Role of tumor mutation burden-related signatures in the prognosis and immune microenvironment of pancreatic ductal adenocarcinoma.
Role of tumor mutation burden-related signatures in the prognosis and immune microenvironment of pancreatic ductal adenocarcinoma.
复制标题
DOI：
10.1186/s12935-021-01900-4
复制
发表时间：
2021-04-07
影响因子：
5.8
通讯作者：
Shi S
中科院分区：
文献类型：
--
作者：
Tang R;Liu X;Wang W;Hua J;Xu J;Liang C;Meng Q;Liu J;Zhang B;Yu X;Shi S
高肿瘤突变负荷（TMB）已逐渐成为预测许多癌症（包括肺癌、膀胱癌和头颈癌）对免疫治疗反应的敏感生物标志物。然而，高TMB是否能预测胰腺导管腺癌（PDAC）对免疫治疗的反应和预后仍不清楚。因此，研究TMB相关基因（TRGs）在PDAC中的作用具有重要意义。PDAC的转录组和突变数据下载自The Cancer Genome Museum-Pancreatic Adenocarcinoma（TCGA）。五个独立的外部数据集的PDAC被选择来验证我们的结果的一部分。还进行了qRT-PCR和免疫组织化学染色，以提高本研究的可靠性。经肿瘤纯度校正后，TMB_low组中位总生存期（OS）较TMB评分高组显著延长（P = 0.03）。718个差异表达的TRG被鉴定并在一些致癌通路中功能富集。PDAC中67个TRG与OS相关。构建了OS的预后模型，并显示出较高的预测准确性（AUC = 0.849）。我们还发现TMB评分与肿瘤微环境中的多种免疫组分和特征相关。此外，我们发现PDAC亚组具有TMB低、微卫星不稳定性高（MSI高）的特点，与OS延长和一个关键分子ANKRD 55相关，可能介导生存获益。本研究分析了TMB在PDAC中的生物学功能、预后价值、突变景观的意义以及对免疫微环境的潜在影响，有助于认识TMB在PDAC中的作用。未来的研究预计将调查这些TRGs如何调节PDAC的启动，发展或抑制。在线版本包含补充材料，可通过10.1186/s12935-021-01900-4获得。
High tumor mutation burden (TMB) has gradually become a sensitive biomarker for predicting the response to immunotherapy in many cancers, including lung, bladder and head and neck cancers. However, whether high TMB predicts the response to immunotherapy and prognosis in pancreatic ductal adenocarcinoma (PDAC) remained obscure. Hence, it is significant to investigate the role of genes related to TMB (TRGs) in PDAC. The transcriptome and mutation data of PDAC was downloaded from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA). Five independent external datasets of PDAC were chosen to validate parts of our results. qRT-PCR and immunohistochemical staining were also performed to promote the reliability of this study. The median overall survival (OS) was significantly increased in TMB_low group compared with the counterpart with higher TMB score after tumor purity adjusted (P = 0.03). 718 differentially expressed TRGs were identified and functionally enriched in some oncogenic pathways. 67 TRGs were associated with OS in PDAC. A prognostic model for the OS was constructed and showed a high predictive accuracy (AUC = 0.849). We also found TMB score was associated with multiple immune components and signatures in tumor microenvironment. In addition, we identified a PDAC subgroup featured with TMBlowMicrosatellite instabilityhigh (MSIhigh) was associated with prolonged OS and a key molecule, ANKRD55, potentially mediating the survival benefits. This study analyzed the biological function, prognosis value, implications for mutation landscape and potential influence on immune microenvironment of TRGs in PDAC, which contributed to get aware of the role of TMB in PDAC. Future studies are expected to investigate how these TRGs regulate the initiation, development or repression of PDAC. The online version contains supplementary material available at 10.1186/s12935-021-01900-4.
登录
查看更多内容
影响因子：
7.7
作者：
Andersen DK;Korc M;Petersen GM;Eibl G;Li D;Rickels MR;Chari ST;Abbruzzese JL
通讯作者：
Abbruzzese JL
PD-1和PD-L1抑制剂作为癌症免疫疗法的一种形式的开发：对注册试验和未来考虑的全面综述。
影响因子：
10.9
作者：
Gong J;Chehrazi-Raffle A;Reddi S;Salgia R
通讯作者：
Salgia R
影响因子：
4.6
作者：
Bonneville R;Krook MA;Kautto EA;Miya J;Wing MR;Chen HZ;Reeser JW;Yu L;Roychowdhury S
通讯作者：
Roychowdhury S
影响因子：
5.7
作者：
Jang, Bum-Sup;Han, Wonsik;Kim, In Ah
通讯作者：
Kim, In Ah
影响因子：
82.9
作者：
Binnewies M;Roberts EW;Kersten K;Chan V;Fearon DF;Merad M;Coussens LM;Gabrilovich DI;Ostrand-Rosenberg S;Hedrick CC;Vonderheide RH;Pittet MJ;Jain RK;Zou W;Howcroft TK;Woodhouse EC;Weinberg RA;Krummel MF
通讯作者：
Krummel MF