Extensive intratumor regional epigenetic heterogeneity in clear cell renal cell carcinoma targets kidney enhancers and is associated with poor outcome.

IF 5.7 2区 医学 Q1 Medicine Clinical Epigenetics Pub Date : 2023-04-29 DOI:10.1186/s13148-023-01471-3
Louis Y El Khoury, Xiaoyu Pan, Ryan A Hlady, Ryan T Wagner, Shafiq Shaikh, Liguo Wang, Mitchell R Humphreys, Erik P Castle, Melissa L Stanton, Thai H Ho, Keith D Robertson
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Abstract

Background: 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.

Results: 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.

Conclusion: 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.

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透明细胞肾细胞癌肿瘤内广泛的区域表观遗传异质性以肾增强因子为靶点,并与不良预后相关。
背景:透明细胞肾细胞癌(ccRCC)是美国癌症相关死亡的第八大原因,由于高水平的肿瘤内异质性(ITH)和缺乏可药物驱动突变,治疗具有挑战性。CcRCC的不同寻常之处在于其高频率的表观遗传调控突变,如SETD2组蛋白H3赖氨酸36三甲基化酶(H3K36me3),和低频率的传统癌症驱动突变。在这项工作中,我们研究了表观遗传水平的ITH,并定义了其与病理特征、肿瘤生物学方面和SETD2突变的关系。结果:多区域采样方法结合EPIC DNA甲基化阵列对正常肾脏和ccRCC队列进行了研究。使用DNA甲基化(5mC)和基于cnv的熵和欧几里得距离来评估ITH。我们发现与正常肾脏相比,ccRCC的5mC异质性和熵升高。可变CpGs在增强子区高度富集。通过类内相关系数分析,我们确定了根据与肿瘤侵袭性相关的临床表型分离肿瘤区域的CpGs。SETD2野生型肿瘤总体上比SETD2突变肿瘤区域具有更高的5mC和拷贝数ITH,这表明SETD2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5mC特征,该特征将原发肿瘤内的区域与转移潜力联系起来。结论:综上所述,我们的研究结果揭示了ccRCC中显著水平的表观遗传ITH与临床相关的肿瘤表型有关,并可能转化为新的表观遗传生物标志物。
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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
期刊最新文献
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