a Cancer Biology and Epigenetics Group - Research Center , Portuguese Oncology Institute of Porto , Porto , Portugal.
b Departments of Pathology , Portuguese Oncology Institute of Porto , Porto , Portugal.
Epigenetics. 2017;12(12):1057-1064. doi: 10.1080/15592294.2017.1385685. Epub 2018 Jan 22.
Increasing detection of small renal masses by imaging techniques entails the need for accurate discrimination between benign and malignant renal cell tumors (RCTs) as well as among malignant RCTs, owing to differential risk of progression through metastization. Although histone methylation has been implicated in renal tumorigenesis, its potential as biomarker for renal cell carcinoma (RCC) progression remains largely unexplored. Thus, we aimed to characterize the differential expression of histone methyltransferases (HMTs) and histone demethylases (HDMs) in RCTs to assess their potential as metastasis biomarkers. We found that SETDB2 and RIOX2 (encoding for an HMT and an HDM, respectively) expression levels was significantly altered in RCTs; these genes were further selected for validation by quantitative RT-PCR in 160 RCTs. Moreover, SETDB2, RIOX2, and three genes encoding for enzymes involved in histone methylation (NO66, SETD3, and SMYD2), previously reported by our group, were quantified (RT-PCR) in an independent series of 62 clear cell renal cell carcinoma (ccRCC) to assess its potential role in ccRCC metastasis development. Additional validation was performed using TCGA dataset. SETDB2 and RIOX2 transcripts were overexpressed in RCTs compared to renal normal tissues (RNTs) and in oncocytomas vs. RCCs, with ccRCC and papillary renal cell carcinoma (pRCC) displaying the lowest levels. Low SETDB2 expression levels and higher stage independently predicted shorter disease-free survival. In our 62 ccRCC cohort, significantly higher RIOX2, but not SETDB2, expression levels were depicted in cases that developed metastasis during follow-up. These findings were not apparent in TCGA dataset. We concluded that SETDB2 and RIOX2 might be involved in renal tumorigenesis and RCC progression, especially in metastatic spread. Moreover, SETDB2 expression levels might independently discriminate among RCC subgroups with distinct outcome, whereas higher RIOX2 transcript levels might identify ccRCC cases with more propensity to endure metastatic dissemination.
影像学技术对小肾肿瘤的检测能力提高，需要准确区分良性和恶性肾细胞肿瘤（RCTs）以及恶性 RCTs，因为转移导致的进展风险不同。尽管组蛋白甲基化已被认为与肾肿瘤发生有关，但它作为肾细胞癌（RCC）进展的生物标志物的潜力在很大程度上仍未得到探索。因此，我们旨在描述 RCTs 中组蛋白甲基转移酶（HMTs）和组蛋白去甲基化酶（HDMs）的差异表达，以评估它们作为转移生物标志物的潜力。我们发现 SETDB2 和 RIOX2（分别编码 HMT 和 HDM）的表达水平在 RCTs 中发生了显著改变；这些基因进一步通过定量 RT-PCR 在 160 个 RCT 中进行验证。此外，我们还在另一个独立的 62 例透明细胞肾细胞癌（ccRCC）系列中对 SETDB2、RIOX2 和我们小组之前报道的三个参与组蛋白甲基化的酶基因（NO66、SETD3 和 SMYD2）进行了定量（RT-PCR），以评估其在 ccRCC 转移发展中的潜在作用。使用 TCGA 数据集进行了额外的验证。与肾正常组织（RNTs）相比，SETDB2 和 RIOX2 的转录本在 RCTs 中过度表达，与肾嗜酸细胞瘤相比，在 RCC 中过度表达，而 ccRCC 和乳头状肾细胞癌（pRCC）的表达水平最低。低表达水平的 SETDB2 和较高的分期独立预测了较短的无病生存期。在我们的 62 例 ccRCC 队列中，在随访期间发生转移的病例中，RIOX2 的表达水平显著升高，但 SETDB2 的表达水平没有明显升高。在 TCGA 数据集中没有出现这种情况。我们得出结论，SETDB2 和 RIOX2 可能参与肾肿瘤发生和 RCC 进展，尤其是在转移扩散方面。此外，SETDB2 表达水平可能独立区分具有不同预后的 RCC 亚组，而较高的 RIOX2 转录本水平可能识别出更倾向于发生转移扩散的 ccRCC 病例。
