Extensive intratumor regional epigenetic heterogeneity in clear cell renal cell carcinoma targets kidney enhancers and is associated with poor outcome.
Extensive intratumor regional epigenetic heterogeneity in clear cell renal cell carcinoma targets kidney enhancers and is associated with poor outcome.
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DOI：
10.1186/s13148-023-01471-3
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发表时间：
2023-04-29
影响因子：
5.7
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中科院分区：
文献类型：
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透明细胞肾细胞癌（ccRCC）是美国癌症相关死亡的第8大原因，由于高水平的瘤内异质性（ITH）和缺乏可药用驱动突变，治疗具有挑战性。CcRCC的不寻常之处在于其高频率的表观遗传调节因子突变，如SETD 2组蛋白H3赖氨酸36三甲基酶（H3 K36 me 3），以及低频率的传统癌症驱动突变。在这项工作中，我们检查了表观遗传水平ITH，并确定了其与病理特征，肿瘤生物学方面和SETD 2突变的关系。在正常肾脏和ccRCC的队列中进行了多区域采样方法与EPIC DNA甲基化阵列的结合。使用DNA甲基化（5 mC）和基于CNV的熵和欧几里得距离评估ITH。我们发现相对于正常肾脏，ccRCC中的5 mC异质性和熵升高。可变CpG在增强子区域中高度富集。使用类内相关系数分析，我们根据与肿瘤侵袭性相关的临床表型鉴定了分离肿瘤区域的CpG。SETD 2野生型肿瘤总体上比SETD 2突变肿瘤区域具有更大的5 mC和拷贝数ITH，这表明SETD 2缺失导致了不同的表观基因组。最后，将我们的区域数据与TCGA相结合，我们确定了将原发性肿瘤内的区域与转移潜力联系起来的5 mC特征。总之，我们的结果揭示了ccRCC中表观遗传ITH的显著水平，其与临床相关的肿瘤表型相关，并可转化为新的表观遗传生物标志物。在线版本包含补充材料，可通过10.1186/s13148-023-01471-3获得。
Clear cell renal cell cancer (ccRCC), the 8th leading cause of cancer-related death in the US, is challenging to treat due to high level intratumoral heterogeneity (ITH) and the paucity of druggable driver mutations. CcRCC is unusual for its high frequency of epigenetic regulator mutations, such as the SETD2 histone H3 lysine 36 trimethylase (H3K36me3), and low frequency of traditional cancer driver mutations. In this work, we examined epigenetic level ITH and defined its relationships with pathologic features, aspects of tumor biology, and SETD2 mutations. A multi-region sampling approach coupled with EPIC DNA methylation arrays was conducted on a cohort of normal kidney and ccRCC. ITH was assessed using DNA methylation (5mC) and CNV-based entropy and Euclidian distances. We found elevated 5mC heterogeneity and entropy in ccRCC relative to normal kidney. Variable CpGs are highly enriched in enhancer regions. Using intra-class correlation coefficient analysis, we identified CpGs that segregate tumor regions according to clinical phenotypes related to tumor aggressiveness. SETD2 wild-type tumors overall possess greater 5mC and copy number ITH than SETD2 mutant tumor regions, suggesting SETD2 loss contributes to a distinct epigenome. Finally, coupling our regional data with TCGA, we identified a 5mC signature that links regions within a primary tumor with metastatic potential. Taken together, our results reveal marked levels of epigenetic ITH in ccRCC that are linked to clinically relevant tumor phenotypes and could translate into novel epigenetic biomarkers. The online version contains supplementary material available at 10.1186/s13148-023-01471-3.
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全基因组甲基化谱揭示了人类衰老速度的定量观点。
影响因子：
16
作者：
Hannum, Gregory;Guinney, Justin;Zhao, Ling;Zhang, Li;Hughes, Guy;Sadda, SriniVas;Klotzle, Brandy;Bibikova, Marina;Fan, Jian-Bing;Gao, Yuan;Deconde, Rob;Chen, Menzies;Rajapakse, Indika;Friend, Stephen;Ideker, Trey;Zhang, Kang
通讯作者：
Zhang, Kang
影响因子：
5.5
作者：
Glazko G;Mushegian A
通讯作者：
Mushegian A
影响因子：
158.5
作者：
Choueiri, T. K.;Tomczak, P.;Powles, T.
通讯作者：
Powles, T.
影响因子：
5.7
作者：
Estrella, Jeannelyn S.;Tetzlaff, Michael T.;Broaddus, Russell R.
通讯作者：
Broaddus, Russell R.
影响因子：
23.4
作者：
Gulati S;Martinez P;Joshi T;Birkbak NJ;Santos CR;Rowan AJ;Pickering L;Gore M;Larkin J;Szallasi Z;Bates PA;Swanton C;Gerlinger M
通讯作者：
Gerlinger M