MED12 突变作为泛癌种免疫检查点抑制剂潜在预测生物标志物

英文原题：MED12 mutation as a potential predictive biomarker for immune checkpoint inhibitors in pan-cancer.

查看英文原题

MED12 mutation as a potential predictive biomarker for immune checkpoint inhibitors in pan-cancer.

PubMed 2022/10/29（内容时间） Eur J Med Res Q2 · IF 4.8（JCR 2025）

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中文摘要

免疫检查点抑制剂（ICIs）治疗在多种癌症中引发了令人瞩目的抗肿瘤反应。越来越多的证据表明其与Mediator复合体亚基12（MED12）、DNA损伤修复（DDR）及TGF-β信号通路存在关联，而关于MED12与ICIs反应相关性的临床数据尚缺乏。

本研究将已发表研究中的临床和外显子组测序（WES）数据合并为WES队列，以探讨MED12突变（MED12-Mut）与ICIs疗效在多种癌症中的关联。随后，使用纪念斯隆-凯特琳癌症中心（MSKCC）队列验证我们的发现。使用癌症基因组图谱（TCGA）队列进行抗肿瘤免疫和预后分析。在WES队列（n = 474）中，MED12-Mut与MED12-野生型（MED12-Wt）患者在持久临床获益（DCB，80.00% vs. 53.67%，P = 0.022）方面检测到显著差异。

此外，MED12-Mut患者中观察到PFS显著延长（mPFS：未达到，NR vs. 5.87个月，HR：0.38，95% CI 0.17-0.85，log-rank P = 0.015）。在纳入年龄、性别、转移、治疗和TMB状态后，多因素Cox比例风险回归结果显示PFS显著更优（HR：0.40，95% CI 0.18-0.92；P = 0.031）。在MSKCC队列（n = 1513）中，MED12-Mut患者获得了总生存期优势（mOS：41 vs. 19个月，HR：0.54，95%CI 0.34-0.85；log-rank P = 0.007），在纳入WES队列中相同的因素后，这一关联仍然存在（HR：0.60，95% CI：0.38-0.96，P = 0.033）。

值得注意的是，在WES和MSKCC队列中均发现MED12-Mut患者的TMB显著更高。进一步的TIL（肿瘤浸润淋巴细胞）和 DDR 相关基因分析揭示了 MED12-Mut 患者的抗肿瘤免疫。

总体而言，MED12-Mut 成功预测了 ICIs 治疗的泛癌队列中更好的临床结局，表明 MED12-Mut 可作为泛癌中免疫检查点抑制剂的潜在预测生物标志物。

展开英文摘要原文

Immune checkpoint inhibitors (ICIs) therapy elicits admirable anti-tumor responses across many types of cancer. Growing evidence point to a link to Mediator complex subunit 12 (MED12) and DNA damage repair (DDR) and TGF-β signing, while the clinical data on the association of MED12 and ICIs response are lacking. In this study, clinical and whole-exome sequencing (WES) data from published studies were merged as a WES cohort to explore the association between MED12 mutation (MED12-Mut) and ICIs efficiency across cancers.

Then, Memorial Sloan Kettering Cancer Center (MSKCC) cohort was used for validating our findings. The Cancer Genome Atlas (TCGA) cohort was used to perform anti-tumor immunity and prognosis analysis. In the WES cohort (n = 474), significant differences were detected between MED12-Mut and MED12-wildtype (MED12-Wt) patients regarding durable clinical benefit (DCB, 80. 00% vs. 53. 67%, P = 0. 022).

In addition, significantly prolonged PFS was observed in MED12-Mut patients (mPFS: not reached, NR vs. 5. 87 months, HR: 0. 38, 95% CI 0. 17-0. 85, log-rank P = 0. 015), After taking into account age, gender, metastasis, treatment and TMB status, the result of multivariable Cox proportional hazards regression showed significantly better PFS (HR:0. 40, 95% CI 0. 18-0. 92; P = 0. 031).

In the MSKCC cohort (n = 1513), overall survival advantage was achieved in MED12-Mut patients (mOS: 41 vs. 19 months, HR:0. 54, 95%CI 0. 34-0. 85; log-rank P = 0. 007), after taking into account same factors in WES cohort, this link still existed (HR: 0. 60, 95% CI: 0. 38-0. 96, P = 0. 033), Notably, TMB was also found significantly higher in MED12-Mut patients in both WES and MSKCC cohort.

Further tumor-infiltrating lymphocytes and DDR-related gene analysis revealed anti-tumor immunity in MED12-Mut patients. Totally, MED12-Mut successfully predicted better clinical outcomes in ICIs-treated pan-cancer cohort, indicating that MED12-Mut could serve as a potential predictive biomarker for immune checkpoint inhibitors in pan-cancer.

论文信息

作者: Zhou Y、Tan Y、Zhang Q、Duan Q、Chen J
第一作者单位: Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.China
通讯作者单位: The 1st Dept of Thoracic Medical Oncology, The Second Hospital Of Dalian Medical University, No. 467, Zhongshan Road, Shahekou District, Dalian, 116027, Liaoning, China. chenjundoc2022@163.com.China
文献类型: 读者来信
期刊: European journal of medical research2022 Oct 29

原文标识: PubMed 36309740　·　DOI 10.1186/s40001-022-00856-z

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