Positive Germline Selection in Pedigrees With Multiple Endocrine Neoplasia Type 2 Carrying V804M Mutation in the RET Gene

BACKGROUND Multiple endocrine neoplasia (MEN) type 2 is an autosomal dominant cancer syndrome associated with the development of thyroid cancer and tumors or hyperplasia in other endocrine organs. It is caused by mutations in the RET gene and can be phenotypically classified into MEN types 2A and 2B. MEN2B is often sporadic resulting from a spontaneous mutation, M981T. A positive paternal germline selection has been reported for this mutation. METHODS We analyzed the V804M mutation in the RET gene which also affects the intracellular domain of the protein but results in a different phenotype, MEN2A. We compared the observed and expected frequencies of the V804M mutation and the paternal and maternal germline transmission frequency of V804M mutation in three previously reported multigenerational families. RESULTS Our analysis indicates that the observed frequency of the V804M mutation is significantly greater than the expected frequency suggesting positive germline selection (P < 0.001). Furthermore, comparative analysis of observed versus expected transmission frequencies from affected parents shows a higher maternal germline transmission frequency (P = 0.001). CONCLUSIONS Our results suggest that in the RET gene, positive germline selection may extend to mutations other than M918T and, furthermore, at least for the V804M mutation in these families, there is evidence for maternal germline selection.