Molecular Subtypes Of Pancreatic Ductal Adenocarcinoma Research Articles

Epigenetic Landscape of DNA Methylation in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by its aggressive progression and dismal prognosis. Advances in epigenetic profiling, specifically DNA methylation analysis, have significantly deepened our understanding of PDAC pathogenesis. This review synthesizes findings from recent genome-wide DNA methylation studies, which have delineated a complex DNA methylation landscape differentiating between normal and cancerous pancreatic tissues, as well as across various stages and molecular subtypes of PDAC. These studies identified specific differentially methylated regions (DMRs) that not only enhance our grasp of the epigenetic drivers of PDAC but also offer potential biomarkers for early diagnosis and prognosis, enabling the customization of therapeutic approaches. The review further explores how DNA methylation profiling could facilitate the development of subtype-tailored therapies, potentially improving treatment outcomes based on precise molecular characterizations. Overall, leveraging DNA methylation alterations as functional biomarkers holds promise for advancing our understanding of disease progression and refining PDAC management strategies, which could lead to improved patient outcomes and a deeper comprehension of the disease’s underlying biological mechanisms.

Cytokines and Pancreatic Ductal Adenocarcinoma: Exploring Their Relationship with Molecular Subtypes and Prognosis.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by its poor prognosis. The current challenge remains the absence of predictive biomarkers. Cytokines are crucial factors in the pathogenesis and prognosis of PDAC. Furthermore, there is growing interest in differentiating between molecular subtypes of PDAC. The aim of our study is to evaluate the association between the analyzed cytokines and the molecular subtypes of PDAC and to determine their prognostic value. Cytokine levels were measured in 73 patients, and molecular subtypes were analyzed in 34 of these patients. Transforming Growth Factor Beta 2 (TGF-β2) levels were independently associated with the basal-like and null subtypes. In patients with locally advanced and metastatic PDAC, elevated levels of interleukin (IL)-1α, IL-1β, IL-6, IL-8, IL-9, and IL-15 were associated with a higher risk of progression during first-line treatment, and increased levels of IL-1β, IL-6, IL-8, IL-9, and IL-15 were related to increased mortality. Furthermore, a significant association was observed between higher percentiles of IL-6 and IL-8 and shorter progression-free survival (PFS) during first-line treatment, and between higher percentiles of IL-8 and shorter overall survival (OS). In the multivariate analysis, only elevated levels of IL-8 were independently associated with a higher risk of progression during first-line treatment and mortality. In conclusion, the results of our study suggest that cytokine expression varies according to the molecular subtype of PDAC and that cytokines also play a relevant role in patient prognosis.

Axon guidance cue SEMA3A promotes the aggressive phenotype of basal-like PDAC

ObjectiveThe dysregulation of the axon guidance pathway is common in pancreatic ductal adenocarcinoma (PDAC), yet our understanding of its biological relevance is limited. Here, we investigated the functional role of...

Whole-genome bisulfite sequencing identifies stage- and subtype-specific DNA methylation signatures in pancreatic cancer

In pancreatic ductal adenocarcinoma (PDAC), no recurrent metastasis-specific mutation has been found, suggesting that epigenetic mechanisms, such as DNA methylation, are the major contributors of late-stage disease progression. Here, we performed the first whole-genome bisulfite sequencing (WGBS) on mouse and human PDAC organoid models to identify stage-specific and molecular subtype-specific DNA methylation signatures. With this approach, we identified thousands of differentially methylated regions (DMRs) that can distinguish between the stages and molecular subtypes of PDAC. Stage-specific DMRs are associated with genes related to nervous system development and cell-cell adhesions, and are enriched in promoters and bivalent enhancers. Subtype-specific DMRs showed hypermethylation of GATA6 foregut endoderm transcriptional networks in the squamous subtype and hypermethylation of EMT transcriptional networks in the progenitor subtype. These results indicate that aberrant DNA methylation contributes to both PDAC progression and subtype differentiation, resulting in significant and reoccurring DNA methylation patterns with diagnostic and prognostic potential.

An integrated analysis identifies six molecular subtypes of pancreatic ductal adenocarcinoma revealing cellular and molecular landscape.

