Clinicopathologic features of kinase fusion-related thyroid carcinomas: an integrative analysis with molecular characterization.
Clinicopathologic features of kinase fusion-related thyroid carcinomas: an integrative analysis with molecular characterization.
复制标题
DOI：
10.1038/s41379-020-0638-5
复制
发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Sadow PM
中科院分区：
文献类型：
--
作者：
Chu YH;Wirth LJ;Farahani AA;Nosé V;Faquin WC;Dias-Santagata D;Sadow PM
可作用激酶基因重排的发现彻底改变了甲状腺癌的治疗前景。尚未解决的挑战包括靶向病例的组织病理学识别，基因型与肿瘤行为之间的相关性，以及对激酶抑制剂（KI）的耐药机制。我们提出了62激酶融合阳性甲状腺癌（KFTC），包括57乳头状甲状腺癌（PTC），两个低分化甲状腺癌（PDTC），两个未分化甲状腺癌（ATC），和一个原发性分泌癌（SC），在57名成人和5名青少年。临床记录，术后组织学和分子特征进行了审查。组织学上，所有KFTC均显示多结节生长，伴有显著的瘤内纤维化。血管侵犯（95%），甲状腺外侵犯（63%），颈淋巴结转移（79%）。鉴定了几种激酶融合：STRN-ALK、EML4-ALK、AGK-BRAF、CUL1-BRAF、MKRN1-BRAF、SND1-BRAF、TTYH3-BRAF、EML4-MET、TFG-MET、IRF2BP2-NTRK1、PPL-NTRK1、SQSTM1-NTRK1、TPR-NTRK1、TPM3-NTRK1、EML4-NTRK3、ETV6-NTRK3、RBPMS-NTRK3、SQSTM1-NTRK3、CCDC6-RET、ERC1-RET、NCOA4-RET、RASAL2-RET、TRIM24-RET、TRIM27-RET，CCDC30-ROS1个别病例还显示EGFR的拷贝数变体和pTERT、TP 53、PIK 3R 1、AKT 2、TSC 2、FBXW 7、JAK 2、MEN 1、VHL、IDH 1、PTCH 1、GNA 11、GNAQ、SMARCA 4和CDH 1中的核苷酸变体和插入缺失。除甲状腺切除术和放射性碘外，10例患者接受多激酶和/或选择性激酶抑制剂治疗，6例患者出现持久客观缓解，4例患者出现疾病进展。在47例随访时间>6个月（中位数[范围]：41 [6 - 480]个月）的病例中，持续/复发疾病、远处转移和甲状腺癌相关死亡的发生率分别为57%、38%和6%。总之，KFTC包括一系列具有重叠临床病理特征和临床侵袭性倾向的分子多样性肿瘤。多结节生长和显著纤维化的特征性组织学，特别是当存在广泛的淋巴血管扩散时，应触发基因重排的分子检测，无论是通过患病率逐步进行还是使用组合面板。我们的研究结果进一步提供了放射性碘难治性甲状腺癌的分子治疗信息。
The discovery of actionable kinase gene rearrangements has revolutionized the therapeutic landscape of thyroid carcinomas. Unsolved challenges include histopathologic recognition of targetable cases, correlation between genotypes and tumor behavior, and evolving resistance mechanisms against kinase inhibitors (KI). We present 62 kinase fusion-positive thyroid carcinomas (KFTC), including 57 papillary thyroid carcinomas (PTC), two poorly differentiated thyroid carcinomas (PDTC), two undifferentiated thyroid carcinomas (ATC), and one primary secretory carcinoma (SC), in 57 adults and 5 adolescents. Clinical records, post-operative histology, and molecular profiles were reviewed. Histologically, all KFTC showed multinodular growth with prominent intratumoral fibrosis. Lymphovascular invasion (95%), extrathyroidal extension, gross and microscopic (63%), and cervical lymph node metastasis (79%) were common. Several kinase fusions were identified: STRN-ALK, EML4-ALK, AGK-BRAF, CUL1-BRAF, MKRN1-BRAF, SND1-BRAF, TTYH3-BRAF, EML4-MET, TFG-MET, IRF2BP2-NTRK1, PPL-NTRK1, SQSTM1-NTRK1, TPR-NTRK1, TPM3-NTRK1, EML4-NTRK3, ETV6-NTRK3, RBPMS-NTRK3, SQSTM1-NTRK3, CCDC6-RET, ERC1-RET, NCOA4-RET, RASAL2-RET, TRIM24-RET, TRIM27-RET, and CCDC30-ROS1. Individual cases also showed copy number variants of EGFR and nucleotide variants and indels in pTERT, TP53, PIK3R1, AKT2, TSC2, FBXW7, JAK2, MEN1, VHL, IDH1, PTCH1, GNA11, GNAQ, SMARCA4 and CDH1. In addition to thyroidectomy and radioactive iodine, 10 patients received multi-kinase and/or selective kinase inhibitor therapy, with 6 durable, objective responses and 4 with progressive disease. Among 47 cases with >6 months of follow-up (median [range]: 41 [6 to 480] months), persistent/recurrent disease, distant metastasis and thyroid cancer-related death occurred in 57%, 38% and 6%, respectively. In summary, KFTC encompass a spectrum of molecularly diverse tumors with overlapping clinicopathologic features and a tendency for clinical aggressiveness. Characteristic histology with multinodular growth and prominent fibrosis, particularly when there is extensive lymphovascular spread, should trigger molecular testing for gene rearrangements, either in a step-wise manner by prevalence or using a combined panel. Our findings further provide information on molecularly therapy in radioiodine-refractory thyroid carcinoma.
登录
查看更多内容
DOI：
10.1073/pnas.1501735112
发表时间：
2015-03-17
影响因子：
11.1
作者：
Kannan, Kalpana;Coarfa, Cristian;Yen, Laising
通讯作者：
Yen, Laising
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
5.6
作者：
Adeniran, AJ;Zhu, ZW;Nikiforov, YE
通讯作者：
Nikiforov, YE
影响因子：
28.2
作者：
Chmielecki, Juliann;Hutchinson, Katherine E.;Stephens, Philip J.
通讯作者：
Stephens, Philip J.
DOI：
10.1073/pnas.1321937111
发表时间：
2014-03-18
影响因子：
11.1
作者：
Kelly, Lindsey M.;Barila, Guillermo;Nikiforov, Yuri E.
通讯作者：
Nikiforov, Yuri E.