Familial papillary thyroid carcinoma is genetically distinct from familialadenomatous polyposis coli

Familial papillary thyroid carcinoma (fPTC) is an inherited tumor syndrome characterized by isolated papillary thyroid carcinoma (PTC) in affected sub jects. Its etiology is unknown. Large multigeneration families with PTC are very rare, and therefore, modern genetic linkage studies have not been app lied extensively to this disorder. Familial adenomatous polyposis coli (FAP ) is an inherited tumor syndrome enriched in PTC. FAP is caused by germline mutations of the adenomatous polyposis coli (APC) gene that is located in the 5q21 region. It is not known if fPTC is a phenotypic variant of FAP, or if it is a genetically distinct disorder. We report a large 3-generation f PTC kindred and use linkage analysis to test the hypothesis that fPTC and F AP are genetically distinct. In this kindred there are 25 living informativ e subjects; 5 have PTC, and 1 is an obligate carrier. Inheritance is autoso mal dominant with incomplete penetrance. There is vertical transmission, mu ltifocal disease, an average age of onset of 36 years, and 1 subject has co lon cancer. The probability is approximately 1 in 2 billion against the clu stering of 5 sporadic PTC cases in this kindred. To test for linkage to the APC gene we used 2 highly polymorphic markers, D5S656 and D5S421, which ar e located within a maximum distance of 1.7 megabase (Mb) of the APC gene an d within an estimated genetic region of less than 1 centimorgan (cM) from e ach other. After polymerase chain reaction (PCR) amplification 18 family me mbers were genotyped. Construction and inspection of haplotypes showed that the affected subjects do not share the same allelic composition. Using a p enetrance ratio of 75%, linkage was excluded at 2 cM and 3 cM on both sides of D5S656 and D5S421, respectively. The combined haplotype of these 2 mark ers provided an exclusion region of 4 cM. We conclude that fPTC is genetica lly distinct from FAP.