Thyroid carcinoma usually occurs in patients with familial adenomatous polyposis in the absence of biallelic inactivation of the adenomatous polyposis coli gene

Papillary thyroid carcinoma (PTC) is a rare extracolonic manifestation of f amilial adenomatous polyposis, determined by germline mutations of the aden omatous polyposis coli (APC) gene. The aim of this study was to assess the presence of loss of heterozygosity of APC in the thyroid tumoral tissue. Sp ecimens from six female patients, aged 20-36, were analyzed for germline an d somatic mutations of the APC gene by restriction enzyme analysis and sequ ence analysis. Five of the six also had analysis for ret/PTC, a chimeric ge ne, the activation of which is restricted to papillary TC. Because a previo us study showed that germline mutations in familial adenomatous polyposis-a ssociated thyroid carcinoma were located between codons 140 and 1513, the s earch for somatic mutations of the APC gene was restricted to this genomic area. Three of the six patients, belonging to the same kindred, had a germl ine mutation at codon 1061. The remaining three, one per kindred, had germl ine mutations at codons 1061, 1061, and 1309, respectively. None of the six patients had loss of heterozygosity for APC or somatic mutation in the exp lored genomic area (codon 545 and codons 1061-1678). Four of five had activ ation of ret/PTC in the thyroid tumoral tissue, as ret/PTC1 isoform. Either APC has a tissue-specific dominant effect in the thyroid gland or th e germline mutation confers a generic susceptibility to cancer development, but other factors (sex-related factors, environmental radiation, modifier genes) are also required for TC development. This usually involves ret/PTC activation, suggesting a possible cooperation between altered function of A PC and gain of function of ret.