Involvement of Chromatin Remodeling Genes and the Rho GTPases RhoB and CDC42 in Ovarian Clear Cell Carcinoma.
Involvement of Chromatin Remodeling Genes and the Rho GTPases RhoB and CDC42 in Ovarian Clear Cell Carcinoma.
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DOI：
10.3389/fonc.2017.00109
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发表时间：
2017
影响因子：
4.7
通讯作者：
Hedenfalk IA
中科院分区：
文献类型：
--
作者：
Arildsen NS;Jönsson JM;Bartuma K;Ebbesson A;Westbom-Fremer S;Måsbäck A;Malander S;Nilbert M;Hedenfalk IA
卵巢透明细胞癌（OCCC）是一种罕见的卵巢癌亚型，具有独特的临床特征，但在形态学上可能难以与其他亚型区分开。对于 ARID1A 之外驱动 OCCC 肿瘤发生的遗传事件的了解有限，据报道 ARID1A 在 30-50% 的 OCCC 中发生突变。我们的目标是通过结合全局转录分析和一组成熟癌症基因的靶向深度测序来进一步表征 OCCC。增加对 OCCC 特异性遗传畸变的了解可能有助于指导针对性治疗的开发，并最终改善患者的治疗结果。使用全基因组 cDNA 介导的退火、选择、延伸和连接 (WG-DASL) 珠阵列对来自主要卵巢癌亚型队列（队列 1；n = 67）的福尔马林固定石蜡包埋 (FFPE) 组织进行基因表达谱分析，然后分别进行通路、基因模块评分和基因本体分析。通过对一组 60 个癌症相关基因进行靶向 DNA 测序，对第二个 FFPE 队列（10 个原发性 OCCC）进行了分析（队列 2）。进一步分析了影响单核苷酸变异和插入或缺失的非同义和无义变异。使用 43 个 OCCC（第 3 组）的组织微阵列通过免疫组织化学和显色原位杂交进行验证。基因表达分析揭示了与其他组织学亚型相比独特的 OCCC 特征，例如 ERBB2、TFAP2A 和与细胞骨架肌动蛋白调节相关的基因在 OCCC 中过度表达。然而，ERBB2 在蛋白质水平上并未过度表达，并且 ERBB2 扩增在验证队列中很少见。靶向深度测序揭示了 11/60 癌症相关基因中的非同义变异或插入/缺失。参与染色质重塑的基因，包括 ARID1A、SPOP 和 KMT2D，在 OCCC 肿瘤中经常发生突变。 OCCC 表现出遗传异质性，但染色质重塑基因频繁发生改变。在 mRNA 水平上观察到与其他卵巢癌亚型相关的 TFAP2A 和 ERBB2 过度表达。然而，OCCC 验证队列中的 HER2 扩增或蛋白过度表达并未反映出 ERBB2 的过度表达。此外，Rho GTPase 依赖性肌动蛋白组织也可能在 OCCC 发病机制中发挥作用，值得进一步研究。这里发现的 OCCC 独特的生物学特征可能为新型靶向治疗策略提供基础。
Ovarian clear cell carcinomas (OCCCs) constitute a rare ovarian cancer subtype with distinct clinical features, but may nonetheless be difficult to distinguish morphologically from other subtypes. There is limited knowledge of genetic events driving OCCC tumorigenesis beyond ARID1A, which is reportedly mutated in 30–50% of OCCCs. We aimed to further characterize OCCCs by combined global transcriptional profiling and targeted deep sequencing of a panel of well-established cancer genes. Increased knowledge of OCCC-specific genetic aberrations may help in guiding development of targeted treatments and ultimately improve patient outcome. Gene expression profiling of formalin-fixed, paraffin-embedded (FFPE) tissue from a cohort of the major ovarian cancer subtypes (cohort 1; n = 67) was performed using whole-genome cDNA-mediated Annealing, Selection, extension and Ligation (WG-DASL) bead arrays, followed by pathway, gene module score, and gene ontology analyses, respectively. A second FFPE cohort of 10 primary OCCCs was analyzed by targeted DNA sequencing of a panel of 60 cancer-related genes (cohort 2). Non-synonymous and non-sense variants affecting single-nucleotide variations and insertions or deletions were further analyzed. A tissue microarray of 43 OCCCs (cohort 3) was used for validation by immunohistochemistry and chromogenic in situ hybridization. Gene expression analyses revealed a distinct OCCC profile compared to other histological subtypes, with, e.g., ERBB2, TFAP2A, and genes related to cytoskeletal actin regulation being overexpressed in OCCC. ERBB2 was, however, not overexpressed on the protein level and ERBB2 amplification was rare in the validation cohort. Targeted deep sequencing revealed non-synonymous variants or insertions/deletions in 11/60 cancer-related genes. Genes involved in chromatin remodeling, including ARID1A, SPOP, and KMT2D were frequently mutated across OCCC tumors. OCCCs appear genetically heterogeneous, but harbor frequent alterations in chromatin remodeling genes. Overexpression of TFAP2A and ERBB2 was observed on the mRNA level in relation to other ovarian cancer subtypes. However, overexpression of ERBB2 was not reflected by HER2 amplification or protein overexpression in the OCCC validation cohort. In addition, Rho GTPase-dependent actin organization may also play a role in OCCC pathogenesis and warrants further investigation. The distinct biological features of OCCC discovered here may provide a basis for novel targeted treatment strategies.