Pancreatic ductal adenocarcinoma (PDA) has been found to have a high mortality rate. Despite continuous efforts, current histopathological classification is insufficient to guide individualized therapies of PDA. We first define the molecular subtypes of PDA (MSOP) based on a meta-cohort of 845 samples from 11 PDA datasets. We then performed functional analyses involving immunity, fibrosis and metabolism. We recognized six molecular subtypes with different survival statistics and molecular composition. The squamous basal-like (SBL) subtype had a poor prognosis and high infiltration of ENO1+ (Enolase 1)/ADM+ (Adrenomedullin) cancer-associated fibroblasts (CAFs). The immune mesenchymal-like (IML) subtype and the normal mesenchymal-like (NML) subtype were characterized by genes associated with extracellular matrix (ECM) activities and immune responses, having favorable prognoses. IML was featured by elevated exhausted immune signaling and inflammatory CAFs infiltration, whereas NML was featured with myofibroblastic CAFs infiltration. The exocrine-like (EL) subtype was high in exocrine signals, while the pure classical-like (PCL) subtype lacked immunocytes infiltration. The quiescent-like (QL) subtype had diminished metabolic signaling and high infiltration of NK cells. SBL, IML and NML were enriched in innate anti-PD-1 resistance signatures. In sum, this MSOP depicts a vivid cell-to-molecular atlas of the tumor microenvironment of PDA and might facilitate to design a precise combination of therapies that target immunity, metabolism and stroma.

Identification of Serum miRNA Signature and Establishment of a Nomogram for Risk Stratification in Patients With Pancreatic Ductal Adenocarcinoma.

The aim of the study was to perform mRNA-miRNA regulatory network analyses to identify a miRNA panel for molecular subtype identification and stratification of high-risk patients with pancreatic ductal adenocarcinoma (PDAC). Recent transcriptional profiling effort in PDAC has led to the identification of molecular subtypes that associate with poor survival; however, their clinical significance for risk stratification in patients with PDAC has been challenging. By performing a systematic analysis in The Cancer Genome Atlas and International Cancer Genome Consortium cohorts, we discovered a panel of miRNAs that associated with squamous and other poor molecular subtypes in PDAC. Subsequently, we used logistic regression analysis to develop models for risk stratification and Cox proportional hazard analysis to determine survival prediction probability of this signature in multiple cohorts of 433 patients with PDAC, including a tissue cohort (n = 199) and a preoperative serum cohort (n = 51). We identified a panel of 9 miRNAs that were significantly upregulated (miR-205-5p and -934) or downregulated (miR-192-5p, 194-5p, 194-3p, 215-5p, 375-3p, 552-3p, and 1251-5p) in PDAC molecular subtypes with poor survival [squamous, area under the receiver operating characteristic curve (AUC) = 0.90; basal, AUC = 0.89; and quasimesenchymal, AUC = 0.83]. The validation of this miRNA panel in a tissue clinical cohort was a significant predictor of overall survival (hazard ratio = 2.48, P < 0.0001), and this predictive accuracy improved further in a risk nomogram which included key clinicopathological factors. Finally, we were able to successfully translate this miRNA predictive signature into a liquid biopsy-based assay in preoperative serum specimens from PDAC patients (hazard ratio: 2.85, P = 0.02). We report a novel miRNA risk-stratification signature that can be used as a noninvasive assay for the identification of high-risk patients and potential disease monitoring in patients with PDAC.

Abstract 4883: A glycan gene signature that robustly predicts prognosis in patients with pancreatic ductal adenocarcinoma

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) remains the fourth leading cause of cancer-related deaths in the United States, with an overall 5-year survival rates of ~8%. The currently used clinicopathological factors (e.g. tumor size and grade, lymph node etc.) for determining patient prognosis are suboptimal. The only FDA-approved molecular non-invasive prognostic biomarker for PDAC patients is CA-19-9, which suffers from inadequate sensitivity and specificity. Nonetheless, the clinical use of CA-19-9, along with the growing evidence that altered glycosylation plays an important role in PDAC pathogenesis, provided us with a rationale to explore the clinical significance of glycan-related genes as potential prognostic biomarkers in PDAC. Experimental design: We performed a comprehensive biomarker discovery (TCGA cohort, n=182), and validation (ICGC, n=80; GSE62452, n=65) to identify a glycan gene signature for predicting overall survival (OS) in PDAC patients. Subsequently, this gene signature was validated in two, independent, clinical cohorts (test cohort, n=103; validation cohort, n=227). The performance of this signature was further evaluated by univariate and multivariate CoxPH analyses. Lastly, using a logistic-regression model, we explored the feasibility of our glycan signature in identifying various molecular subtypes of PDAC. Results: A comprehensive analysis of 411 glycan genes using Cox-LASSO regression modelling led to the identification of a 12-glycan gene signature, which robustly predicted overall survival (OS) of PDAC patients in the discovery (AUC=0.78), and two validation cohorts (ICGC, AUC=0.72; and GSE62452, AUC=0.70). Subsequent qRT-PCR validation in two in-house clinical cohorts revealed that a 9-gene signature was a robust predictor of OS (Test Cohort, HR: 1.81, 95% CI, 1.22-2.69, p=0.003; Validation Cohort, HR: 2.72, 95% CI, 2.00-3.69, p&amp;lt;0.0001). In univariate analysis, in addition to the 9-gene signature, the nodal status and CA-19-9 levels were significant predictors; while in the multivariate analyses, the gene signature emerged as an independent predictor of OS. A risk-assessment model including the 9-gene signature and the two clinical factors further improved the OS prediction (Test Cohort, HR: 2.71, 95% CI, 1.85-3.99, p&amp;lt;0.0001; Validation Cohort, HR: 2.72, 95% CI, 2.03-3.63, p&amp;lt;0.0001). Intriguingly, our signature was also highly accurate in identifying PDAC subtype with poor survival (i.e. squamous subtype) in the TCGA (AUC=0.87, P&amp;lt;0.0001) and the ICGC cohorts (AUC=0.89, P&amp;lt;0.0001). Conclusion: Our systematic biomarker discovery and validation efforts led to the identification and establishment of a 9-gene glycan signature that robustly predicts survival in PDAC patients, and can accurately identify poor PDAC subtypes - highlighting its potential clinical significance for the personalized management of PDAC patients. Citation Format: Priyanka Sharma, Raju Kandimalla, Jasjit K. Banwait, Masayuki Sho, Yasuhiro Kodera, Ajay Goel. A glycan gene signature that robustly predicts prognosis in patients with pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4883.

