Papillary thyroid carcinoma associated with papillary renal neoplasia: genetic linkage analysis of a distinct heritable tumor syndrome

Papillary thyroid carcinoma usually is sporadic, but may occur in a familia l form. The complete clinical and pathological phenotype of familial papill ary thyroid carcinoma (fPTC) has not been determined, and the susceptibilit y gene(s) is unknown. We investigated the clinical and pathological charact eristics of an unusually large three-generation fPTC kindred to characteriz e more fully the clinical phenotype. We performed linkage analysis to deter mine the chromosomal location of a fPTC susceptibility gene. In addition to the known association of fPTC with nodular thyroid disease, we observed th e otherwise rare entity of papillary renal neoplasia (PRN) in two kindred m embers, one affected with PTC and the other an obligate carrier. The multif ocality of PRN in one subject adds weight to the likelihood of a true genet ic predisposition to PRN. Both genetic linkage and sequence analysis exclud ed MET, the protooncogene of isolated familial PRN, as the cause of the fPT C/PRN phenotype. A genome-wide screening and an investigation of specific c andidate genes demonstrated that the fPTC/PRN phenotype was linked to 1q21. A maximum three-point log of likelihood ratio score of 3.58 was observed f or markers D1S2343 and D1S2345 and for markers D1S2343 and D1S305. Critical recombination events limited the region of linkage to approximately 20 cM. A distinct inherited tumor syndrome has been characterized as the familial association of papillary thyroid cancer, nodular thyroid disease, and papi llary renal neoplasia. The predisposing gene in a large kindred with this s yndrome has been mapped to 1q21.