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Germline Mutations of the APC Gene in Patients with Familial Adenomatous Polyposis-Associated Thyroid Carcinoma: Results from a European Cooperative Study¹

Interuniversity Center for Research in Hepatobiliary Disease, Institute of Surgical Clinics, University of Siena, 53100 Siena; and the Department of Pathology, University of Chieti (M.C.C., A.C.), 66013 Chieti, Italy; and Fondation Jean Dausset (S.O.), 75010 Paris, France

Address all correspondence and requests for reprints to: Francesco Cetta, M.D., Institute of Surgical Clinics, University of Siena, Nuovo Policlinico, Viale Bracci, 53100 Siena, Italy.

Papillary thyroid carcinoma (PTC) is one extracolonic manifestation affecting about 1–2% of patients with familial adenomatous polyposis (FAP). Ninety-seven patients with FAP-associated PTC have previously been reported, including 6 pairs of siblings. During a European collaborative study, 15 patients with FAP-associated PTC were collected. All 15 patients were females. The mean age at thyroidectomy was 24.9 yr (range, 19–39 yr). In 13 subjects, APC germline mutations had been detected; they were at codons 140, 593, 778, 976, 993, 1061 (n = 5), 1105 (n = 1), and 1309 (n = 2), respectively. A review of the literature added 11 other patients with FAP-associated PTC and detection of germline APC mutations; they were at codons 313 (n = 2), 698 (n = 3), 848 (n = 2), 1209 (n = 2), 1061 (n = 1), and 1105 (n = 1), respectively. The latter led to formation of the same stop codon (TAA) at 1125–1126 as the mutation at codon 1061. Therefore, 21 of 24 mutations were in exon 15 in the genomic area usually associated with congenital hypertrophy of the retinal pigment epithelium (CHRPE), i.e. codons 463-1387. Typical CHRPE was found in 17 of 18 affected patients who had specific screening. Interestingly, 22 of the 24 patients had their mutation out of the mutation cluster region (codons 1286–1513), which is currently considered the hot spot mutation area, in particular for extracolonic manifestations of FAP. The difference in the incidence of germline mutations before and after codon 1220 between PTC and non-PTC FAP patients was statistically significant (P < 0.05) for both patients and kindreds (P = 0.005 and P = 0.049, respectively). Even if most mutations were scattered throughout the entire 5'-portion of exon 15, 8 of 23 patients (6 with mutation at 1061 and 2 with mutation at 1105; i.e. more than one third) had the same truncated protein product. The awareness that patients with PTC usually have APC mutations that cluster in a well defined genomic area, in addition to giving a deeper insight into gene function, could facilitate both earlier diagnosis and better treatment. In particular, intensive screening for thyroid nodules after age 15 yr is recommended when a single patient or an entire kindred have CHRPE and/or mutations in the 5'-portion of exon 15.

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