In:
Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 14 ( 2020-07-15), p. 3641-3648
Abstract:
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 & lt; 0.0001]. This signature also robustly predicted survival in three independent validation cohorts ICGC [HR, 2.63 (1.56–4.41); P & lt; 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 & lt; 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.
Type of Medium:
Online Resource
ISSN:
1078-0432
,
1557-3265
DOI:
10.1158/1078-0432.CCR-19-4044
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2020
detail.hit.zdb_id:
1225457-5
detail.hit.zdb_id:
2036787-9
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