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A 15-Gene Immune, Stromal, and Proliferation Gene Signature that Significantly Associates with Poor Survival in Patients with Pancreatic Ductal Adenocarcinoma.
Clinical Cancer Research ( IF 11.5 ) Pub Date : 2020-07-15 , DOI: 10.1158/1078-0432.ccr-19-4044
Raju Kandimalla 1 , Hideo Tomihara 1, 2 , Jasjit K Banwait 1 , Kensuke Yamamura 3 , Gagandeep Singh 4 , Hideo Baba 3 , Ajay Goel 1, 5
Affiliation  

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with dismal survival rates. Tumor microenvironment (TME), comprising of immune cells and cancer-associated fibroblasts, plays a key role in driving poor prognosis and resistance to chemotherapy. Herein, we aimed to identify a TME-associated, risk-stratification gene biomarker signature in PDAC. Experimental Design: The initial biomarker discovery was performed in The Cancer Genome Atlas (TCGA, n = 163) transcriptomic data. This was followed by independent validation of the gene signature in the International Cancer Genome Consortium (ICGC, n = 95), E-MTAB-6134 ( n = 288), and GSE71729 ( n = 123) datasets for predicting overall survival (OS), and for its ability to detect poor molecular subtypes. Clinical validation and nomogram establishment was undertaken by performing multivariate Cox regression analysis. Results: Our biomarker discovery effort identified a 15-gene immune, stromal, and proliferation (ISP) gene signature that significantly associated with poor OS [HR, 3.90; 95% confidence interval (CI), 2.36–6.41; P < 0.0001]. This signature also robustly predicted survival in three independent validation cohorts ICGC [HR, 2.63 (1.56–4.41); P < 0.0001], E-MTAB-6134 [HR, 1.53 (1.14–2.04); P = 0.004], and GSE71729 [HR, 2.33 (1.49–3.63); P < 0.0001]. Interestingly, the ISP signature also permitted identification of poor molecular PDAC subtypes with excellent accuracy in all four cohorts; TCGA (AUC = 0.94), ICGC (AUC = 0.91), E-MTAB-6134 (AUC = 0.80), and GSE71729 (AUC = 0.83). The ISP-derived high-risk patients exhibited significantly poor OS in a clinical validation cohort [ n = 119; HR, 2.62 (1.50–4.56); P = 0.0004]. A nomogram was established which included the ISP, CA19-9, and T- and N-stage for eventual clinical translation. Conclusions: We report a novel gene signature for risk-stratification and robust identification of patients with PDAC with poor molecular subtypes.

中文翻译:

与胰腺导管腺癌患者的不良生存率显着相关的 15 基因免疫、基质和增殖基因特征。

目的:胰腺导管腺癌(PDAC)是一种致命疾病,生存率很低。肿瘤微环境(TME)由免疫细胞和癌症相关成纤维细胞组成,在导致不良预后和化疗耐药性方面发挥着关键作用。在此,我们的目的是确定 PDAC 中与 TME 相关的风险分层基因生物标志物特征。实验设计:最初的生物标志物发现是在癌症基因组图谱(TCGA,n = 163)转录组数据中进行的。随后对国际癌症基因组联盟 (ICGC,n = 95)、E-MTAB-6134 (n = 288) 和 GSE71729 (n = 123) 数据集中的基因特征进行独立验证,用于预测总生存期 (OS) ,以及其检测不良分子亚型的能力。通过执行多元 Cox 回归分析进行临床验证和列线图建立。结果:我们的生物标志物发现工作发现了 15 个基因的免疫、基质和增殖 (ISP) 基因特征,该特征与 OS 较差显着相关 [HR,3.90;95% 置信区间 (CI),2.36–6.41;P<0.0001]。该特征还有力地预测了三个独立验证队列 ICGC 的生存率 [HR, 2.63 (1.56–4.41);P < 0.0001],E-MTAB-6134 [HR,1.53 (1.14–2.04);P = 0.004] 和 GSE71729 [HR,2.33 (1.49–3.63);P<0.0001]。有趣的是,ISP 签名还可以在所有四个队列中以极高的准确性识别较差的分子 PDAC 亚型;TCGA(AUC = 0.94)、ICGC(AUC = 0.91)、E-MTAB-6134(AUC = 0.80)和GSE71729(AUC = 0.83)。ISP 衍生的高风险患者在临床验证队列中表现出明显较差的 OS [ n = 119;心率,2.62(1.50–4.56);P = 0.0004]。建立了列线图,其中包括 ISP、CA19-9 以及用于最终临床转化的 T 期和 N 期。结论:我们报告了一种新的基因特征,用于对分子亚型较差的 PDAC 患者进行风险分层和稳健识别。
更新日期:2020-07-15
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