A comprehensive analysis of MNG1, TCO1, fPTC, PTEN, TSHR, and TRKA in familial nonmedullary thyroid cancer: Confirmation of linkage to TCO1

About 5% of nonmedullary thyroid cancer is familial. These familial nonmedu llary thyroid cancer cases are characterized by an earlier age of onset, mo re aggressive phenotype, and in some families a high propensity to benign t hyroid disease. Little is known about the genes conferring predisposition t o nonmedullary thyroid cancer. Three loci have been identified through gene tic linkage: MNG1 on 14q32, TCO1 on 19p13.2, and fPTC on 1p21. In addition to these putative genes, a number of loci represent candidate familial nonm edullary thyroid cancer predisposition genes by virtue of their involvement in sporadic disease (TRKA), their role in benign disease (TSHR), and becau se they underlie syndromes with a risk of nonmedullary thyroid cancer (PTEN ). To evaluate the roles of MNG1, TCO1, fPTC, PTEN, TSHR, and TRKA in famil ial nonmedullary thyroid cancer, we have carried out a comprehensive mutati on and linkage analysis of these genes in 22 families. One family was linke d to chromosome 19q13.2, confirming that TCO1 underlies a subset of familia l nonmedullary thyroid cancer. None of the families was linked to MNG1 or f PTC, and there was no evidence to support the roles of PTEN, TSHR, or TRKA. Familial nonmedullary thyroid cancer is an emerging clinical phenotype tha t is genetically heterogeneous, and none of the currently identified genes accounts for the majority of families.