Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
The Medical Department, The State Key Lab of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing Simcere Medical Laboratory Science Co., Ltd, Jiangsu Simcere Diagnostics Co., Ltd, Building 5, No. 699-18 Xuanwu Avenue, Xuanwu District, Nanjing, Jiangsu, China.
Eur J Med Res. 2022 Oct 29;27(1):225. doi: 10.1186/s40001-022-00856-z.
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.
免疫检查点抑制剂 (ICIs) 疗法在多种癌症中引发了令人钦佩的抗肿瘤反应。越来越多的证据表明，它与 Mediator 复合物亚基 12 (MED12) 和 DNA 损伤修复 (DDR) 和 TGF-β 信号有关，而关于 MED12 与 ICI 反应相关性的临床数据尚缺乏。在这项研究中，将已发表研究的临床和全外显子组测序 (WES) 数据合并为 WES 队列，以探索癌症中 MED12 突变 (MED12-Mut) 与 ICI 疗效之间的关联。然后，使用纪念斯隆凯特琳癌症中心 (MSKCC) 队列来验证我们的发现。癌症基因组图谱 (TCGA) 队列用于进行抗肿瘤免疫和预后分析。在 WES 队列 (n=474) 中，MED12-Mut 和 MED12-野生型 (MED12-Wt) 患者在持久临床获益 (DCB，80.00% vs. 53.67%，P=0.022) 方面存在显著差异。此外，在 MED12-Mut 患者中观察到明显延长的无进展生存期 (mPFS：未达到，NR vs. 5.87 个月，HR：0.38，95%CI 0.17-0.85，对数秩检验 P=0.015)。在考虑年龄、性别、转移、治疗和 TMB 状态后，多变量 Cox 比例风险回归的结果表明，PFS 明显更好 (HR：0.40，95%CI 0.18-0.92；P=0.031)。在 MSKCC 队列 (n=1513) 中，在 MED12-Mut 患者中观察到总生存期优势 (mOS：41 个月 vs. 19 个月，HR：0.54，95%CI 0.34-0.85；对数秩检验 P=0.007)，在考虑到 WES 队列中相同因素后，这种关联仍然存在 (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，MED12-Mut 患者的 TMB 也明显更高。进一步的肿瘤浸润淋巴细胞和 DDR 相关基因分析显示 MED12-Mut 患者具有抗肿瘤免疫活性。总的来说，在接受 ICI 治疗的泛癌队列中，MED12-Mut 成功预测了更好的临床结局，表明 MED12-Mut 可作为泛癌免疫检查点抑制剂的潜在预测生物标志物。
