Genetic alterations in cell cycle regulation-associated genes may promote primary progression of gastrointestinal stromal tumors
Genetic alterations in cell cycle regulation-associated genes may promote primary progression of gastrointestinal stromal tumors
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DOI：
10.1038/s41374-019-0322-x
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发表时间：
2020-03-01
影响因子：
5
通讯作者：
Wang, Zhe
中科院分区：
文献类型：
--
作者：
Li, Peifeng;Li, Mingyang;Wang, Zhe
胃肠道间质瘤（GIST）是最常见的间叶肿瘤类型之一，通常含有KIT或PDGFRA突变。在临床实践中可以看到伴有低级别和高级别成分的GIST。在此，我们回顾性分析了22例胃肠道间质瘤的组织学特征和免疫组化结果，同时伴有低级别和高级别肿瘤。对10对高级别GIST样本和匹配的低级别样本进行全外显子组测序（WES）。鉴别出仅在高级别GIST中突变的差异癌基因，并通过桑格测序证实。荧光原位杂交检测MYC拷贝数的变化。与匹配的低级别肿瘤相比，高级别GIST更可能具有较低的CD 34表达和较高的Ki-67增殖指数。WES确定了30个仅在高级别GIST中突变的差异性癌症相关基因;桑格测序证实了9个基因（MGA、ARID 1A、LATS 2、MAX、PIK 3CA、RB 1、RPS 6 KB 2、SDHA和SET D2）中的10个相关差异性致癌突变。两名患者有MGA突变，而其他基因突变仅发生在一名患者中。大多数差异癌相关基因主要参与细胞周期调控。MYC拷贝数增加是一种常见的遗传变异。高级别GIST比匹配的低级别肿瘤显示出更多的MYC拷贝数增加，而与高级别成分共存的低级别GIST比纯低级别GIST显示出更多的MYC拷贝数增加。此外，MYC拷贝数增加与有丝分裂指数和Ki-67增殖指数呈正相关。细胞周期调控相关基因的改变（如基因突变和MYC拷贝数增加）可通过调节肿瘤细胞增殖促进低级别GIST向高级别肿瘤的原发进展，而大多数仅在高级别胃肠道间质瘤（GIST）中发生突变的癌症相关基因主要参与细胞周期调控。高级别GIST比匹配的低级别肿瘤有更多的MYC拷贝数增加。作者表明，细胞周期调控相关基因的改变可能通过调节肿瘤细胞增殖促进从低级别GIST向高级别肿瘤的原发进展。
Gastrointestinal stromal tumors (GISTs) are one of the most common mesenchymal tumor types and usually contain KIT or PDGFRA mutations. GISTs with concomitant low- and high-grade components are seen in clinical practice. Herein, we retrospectively analyzed the histological characteristics and immunohistochemical results of 22 GIST cases with concomitant low- and high-grade tumors. Whole-exome sequencing (WES) was performed on ten pairs of high-grade GIST specimens and matched low-grade samples. Differential oncogenes mutated only in high-grade GISTs were identified, which were confirmed by Sanger sequencing. Fluorescence in situ hybridization was employed to detect MYC copy number variation. High-grade GISTs were more likely to have lower CD34 expression and a higher Ki-67 proliferation index compared to the matched low-grade tumors. WES identified 30 differential cancer-associated genes mutated only in high-grade GISTs; Sanger sequencing confirmed ten relevant differential oncogenic mutations in nine genes (MGA, ARID1A, LATS2, MAX, PIK3CA, RB1, RPS6KB2, SDHA, and SETD2). Two patients had MGA mutations, whereas other gene mutations occurred in only one patient. Most of the differential cancer-associated genes are mainly involved in cell cycle control. MYC copy number gain was a common genetic variation. High-grade GISTs revealed more MYC copy number gains than matched low-grade tumors, and low-grade GISTs with coexisting high-grade components showed more MYC copy number gains than pure low-grade GISTs. Moreover, MYC copy number gain was positively correlated with the mitotic index and Ki-67 proliferation index. Alterations in cell cycle regulation-associated genes, such as genetic mutations and MYC copy number gain, may promote primary progression from low-grade GISTs to high-grade tumors by regulating tumor cell proliferation.Most of the cancer-associated genes mutated only in high-grade gastrointestinal stromal tumors (GISTs) are mainly involved in cell cycle control. High-grade GISTs had more MYC copy number gains than matched low-grade tumors. The authors show that alterations in cell cycle regulation-associated genes, may promote primary progression from low-grade GISTs to high-grade tumors by regulating tumor cell proliferation.