Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
J Transl Med. 2021 Feb 16;19(1):73. doi: 10.1186/s12967-021-02740-6.
Neurotrophic tropomyosin receptor kinases (NTRKs) are a gene family function as oncogene or tumor suppressor gene in distinct cancers. We aimed to investigate the methylation and expression profiles and prognostic value of NTRKs gene in colorectal cancer (CRC).
An analysis of DNA methylation and expression profiles in CRC patients was performed to explore the critical methylations within NTRKs genes. The methylation marker was validated in a retrospectively collected cohort of 229 CRC patients and tested in other tumor types from TCGA. DNA methylation status was determined by quantitative methylation-specific PCR (QMSP).
The profiles in six CRC cohorts showed that NTRKs gene promoter was more frequently methylated in CRC compared to normal mucosa, which was associated with suppressed gene expression. We identified a specific methylated region within NTRK3 promoter targeted by cg27034819 and cg11525479 that best predicted survival outcome in CRC. NTRK3 promoter methylation showed independently predictive value for survival outcome in the validation cohort (P = 0.004, HR 2.688, 95% CI [1.355, 5.333]). Based on this, a nomogram predicting survival outcome was developed with a C-index of 0.705. Furthermore, the addition of NTRK3 promoter methylation improved the performance of currently-used prognostic model (AIC: 516.49 vs 513.91; LR: 39.06 vs 43.64, P = 0.032). Finally, NTRK3 promoter methylation also predicted survival in other tumors, including pancreatic cancer, glioblastoma and stomach adenocarcinoma.
This study highlights the essential value of NTRK3 methylation in prognostic evaluation and the potential to improve current prognostic models in CRC and other tumors.
神经营养性原肌球蛋白受体激酶（NTRKs）是一个基因家族，在不同的癌症中作为癌基因或肿瘤抑制基因发挥作用。我们旨在研究 NTRKs 基因在结直肠癌（CRC）中的甲基化和表达谱及其预后价值。
对 CRC 患者的 DNA 甲基化和表达谱进行分析，以探索 NTRKs 基因内的关键甲基化。在 229 例 CRC 患者的回顾性队列中验证了甲基化标志物，并在 TCGA 的其他肿瘤类型中进行了测试。通过定量甲基化特异性 PCR（QMSP）测定 DNA 甲基化状态。
在六个 CRC 队列的分析中，与正常黏膜相比，NTRKs 基因启动子在 CRC 中更频繁地发生甲基化，这与基因表达受抑制有关。我们确定了 NTRK3 启动子内一个特定的甲基化区域，该区域由 cg27034819 和 cg11525479 靶向，可最好地预测 CRC 的生存结果。在验证队列中，NTRK3 启动子甲基化对生存结果具有独立的预测价值（P=0.004，HR 2.688，95%CI [1.355，5.333]）。基于此，开发了一个预测生存结果的列线图，其 C 指数为 0.705。此外，添加 NTRK3 启动子甲基化可改善当前用于预后模型的性能（AIC：516.49 与 513.91；LR：39.06 与 43.64，P=0.032）。最后，NTRK3 启动子甲基化也预测了其他肿瘤的生存情况，包括胰腺癌、胶质母细胞瘤和胃腺癌。
本研究强调了 NTRK3 甲基化在预后评估中的重要价值，并有潜力改善 CRC 和其他肿瘤中的当前预后模型。
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