School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
Front Immunol. 2023 Feb 24;14:1090838. doi: 10.3389/fimmu.2023.1090838. eCollection 2023.
Tumor mutation burden (TMB) has been recognized as a predictive biomarker for immunotherapy response in cancer. Systematic identification of molecular features correlated with TMB is significant, although such investigation remains insufficient.
We analyzed associations of somatic mutations, pathways, protein expression, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), competing endogenous RNA (ceRNA) antitumor immune signatures, and clinical features with TMB in various cancers using multi-omics datasets from The Cancer Genome Atlas (TCGA) program and datasets for cancer cohorts receiving the immune checkpoint blockade therapy.
Among the 32 TCGA cancer types, melanoma harbored the highest percentage of high-TMB (≥ 10/Mb) cancers (49.4%), followed by lung adenocarcinoma (36.9%) and lung squamous cell carcinoma (28.1%). Three hundred seventy-six genes had significant correlations of their mutations with increased TMB in various cancers, including 11 genes (, , , , , , , , , ,and ) with the characteristic of their mutations associated with a favorable response to immunotherapy. Based on the mutation profiles in three genes (, , and ), we defined the TMB prognostic score that could predict cancer survival prognosis in the immunotherapy setting but not in the non-immunotherapy setting. It suggests that the TMB prognostic score's ability to predict cancer prognosis is associated with the positive correlation between immunotherapy response and TMB. Nine cancer-associated pathways correlated positively with TMB in various cancers, including nucleotide excision repair, DNA replication, homologous recombination, base excision repair, mismatch repair, cell cycle, spliceosome, proteasome, and RNA degradation. In contrast, seven pathways correlated inversely with TMB in multiple cancers, including Wnt, Hedgehog, PI3K-AKT, MAPK, neurotrophin, axon guidance, and pathways in cancer. High-TMB cancers displayed higher levels of antitumor immune signatures and expression than low-TMB cancers in diverse cancers. The association between TMB and survival prognosis was positive in bladder, gastric, and endometrial cancers and negative in liver and head and neck cancers. TMB also showed significant associations with age, gender, height, weight, smoking, and race in certain cohorts.
The molecular and clinical features significantly associated with TMB could be valuable predictors for TMB and immunotherapy response and therefore have potential clinical values for cancer management.
肿瘤突变负荷（TMB）已被认为是癌症免疫治疗反应的预测性生物标志物。系统性地鉴定与 TMB 相关的分子特征具有重要意义，但此类研究仍不够充分。
我们使用来自癌症基因组图谱（TCGA）计划的多组学数据集以及接受免疫检查点阻断治疗的癌症队列数据集，分析了各种癌症中体细胞突变、途径、蛋白表达、microRNAs（miRNAs）、长链非编码 RNA（lncRNA）、竞争性内源性 RNA（ceRNA）抗肿瘤免疫特征以及临床特征与 TMB 的相关性。
在 32 种 TCGA 癌症类型中，黑色素瘤（49.4%）中高 TMB（≥10/Mb）癌症的比例最高，其次是肺腺癌（36.9%）和肺鳞状细胞癌（28.1%）。在各种癌症中，有 376 个基因的突变与其 TMB 的增加具有显著相关性，其中 11 个基因（,,,,,,,,,,and ）具有突变特征，与免疫治疗的有利反应相关。基于三个基因（,, 和 ）的突变谱，我们定义了 TMB 预后评分，该评分可预测免疫治疗背景下的癌症生存预后，但不能预测非免疫治疗背景下的癌症生存预后。这表明 TMB 预后评分预测癌症预后的能力与免疫治疗反应与 TMB 之间的正相关有关。在各种癌症中，有 9 个癌症相关途径与 TMB 呈正相关，包括核苷酸切除修复、DNA 复制、同源重组、碱基切除修复、错配修复、细胞周期、剪接体、蛋白酶体和 RNA 降解。相反，在多种癌症中，有 7 个途径与 TMB 呈负相关，包括 Wnt、Hedgehog、PI3K-AKT、MAPK、神经营养因子、轴突导向和癌症途径。高 TMB 癌症在多种癌症中显示出比低 TMB 癌症更高水平的抗肿瘤免疫特征和 表达。在膀胱癌、胃癌和子宫内膜癌中，TMB 与生存预后呈正相关，而在肝癌和头颈部癌症中呈负相关。TMB 还与某些队列中的年龄、性别、身高、体重、吸烟和种族显著相关。
与 TMB 显著相关的分子和临床特征可能是 TMB 和免疫治疗反应的有价值预测因子，因此对癌症管理具有潜在的临床价值。
