EXPRESSION OF PAPILLARY THYROID-CARCINOMA IN MULTIPLE ENDOCRINE NEOPLASIA TYPE-2A

Background. The ret protooncogene (RET), shown to be rearranged in hum an papillary thyroid cancers (PTC), has been mapped by in situ hybridi zation to 10q11.2 near the predisposition locus for the inherited canc er syndrome multiple endocrine neoplasia type 2 (MEN 2). To date PTC h as not been an observed characteristic of MEN 2; however, linkage stud ies in affected families have shown no meiotic recombinants between th e MEN 2A gene and RET suggesting light linkage between loci. Furthermo re, RET appears to be expressed in medullary thyroid carcinoma (MTC) a nd pheochromocytoma and for these reasons has emerged as a candidate g ene for MEN 2. Methods. Two patients from a single kindred with MEN 2A (18 affected) are presented in which expression of PTC appeared to co segregate with the MEN2 gene. In both patients the diagnosis of occult C-cell disease was suspected by an elevation in the basal and pentaga strin-stimulated peak calcitonin levels. Histologic examination of the thyroid gland after operation for MTC revealed tumor nodules consiste nt with PTC. There was no history of radiation exposure. Characteristi cs of MEN 2A syndrome in the kindred in addition to MTC and PTC includ e hyperparathyroidism and Hirschsprung's disease in three and two pati ents, respectively. Results. Two-point linkage analysis with a new hig hly polymorphic DNA marker, LGfd01, derived from a cosmid clone mappin g to 10q11.2 assigns the MEN 2 predisposition locus in this kindred to chromosome 10q11.2 (0 = 0.00; maximum LOD, 4.78). Recombination betwe en MEN 2A and a polymorphic microsatellite from the RET locus could no t be shown among informative meioses. Conclusion. The observed associa tion of MEN 2A and PTC is intriguing and suggests that the variation i n expression of the syndrome may be due to the presence of a structura l alteration affecting several contiguous genes spanning the putative MEN 2 region.