Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
Department of Medical and Clinical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Thyroid. 2020 Mar;30(3):380-388. doi: 10.1089/thy.2019.0561.
Familial adenomatous polyposis (FAP) is a condition typically caused by pathogenic germline mutations in the gene. In addition to colon polyps, individuals with FAP have a substantially increased risk of developing papillary thyroid cancer (PTC). Little is known about the events underlying this association, and the prevalence of somatic "second-hit" mutations in is controversial. Whole-genome sequencing was performed on paired thyroid tumor and normal DNA from 12 FAP patients who developed PTC. Somatic mutation profiles were compared with clinical characteristics and previously sequenced sporadic PTC cases. Germline variant profiling was performed to assess the prevalence of variants in genes previously shown to have a role in PTC predisposition. All 12 patients harbored germline mutations in , consistent with FAP. Seven patients also had somatic mutations in , and seven patients harbored somatic mutations in , which encodes a lysine methyl transferase. Mutation of these genes is extremely rare in sporadic PTCs. Notably, only two of the tumors harbored the somatic p.V600E mutation, which is the most common driver mutation found in sporadic PTCs. Six tumors displayed a cribriform-morular variant of PTC (PTC-CMV) histology, and all six had somatic mutations in . Additionally, nine FAP-PTC patients had rare germline variants in genes that were previously associated with thyroid carcinoma. Our data indicate that FAP-associated PTCs typically have distinct mutations compared with sporadic PTCs. Roughly half of the thyroid cancers that arise in FAP patients have somatic "second-hits" in , which is associated with PTC-CMV histology. Somatic p.V600E variants also occur in some FAP patients, a novel finding. We speculate that in carriers of heterozygous pathogenic mutations of tumor suppressor genes such as , a cooperating second-hit somatic variant may occur in a different gene such as or , leading to differences in phenotypes. The role of germline variance in genes other than APC (9 of the 12 patients in this series) needs further research.
家族性腺瘤性息肉病（FAP）通常是由 APC 基因的致病性种系突变引起的。除了结直肠息肉外，FAP 患者发生甲状腺乳头状癌（PTC）的风险显著增加。目前对于这种相关性的潜在机制知之甚少，并且 APC 基因中体细胞“二次打击”突变的发生率存在争议。对 12 例发生 PTC 的 FAP 患者的甲状腺肿瘤和正常 DNA 进行全基因组测序。比较了体细胞突变谱与临床特征和先前测序的散发性 PTC 病例。对种系变异谱进行分析，以评估先前显示与 PTC 易感性相关的基因中的变异发生率。所有 12 例患者均携带 APC 基因的种系突变，符合 FAP 诊断。7 例患者还存在 的体细胞突变，7 例患者存在编码赖氨酸甲基转移酶的 的体细胞突变。这些基因的突变在散发性 PTC 中极为罕见。值得注意的是，只有 2 例肿瘤携带体细胞 p.V600E 突变，这是散发性 PTC 中最常见的驱动突变。6 例肿瘤显示出具有筛状-绒毛状变异型的 PTC（PTC-CMV）组织学特征，且均存在 的体细胞突变。此外，9 例 FAP-PTC 患者在先前与甲状腺癌相关的基因中存在罕见的种系变异。我们的数据表明，与散发性 PTC 相比，FAP 相关的 PTC 通常具有不同的突变。大约一半在 FAP 患者中发生的甲状腺癌存在 的体细胞“二次打击”，这与 PTC-CMV 组织学相关。体细胞 p.V600E 变异也发生在一些 FAP 患者中，这是一个新的发现。我们推测，在 APC 等肿瘤抑制基因的杂合致病性突变携带者中，可能会在另一个基因（如 或 ）中发生协同的体细胞二次打击变异，导致表型的差异。除 APC 以外的基因（本系列中的 12 例患者中有 9 例）的种系变异的作用需要进一步研究。
