Expression of papillary thyroid carcinoma in multiple endocrine neoplasia type 2A.

BACKGROUND

The ret protooncogene (RET), shown to be rearranged in human papillary thyroid cancers (PTC), has been mapped by in situ hybridization to 10q11.2 near the predisposition locus for the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). To date PTC has not been an observed characteristic of MEN 2; however, linkage studies in affected families have shown no meiotic recombinants between the MEN 2A gene and RET suggesting tight linkage between loci. Furthermore, RET appears to be expressed in medullary thyroid carcinoma (MTC) and pheochromocytoma and for these reasons has emerged as a candidate gene for MEN 2.

METHODS

Two patients from a single kindred with MEN 2A (18 affected) are presented in which expression of PTC appeared to cosegregate with the MEN2 gene. In both patients the diagnosis of occult C-cell disease was suspected by an elevation in the basal and pentagastrin-stimulated peak calcitonin levels. Histologic examination of the thyroid gland after operation for MTC revealed tumor nodules consistent with PTC. There was no history of radiation exposure. Characteristics of MEN 2A syndrome in the kindred in addition to MTC and PTC include hyperparathyroidism and Hirschsprung's disease in three and two patients, respectively.

RESULTS

Two-point linkage analysis with a new highly polymorphic DNA marker, LGfd01, derived from a cosmid clone mapping to 10q11.2 assigns the MEN 2 predisposition locus in this kindred to chromosome 10q11.2 (0 = 0.00; maximum LOD, 4.78). Recombination between MEN 2A and a polymorphic microsatellite from the RET locus could not be shown among informative meioses.

CONCLUSIONS

The observed association of MEN 2A and PTC is intriguing and suggests that the variation in expression of the syndrome may be due to the presence of a structural alteration affecting several contiguous genes spanning the putative MEN 2 region.