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Papillary thyroid carcinoma (PTC) is a rare extracolonic manifestation of familial adenomatous polyposis, determined by germline mutations of the adenomatous 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. Specimens from six female patients, aged 20-36, were analyzed for germline and somatic mutations of the APC gene by restriction enzyme analysis and sequence analysis. Five of the six also had analysis for ret/PTC, a chimeric gene, the activation of which is restricted to papillary TC. Because a previous study showed that germline mutations in familial adenomatous polyposis-associated thyroid carcinoma were located between codons 140 and 1513, the search 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 germline mutation at codon 1061. The remaining three, one per kindred, had germline mutations at codons 1061, 1061, and 1309, respectively. None of the six patients had loss of heterozygosity for APC or somatic mutation in the explored genomic area (codon 545 and codons 1061-1678). Four of five had activation 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 the 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 APC and gain of function of ret.

The recent paper by Soravia et al 1 describes two kindreds with thyroid carcinoma associated with familial adenomatous polyposis (FAP). The former included three and the latter two FAP siblings with papillary thyroid carcinoma (PTC). The patients had a germline mutation of APC, the tumor suppressor gene responsible for FAP, 2 at codons 698 and 313, respectively, and activation of ret/PTC, a chimeric gene that is restricted to the papillary histotype, 3 in the thyroid tumoral tissue of three out of three subjects. Interestingly, ret/PTC was always found as its most frequent isoform, ret/PTC1. 3 This commentary discusses the issues of PTC as an extracolonic manifestation that is integral to FAP, genotype-phenotype correlations, the presence or absence of somatic mutations of the APC gene in the thyroid tumoral tissue, ret/PTC activation, possible cooperation among genes, histological significance of molecular alterations, and the natural history of these particular tumors.