Department of Radiation Oncology, Department of Pathology, Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.
Department of Health Statistics, Key Laboratory of Medicine and Health of Shandong Province, School of Public Health, Shandong Second Medical University, Weifang, Shandong, China.
Front Immunol. 2024 Nov 1;15:1423796. doi: 10.3389/fimmu.2024.1423796. eCollection 2024.
Currently developed molecular markers can predict the effectiveness of cancer immunotherapy and screen beneficiaries to some extent, but they are not stable enough. Therefore, there is an urgent need for discovering novel biomarkers. At the same time, sex factor plays a vital role in the response to immunotherapy, so it is particularly important to identify sex-related molecular indicators.
We integrated a pan-cancer cohort consisting of 2348 cancer patients who received immune checkpoint inhibitors and targeted sequencing. Using somatic mutation profiles, we identified mutational signatures, molecular subtypes, and frequently mutated genes, and analyzed their relationships with immunotherapeutic outcomes. We also explored sex disparities of determined biomarkers in response to treatments.
We found that male patients exhibited better immunotherapy outcomes and higher tumor mutational burden. A total of seven mutational signatures were identified, among which signatures 1 and 3 were associated with worse immunotherapy outcomes, while signatures 2 and 6 correlated with better outcomes. Gender-based analysis revealed that mutational signature 1 continued to show a worse immunotherapy outcome in female patients, whereas signature 6 demonstrated a better outcome in male patients. Based on mutational activities, we identified four potential molecular subtypes with gender differences and relevance to treatment outcomes. PI3K-AKT, RAS signaling pathways, and 68 significantly mutated genes were identified to be associated with immunotherapy outcomes, with nine genes (i.e., ATM, ATRX, DOT1L, EP300, EPHB1, NOTCH1, PBRM1, RBM10, and SETD2) exhibiting gender differences. Finally, we discovered co-mutated gene pairs and TP53 p.R282W mutations related to treatment outcomes, highlighting their gender-specific differences.
This study identified several molecular biomarkers related to cancer immunotherapy outcomes in terms of mutational signatures, molecular subtypes, and mutated genes, and explored their gender-relatedness in order to provide clues and basis for clinical treatment efficacy evaluation and patient selection.
目前开发的分子标志物可以在一定程度上预测癌症免疫治疗的效果，并筛选受益人群，但它们还不够稳定。因此，迫切需要发现新的生物标志物。同时，性别因素在免疫治疗反应中起着至关重要的作用，因此，确定与性别相关的分子指标尤为重要。
我们整合了一个包含 2348 名接受免疫检查点抑制剂和靶向测序的癌症患者的泛癌队列。利用体细胞突变谱，我们确定了突变特征、分子亚型和高频突变基因，并分析了它们与免疫治疗结果的关系。我们还探索了确定生物标志物对治疗反应的性别差异。
我们发现男性患者的免疫治疗效果更好，肿瘤突变负担更高。共确定了 7 种突变特征，其中特征 1 和 3 与免疫治疗效果较差相关，而特征 2 和 6 与较好的效果相关。基于性别的分析表明，在女性患者中，突变特征 1 继续显示出免疫治疗效果较差，而在男性患者中，特征 6 显示出较好的效果。基于突变活动，我们确定了四个具有性别差异和与治疗结果相关的潜在分子亚型。PI3K-AKT、RAS 信号通路和 68 个显著突变基因与免疫治疗结果相关，其中 9 个基因（即 ATM、ATR、DOT1L、EP300、EPHB1、NOTCH1、PBRM1、RBM10 和 SETD2）表现出性别差异。最后，我们发现了与治疗结果相关的共突变基因对和 TP53 p.R282W 突变，突出了它们的性别特异性差异。
本研究从突变特征、分子亚型和突变基因等方面确定了与癌症免疫治疗结果相关的几个分子生物标志物，并探讨了它们的性别相关性，为临床治疗效果评估和患者选择提供了线索和依据。