Abstract 762: A non-invasive miRNA signature for the identification of pancreatic ductal adenocarcinoma (PDAC) patients with poor molecular subtypes and worse prognosis

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with dismal prognosis. Recent advances in treatment paradigms have been encouraging; however, identification of appropriate patient populations and a better understanding of the underlying tumor heterogeneity could further improve patient outcomes. Recently, four distinct molecular subtypes of PDAC were established, and in particular, squamous subtype was attributed with worse prognosis. Nonetheless, the clinical application of genome-wide transcriptome-based subtyping is cumbersome. Therefore, in this study, we identified miRNA networks regulating the expression of various genes in each PDAC subtype, with a goal to develop tissue and liquid biopsy-based miRNA biomarkers that can be translated into the clinic. Experimental Design: We used a mRNA-miRNA network-based approach to unravel miRNA networks regulating various PDAC subtypes. Using logistic regression models and area under the curve (AUC) analysis, we evaluated the performance of a miRNA-signature for identifying poor molecular subtypes of PDAC. Using qRT-PCR assays, we also analyzed the prognostic significance of the miRNA panel in 433 PDAC patients, including TCGA (n=183), multiple in-house retrospective, tissue cohorts (n=199) and a prospective, preoperative serum cohort (n=51). Univariate and multivariate Cox-proportional hazard models were used for data analysis, and Youden’s index derived cut-off thresholds were used to plot the Kaplan Meier (KM) curves for overall survival. Results: We identified a panel of 9-miRNAs that were significantly dysregulated (upregulated: miR-205-5p and -934; downregulated: miR-192-5p, 194-5p, 194-3p, 215-5p, 375-3p, 552-3p and 1251-5p) in squamous subtype; and was highly accurate in identifying all poor molecular PDAC subtypes proposed previously (Squamous AUC=0.90, Basal AUC=0.89 and Quasimesenchymal AUC=0.83). Intriguingly, expression level of all these 9-miRNAs clearly stratified overall survival (OS) in patient subgroups, and patients with high-risk scores exhibited significantly worse OS (Hazard ratio (HR): 2.48, p&amp;lt;0.0001). Intriguingly, our miRNA signature was equally robust even in pre-operative serum specimens for identifying patients with poor OS (HR: 2.85, p=0.02), highlighting its significance for treatment decision-making in the clinic. Conclusions: We for the first time report a unique miRNA signature for identifying patients with poor molecular subtype PDAC who are at risk for worse overall survival. Our 9-miRNA signature can be easily adapted into the clinical setting using simple qRT-PCR based assays. The discrimination of high-risk patients even in the preoperative setting could improve the selection of PDAC patients for neoadjuvant treatment, especially in those with unresectable disease. Citation Format: Raju Kandimalla, Tadanobu Shimura, Saurav Mallik, Susan Tsai, Douglas B. Evans, Hideo Baba, Yasuhiro Kodera, Xi Chen, Ajay Goel. A non-invasive miRNA signature for the identification of pancreatic ductal adenocarcinoma (PDAC) patients with poor molecular subtypes and worse prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 762.

KRAS above and beyond - EGFR in pancreatic cancer

KRAS above and beyond - EGFR in pancreatic cancer