Mutational Analysis of the APC Gene in Cribriform‐Morula Variant of Papillary Thyroid Carcinoma

Introduction Familial adenomatous polyposis (FAP) is an inherited autosomal dominant syndrome caused by germline mutations in the adenomatous polyposis coli (APC) gene. Papillary thyroid cancer is one of the extracolonic manifestations of FAP. A characteristic histologic feature of this type of thyroid tumor is the cribriform‐morula variant of papillary thyroid carcinoma (CMVPTC). Methods To investigate roles of the APC and β‐catenin genes in the development of CMVPTC, we examined germline and somatic mutations of these genes in a female patient with CMVPTC and FAP. The patient had undergone total colectomy at the age of 19 years and total thyroidectomy at age 25 years. Results Numerous tumors were disseminated in both lobes of the thyroid gland, and histopathologic examination revealed typical CMVPTC. DNA was extracted from peripheral blood leukocytes and 12 CMVPTC tumors, and exons 1–15 of the APC gene and exon 3 of the β‐catenin gene were examined. A germline mutation was detected in exon 13 of the APC gene, and this mutation generated a premature stop codon. Six somatic mutations (922delC, 1602delA, 1821delT, 1920delG, 2706del20, 2804insA) were found in the CMVPTC specimens. All mutations were truncating mutations in the N‐terminus of the APC protein. Loss of heterozygosity was not observed in the remaining tumor tissues without somatic APC mutations. There were no mutations of the β‐catenin gene in peripheral blood leukocytes or 12 CMVPTC specimens. Conclusions These results suggest that APC mutations play an important role in the development of CMVPTC and occur predominantly in the 5′ side of the APC gene between codons 308 and 935.