Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia.
Department of Biostatistics, Epidemiology & Scientific Computing, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia.
J Clin Endocrinol Metab. 2023 Aug 18;108(9):e704-e711. doi: 10.1210/clinem/dgad185.
Diffuse sclerosing papillary thyroid cancer (DSPTC) is rare, with limited data on its molecular genetics.
We studied the molecular genetics of a cohort of DSPTC.
DNA was isolated from paraffin blocks of 22 patients with DSPTC (15 females, 7 males, median age 18 years, range 8-81). We performed polymerase chain reaction-based Sanger sequencing and a next-generation sequencing (NGS) gene panel to characterize the genomic landscape of these tumors. We classified genetic alterations to definitely or probably pathogenic. Definitely pathogenic are genetic alterations that are well known to be associated with PTC (e.g., BRAFV600E). Probably pathogenic are other alterations in genes that were reported in The Cancer Genome Atlas or the poorly differentiated and anaplastic thyroid cancer datasets.
Three tumors were tested only by Sanger sequencing and were negative for BRAFV600E, HRAS, KRAS, NRAS, TERT promoter, PTEN, and PIK3CA mutations. The other 19 tumors tested by NGS showed definitely pathogenic alterations in 10 patients (52.6%): 2/19 (10.5%) BRAFV600E, 5/19 (26.3%) CCDC6-RET (RET/PTC1), 1/19 (5.3%) NCOA4-RET (RET/PTC3), 1/19 (5.3%) STRN-ALK fusion, and 2/19 (10.6%) TP53 mutations. Probably pathogenic alterations occurred in 13/19 tumors (68.4%) and included variants in POLE (31.6%), CDKN2A (26%), NF1 (21%), BRCA2 (15.8%), SETD2 (5.3%), ATM (5.3%), FLT3 (5.3%), and ROS1 (5.3%). In 1 patient, the gene panel showed no alterations. No mutations were found in the RAS, PTEN, PIK3CA, or TERT promoter in all patients. There was no clear genotype/phenotype correlation.
In DSPTC, fusion genes are common, BRAFV600E is rare, and other usual point mutations are absent. Pathogenic and likely pathogenic variants in POLE, NF1, CDKN2A, BRCA2, TP53, SETD2, ATM, FLT3, and ROS1 occur in about two-thirds of DTPTC.
弥漫性硬化性乳头状甲状腺癌（DSPTC）较为罕见，其分子遗传学数据有限。
我们研究了一组 DSPTC 患者的分子遗传学特征。
从 22 例 DSPTC 患者的石蜡块中提取 DNA（15 例女性，7 例男性，中位年龄 18 岁，范围 8-81 岁）。我们采用聚合酶链反应（PCR）-Sanger 测序和下一代测序（NGS）基因panel 来分析这些肿瘤的基因组图谱。我们将基因改变分类为明确或可能为致病性的。明确致病性的是那些已知与甲状腺癌（PTC）相关的基因改变（如 BRAFV600E）。可能致病性的是在癌症基因组图谱或低分化和间变性甲状腺癌数据集报道的其他基因改变。
有 3 例仅通过 Sanger 测序进行了检测，结果均为 BRAFV600E、HRAS、KRAS、NRAS、TERT 启动子、PTEN 和 PIK3CA 突变阴性。另外 19 例通过 NGS 检测的肿瘤中，有 10 例（52.6%）存在明确的致病性改变：2/19（10.5%）BRAFV600E，5/19（26.3%）CCDC6-RET（RET/PTC1），1/19（5.3%）NCOA4-RET（RET/PTC3），1/19（5.3%）STRN-ALK 融合，2/19（10.6%）TP53 突变。13 例（68.4%）肿瘤存在可能的致病性改变，包括 POLE（31.6%）、CDKN2A（26%）、NF1（21%）、BRCA2（15.8%）、SETD2（5.3%）、ATM（5.3%）、FLT3（5.3%）和 ROS1（5.3%）的变体。在 1 例患者中，基因panel 未显示任何改变。在所有患者中，RAS、PTEN、PIK3CA 或 TERT 启动子均未发现突变。没有明显的基因型/表型相关性。
在 DSPTC 中，融合基因很常见，BRAFV600E 罕见，其他常见的点突变缺失。POLE、NF1、CDKN2A、BRCA2、TP53、SETD2、ATM、FLT3 和 ROS1 的致病性和可能致病性变体约出现在三分之二的 DSPTC 中。
