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

Abstract

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.

Sclerosing mucoepidermoid carcinoma with eosinophilia of the thyroid: Case report of a rare lesion with novel genetic mutation

“…In contrast, other primary lesions of the thyroid mimicking salivary gland neoplasms have demonstrated the genetic abnormalities of their primary salivary gland tumor analogues . APC gene mutations have been observed in patients with familial adenomatous polyposis (FAP) who have papillary thyroid carcinoma . There is a strong correlation between cribriform‐morular variant papillary thyroid carcinoma and APC gene mutations …”

“…23,24 APC gene mutations have been observed in patients with familial adenomatous polyposis (FAP) who have papillary thyroid carcinoma. [25][26][27] There is a strong correlation between cribriform-morular variant papillary thyroid carcinoma and APC gene mutations. 28,29 This case report describes a case of a rare thyroid tumor, SMECE, that mimics a primary salivary gland neoplasm.…”

65 YEARS OF THE DOUBLE HELIX: Endocrine tumour syndromes in children and adolescents

“…It is estimated that a third of patients are diagnosed concomitantly with PTC and FAP, a third with PTC and a third with FAP prior to the diagnosis of thyroid cancer. Clinically recognised PTCs develop in 0.4-2.3% of patients with FAP patients, with a female-to-male ratio of 10:1 and occur most often in the first 2 decades (Cetta et al 2000, Steinhagen et al 2012. The actual prevalence is higher (2-12%), as suggested in studies involving thyroid ultrasound surveillance in patients with FAP (Herraiz et al 2007).…”

“…The actual prevalence is higher (2-12%), as suggested in studies involving thyroid ultrasound surveillance in patients with FAP (Herraiz et al 2007). Germline pathogenic variants in APC in patients with PTCs are typically located in the 5′ position of the gene, in the similar genomic area usually associated with congenital retinal pigment epithelial hypertrophy (between codons 457 and 1444) (Cetta et al 2000, Kim et al 2005.…”

Highly penetrant hereditary cancer syndromes

“…There is more concern for the adenomas that invariably form in the second and third portions of the duodenum (97%), especially in the periampullary region, as these present an increased risk (4-12%) for malignancy (Bulow et al, 1995;Heiskanen et al, 1999;Kadmon et al, 2001). Papillary thyroid carcinoma occurs in approximately 2% of individuals with FAP, most often in female carriers, and at an average age of 28 years (Cetta et al, 2000). Other cancers observed in FAP include hepatoblastoma in children (risk of 1.6% to age 6 years), pancreatic carcinoma (approximately 2% lifetime risk), and CNS tumours in the Turcot variant (MIM 276300) (Giardiello et al, 1993(Giardiello et al, , 1996.…”