Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
Genes Chromosomes Cancer. 2012 Mar;51(3):283-9. doi: 10.1002/gcc.20953. Epub 2011 Nov 25.
Familial adenomatous polyposis (FAP) is an autosomal dominant cancer predisposition syndrome that accounts for approximately 0.5-1% of all colorectal cancer cases. It is caused by germline mutations in the gene encoding the adenomatous polyposis coli (APC) tumor suppressor. Somatic APC inactivation due to mutation or loss of heterozygosity (LOH) promotes the development of adenomatous polyps by stabilizing the transcriptional coactivator β-catenin. Although colorectal cancer is by far the most common malignancy seen in FAP patients, the widespread use of prophylactic colectomy in these patients has increased the clinical importance of extracolonic tumors that are part of the neoplastic spectrum in FAP. Many of these tumors exhibit LOH or somatic APC mutation, strongly supporting a causative role of APC inactivation in their pathogenesis. Here we describe a 47-year-old female FAP patient with clinical manifestations of virilization who was found to have an ovarian steroid cell tumor, a rare neoplasm not known to be associated with FAP. Immunohistochemical analysis of the ovarian tumor demonstrated strong nuclear β-catenin staining consistent with somatic APC inactivation, and molecular analysis confirmed biallelic APC inactivation in the tumor. Our findings provide the first evidence that ovarian steroid cell tumors may be an extracolonic manifestation of FAP and implicate β-catenin activation as an oncogenic mechanism in ovarian steroid cell tumorigenesis.
家族性腺瘤性息肉病（FAP）是一种常染色体显性遗传的癌症易感性综合征，约占所有结直肠癌病例的 0.5-1%。它是由编码腺瘤性结肠息肉病（APC）肿瘤抑制基因的种系突变引起的。由于突变或杂合性丢失（LOH）导致的体细胞 APC 失活，通过稳定转录共激活因子β-连环蛋白，促进了腺瘤性息肉的发展。尽管结直肠癌是迄今为止 FAP 患者中最常见的恶性肿瘤，但这些患者中广泛采用预防性结肠切除术，增加了 FAP 中肿瘤谱的一部分的结外肿瘤的临床重要性。这些肿瘤中的许多表现出 LOH 或体细胞 APC 突变，强烈支持 APC 失活在其发病机制中的因果作用。在这里，我们描述了一位 47 岁的 FAP 女性患者，表现为男性化的临床表现，被发现患有卵巢类固醇细胞瘤，这是一种罕见的与 FAP 无关的肿瘤。对卵巢肿瘤的免疫组织化学分析显示，核β-连环蛋白染色强烈，与体细胞 APC 失活一致，分子分析证实肿瘤中 APC 失活的双等位基因。我们的发现首次提供了证据表明，卵巢类固醇细胞瘤可能是 FAP 的结外表现，并提示β-连环蛋白激活是卵巢类固醇细胞瘤发生的致癌机制。
