of which were microdissected) from patients with MEN 2A. Using polymorphic marker and phosphorimage densitometry analyses, we found allelic imbalance of the mutated and wild-type RET allele in six of 19 DNA MTC samples. Of note, two of the four microdissected tumor DNA samples showed allelic imbalance of RET, whereas only four of the 15 non-microdissected MTC samples did. These results underscore the significance of microdissection in the analysis of tumor DNA. In our study, some of the non-microdissected tumor DNA samples may have failed to display allelic imbalance of RET, because of contamination of tumor DNA with nonneoplastic DNA or noninformative microsatellite marker analysis. Taken together, our results suggest allelic imbalance between mutated and wild-type RET as a possible mechanism for tumor formation in some patients with MEN 2A-related MTC.
Koch
C A
CA
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Disease (NICHD), National Institutes of Health, Bethesda, Maryland 20892, USA. kochc@exchange.nih.gov
Huang
S C
SC
Moley
J F
JF
Azumi
N
N
Chrousos
G P
GP
Gagel
R F
RF
Zhuang
Z
Z
Pacak
K
K
Vortmeyer
A O
AO
D000483:Alleles; D022981:Allelic Imbalance / Q000235:genetics*; D018276:Carcinoma, Medullary / Q000150:complications / Q000235:genetics*; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D029721:Drosophila Proteins; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D018813:Multiple Endocrine Neoplasia Type 2a / Q000150:complications* / Q000235:genetics*; D016133:Polymerase Chain Reaction; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D011519:Proto-Oncogenes / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000150:complications / Q000235:genetics*
D004273:DNA, Neoplasm; D029721:Drosophila Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila