赖氨酸特异性去甲基化酶 6A（KDM6A）与错配修复（MMR）状态的联合是结直肠癌的一个潜在预后因素。
Combination of lysine-specific demethylase 6A (KDM6A) and mismatch repair (MMR) status is a potential prognostic factor in colorectal cancer.
机构信息
College of Pharmacy and Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China.
Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, China.
出版信息
Cancer Med. 2021 Jan;10(1):317-324. doi: 10.1002/cam4.3602. Epub 2020 Nov 11.
PURPOSE
To evaluate the relationship between the DNA mismatch repair (MMR) status and histone lysine-specific demethylase 6A (KDM6A) on the prognosis of colorectal cancer (CRC).
METHODS
About 594 patients with CRC from The Cancer Genome Atlas (TCGA) were enrolled in this retrospective study. Subsequently, a series of different classification tests for MMR status, cancer types, and target gene expression was conducted.
RESULTS
After filtering out the KDMs group of genes, we selected KDM6A as the target gene. A significant difference in the performance of KDM6A in tumor and normal tissues were confirmed. Our results showed a lower KDM6A expression, lower KDM6A exon expression, and higher KDM6A DNA methylation than their corresponding normal tissues in colon adenocarcinoma (COAD). Notably, the main MMR genes were highly expressed in tumor tissues than normal tissues both in COAD and rectum adenocarcinoma (READ). Moreover, proficient DNA mismatch repair (pMMR) was found to be an important poor prognostic factor in COAD (p = 0.0064) and the low KDM6A expression was an important factor for poor prognosis in READ (p = 0.0217). Based on these results, we consequently relate MMR status with KDM6A expression in predicting the prognosis of patients with CRC. Moreover, patients with pMMR exhibited a low KDM6A expression in COAD (p = 0.0250). Samples were divided into two groups based on the KDM6A expression. Interestingly, the group with low KDM6A expression showed no difference between pMMR and deficient DNA mismatch repair (dMMR) in prognosis, whereas the group with high KDM6A expression was closely related to MMR status in OS (p = 0.0082). Besides, COAD patients with high KDM6A expression and pMMR status had poor OS (p = 0.0082).
CONCLUSIONS
The KDM6A/MMR classification-based subtypes of low KDM6A expression/READ, high KDM6A expression/pMMR, and COAD/pMMR were associated with poor prognosis. This classification can be a novel prognostic approach in CRC.
目的
评估 DNA 错配修复（MMR）状态与组蛋白赖氨酸特异性去甲基酶 6A（KDM6A）对结直肠癌（CRC）预后的关系。
方法
本回顾性研究纳入了来自癌症基因组图谱（TCGA）的 594 例 CRC 患者。随后，对 MMR 状态、癌症类型和靶基因表达进行了一系列不同的分类测试。
结果
在剔除 KDMs 基因组后，我们选择 KDM6A 作为靶基因。在肿瘤组织和正常组织中，KDM6A 的性能有显著差异。我们的结果显示，在结肠腺癌（COAD）中，肿瘤组织中的 KDM6A 表达、KDM6A 外显子表达较低，KDM6A DNA 甲基化程度较高。值得注意的是，在 COAD 和直肠腺癌（READ）中，主要的 MMR 基因在肿瘤组织中的表达均高于正常组织。此外，在 COAD 中，功能型 DNA 错配修复（pMMR）被发现是一个重要的预后不良因素（p=0.0064），而在 READ 中，低 KDM6A 表达是预后不良的一个重要因素（p=0.0217）。基于这些结果，我们将 MMR 状态与 KDM6A 表达联系起来，以预测 CRC 患者的预后。此外，在 COAD 中，pMMR 患者的 KDM6A 表达较低（p=0.0250）。根据 KDM6A 表达将样本分为两组。有趣的是，低 KDM6A 表达组在预后方面，pMMR 和缺乏 DNA 错配修复（dMMR）之间没有差异，而高 KDM6A 表达组与 OS 中的 MMR 状态密切相关（p=0.0082）。此外，COAD 中高 KDM6A 表达和 pMMR 状态的患者 OS 较差（p=0.0082）。
结论
基于 KDM6A/MMR 分类的低 KDM6A 表达/READ、高 KDM6A 表达/pMMR 和 COAD/pMMR 亚组与预后不良相关。这种分类可能是 CRC 一种新的预后方法。
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