Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America.
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America.
PLoS One. 2022 Dec 1;17(12):e0278108. doi: 10.1371/journal.pone.0278108. eCollection 2022.
Germline mutations within the Krebs cycle enzyme genes fumarate hydratase (FH) or succinate dehydrogenase (SDHB, SDHC, SDHD) are associated with an increased risk of aggressive and early metastasizing variants of renal cell carcinoma (RCC). These RCCs express significantly increased levels of intracellular fumarate or succinate that inhibit 2-oxoglutarate-dependent dioxygenases, such as the TET enzymes that regulate DNA methylation. This study evaluated the genome-wide methylation profiles of 34 RCCs from patients with RCC susceptibility syndromes and 11 associated normal samples using the Illumina HumanMethylation450 BeadChip. All the HLRCC (FH mutated) and SDHB-RCC (SDHB mutated) tumors demonstrated a distinct CpG island methylator phenotype (CIMP). HLRCC tumors demonstrated an extensive and relatively uniform level of hypermethylation that showed some correlation with tumor size. SDHB-RCC demonstrated a lesser and more varied pattern of hypermethylation that overlapped in part with the HLRCC hypermethylation. Combined methylation and mRNA expression analysis of the HLRCC tumors demonstrated hypermethylation and transcription downregulation of genes associated with the HIF pathway, HIF3A and CITED4, the WNT pathway, SFRP1, and epithelial-to-mesenchymal transition and MYC expression, OVOL1. These observations were confirmed in the TCGA CIMP-RCC tumors. A selected panel of probes could identify the CIMP tumors and differentiate between HLRCC and SDHB-RCC tumors. This panel accurately detected all CIMP-RCC tumors within the TCGA RCC cohort, identifying them as HLRCC -like, and could potentially be used to create a liquid biopsy-based screening tool. The CIMP signature in these aggressive tumors could provide both a useful biomarker for diagnosis and a target for novel therapies.
Krebs 循环酶基因富马酸水合酶（FH）或琥珀酸脱氢酶（SDHB、SDHC、SDHD）中的种系突变与肾细胞癌（RCC）侵袭性和早期转移变体的风险增加相关。这些 RCC 表达显著增加的细胞内富马酸或琥珀酸，抑制 2-氧戊二酸依赖性加双氧酶，如调节 DNA 甲基化的 TET 酶。本研究使用 Illumina HumanMethylation450 BeadChip 评估了 34 例来自 RCC 易感性综合征患者和 11 例相关正常样本的 RCC 全基因组甲基化谱。所有 HLRCC（FH 突变）和 SDHB-RCC（SDHB 突变）肿瘤均表现出明显的 CpG 岛甲基化表型（CIMP）。HLRCC 肿瘤表现出广泛且相对均匀的高甲基化水平，与肿瘤大小有一定相关性。SDHB-RCC 表现出较小且更多样化的高甲基化模式，部分与 HLRCC 高甲基化重叠。HLRCC 肿瘤的联合甲基化和 mRNA 表达分析显示，与 HIF 途径、HIF3A 和 CITED4、WNT 途径、SFRP1 以及上皮-间充质转化和 MYC 表达、OVOL1 相关的基因发生了高甲基化和转录下调。这些观察结果在 TCGA CIMP-RCC 肿瘤中得到了证实。一组选定的探针可识别 CIMP 肿瘤，并区分 HLRCC 和 SDHB-RCC 肿瘤。该探针可准确检测 TCGA RCC 队列中的所有 CIMP-RCC 肿瘤，将其鉴定为 HLRCC 样，并可能用于创建基于液体活检的筛查工具。这些侵袭性肿瘤中的 CIMP 特征可为诊断提供有用的生物标志物，并为新疗法提供靶标。
