Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
Department of Clinical Nutrition, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
Department of Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China.
Department of Hepatobiliary Surgery, The Affiliated Hospital of North Sichuan Medical College, Sichuan 637000, China.
Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Sichuan 637000, China.
背景
。目前，免疫治疗广泛用于乳腺癌（BC）患者，肿瘤突变负荷（TMB）被认为是免疫治疗反应的有价值的独立预测因子。然而，特定基因突变及其与 BC 中 TMB 和肿瘤浸润性免疫细胞的关系尚不完全清楚。
方法
. 使用来自癌症基因组图谱 (TCGA) 和国际癌症基因组联盟 (ICGC) 数据集的数据进行全面的生物信息学分析。通过 Kaplan-Meier 分析分析生存曲线。单变量和多变量 Cox 回归分析用于预后分析。进行基因集富集分析（GSEA）以探索调控机制和功能。CIBERSORT 算法用于计算肿瘤浸润免疫细胞分数。
结果
. 我们分析了来自 TCGA 和 ICGC 数据集的 BC 体细胞突变数据，发现两个队列均报告了 19 个频繁突变的基因，即 SPTA1、TTN、MUC17、MAP3K1、CDH1、FAT3、SYNE1、FLG、HMCN1、RYR2（兰尼碱受体 2 )、GATA3、MUC4、PIK3CA、KMT2C、TP53、PTEN、ZFHX4、MUC16 和 USH2A。其中，我们观察到 RYR2 突变与更高的 TMB 和更好的临床预后显着相关。此外，GSEA 揭示 RYR2 突变富集的信号通路与免疫相关通路有关。此外，基于 CIBERSORT 算法，我们发现 RYR2 突变通过富集 CD8+ T 细胞、激活记忆 CD4+ T 细胞和 M1 巨噬细胞来增强抗肿瘤免疫反应。
结论
. RYR2在BC中经常发生突变，其突变与TMB增加有关，促进抗肿瘤免疫；因此，RYR2 可以作为一种有价值的生物标志物来预测免疫反应。
Background
. Currently, immunotherapy is widely used for breast cancer (BC) patients, and tumor mutation burden (TMB) is regarded as a valuable independent predictor of response to immunotherapy. However, specific gene mutations and their relationship with TMB and tumor-infiltrating immune cells in BC are not fully understood.
Methods
. Comprehensive bioinformatic analyses were performed using data from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets. Survival curves were analyzed via Kaplan-Meier analysis. Univariate and multivariate Cox regression analyses were used for prognosis analysis. Gene set enrichment analysis (GSEA) was performed to explore regulatory mechanisms and functions. The CIBERSORT algorithm was used to calculate the tumor-infiltrating immune cell fractions.
Results
. We analyzed somatic mutation data of BC from TCGA and ICGC datasets and found that 19 frequently mutated genes were reported in both cohorts, namely, SPTA1, TTN, MUC17, MAP3K1, CDH1, FAT3, SYNE1, FLG, HMCN1, RYR2 (ryanodine receptor 2), GATA3, MUC4, PIK3CA, KMT2C, TP53, PTEN, ZFHX4, MUC16, and USH2A. Among them, we observed that RYR2 mutation was significantly associated with higher TMB and better clinical prognosis. Moreover, GSEA revealed that RYR2 mutation-enriched signaling pathways were related to immune-associated pathways. Furthermore, based on the CIBERSORT algorithm, we found that RYR2 mutation enhanced the antitumor immune response by enriching CD8+ T cells, activated memory CD4+ T cells, and M1 macrophages.
Conclusion
. RYR2 is frequently mutated in BC, and its mutation is related to increased TMB and promotes antitumor immunity; thus, RYR2 may serve as a valuable biomarker to predict the immune response.
