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Methylation profiling and evaluation of demethylating therapy in renal cell carcinoma

机译：肾细胞癌的甲基化概况及去甲基化治疗的评价

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BackgroundDespite therapeutic advances in targeted therapy, metastatic renal cell carcinoma (RCC) remains incurable for the vast majority of patients. Key molecular events in the pathogenesis of RCC include inactivation of the VHL tumour suppressor gene (TSG), inactivation of chromosome 3p TSGs implicated in chromatin modification and remodelling and de novo tumour-specific promoter methylation of renal TSGs. In the light of these observations it can be proposed that, as in some haematological malignancies, demethylating agents such as azacitidine might be beneficial for the treatment of advanced RCC. ResultsHere we report that the treatment of RCC cell lines with azacitidine suppressed cell proliferation in all 15 lines tested. A marked response to azacitidine therapy (>50% reduction in colony formation assay) was detected in the three cell lines with VHL promoter methylation but some RCC cell lines without VHL TSG methylation also demonstrated a similar response suggesting that multiple methylated TSGs might determine the response to demethylating therapies. To identify novel candidate methylated TSGs implicated in RCC we undertook a combined analysis of copy number and CpG methylation array data. Candidate novel epigenetically inactivated TSGs were further prioritised by expression analysis of RCC cell lines pre and post-azacitidine therapy and comparative expression analysis of tumourormal pairs. Thus, with subsequent investigation two candidate genes were found to be methylated in more than 25% of our series and in the TCGA methylation dataset for 199 RCC samples: RGS7 (25.6% and 35.2% of tumours respectively) and NEFM in (25.6% and 30.2%). In addition three candidate genes were methylated in >10% of both datasets ( TMEM74 (15.4% and 14.6%), GCM2 (41.0% and 14.6%) and AEBP1 (30.8% and 13.1%)). Methylation of GCM2 ( P = 0.0324), NEFM (P = 0.0024) and RGS7 ( P = 0.0067) was associated with prognosis. ConclusionsThese findings provide preclinical evidence that treatment with demethylating agents such as azacitidine might be useful for the treatment of advanced RCC and further insights into the role of epigenetic changes in the pathogenesis of RCC.
机译：背景尽管有针对性的治疗进展，但对于大多数患者而言，转移性肾细胞癌（RCC）仍无法治愈。 RCC发病机理中的关键分子事件包括VHL肿瘤抑制基因（TSG）失活，与染色质修饰和重塑有关的3p染色体TSG失活以及肾脏TSG的肿瘤特异性启动子甲基化。根据这些观察结果，可以建议像某些血液系统恶性肿瘤一样，去甲基化剂（例如阿扎胞苷）可能对晚期RCC的治疗有益。结果在此我们报道了用阿扎胞苷处理RCC细胞系在所有测试的15个细胞系中均抑制了细胞增殖。在三种具有VHL启动子甲基化的细胞系中检测到对阿扎胞苷疗法的显着反应（集落形成测定减少了50％以上），但一些没有VHL TSG甲基化的RCC细胞系也显示出类似的反应，表明多个甲基化的TSG可能决定了该反应去甲基化疗法。为了鉴定与RCC有关的新型候选甲基化TSG，我们对拷贝数和CpG甲基化阵列数据进行了组合分析。通过在阿扎胞苷治疗之前和之后对RCC细胞系的表达分析以及对肿瘤/正常对的比较表达分析，进一步确定了候选的新型表观遗传失活的TSG。因此，在随后的研究中，发现两个候选基因在我们系列的25％以上以及199个RCC样品的TCGA甲基化数据集中被甲基化：RGS7（分别为肿瘤的25.6％和35.2％）和NEFM（分别为25.6％和35.2％）。 30.2％）。此外，在两个数据集的> 10％中，三个候选基因被甲基化（TMEM74（15.4％和14.6％），GCM2（41.0％和14.6％）和AEBP1（30.8％和13.1％））。 GCM2（P = 0.0324），NEFM（P = 0.0024）和RGS7（P = 0.0067）的甲基化与预后相关。结论这些发现提供了临床前证据，即用去甲基化剂（例如阿扎胞苷）治疗可能对晚期RCC的治疗有用，并进一步了解表观遗传学变化在RCC发病机理中的作用。

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