Molecular Subtypes Of Pancreatic Cancer Research Articles

Abstract 719: Pathobiological implications of Trefoil Factors in the progression and metastasis of pancreatic cancer

Abstract Background: Pancreatic cancer (PC) is a highly lethal malignancy and the disastrous statistics warrants an urgent need to develop new diagnostic and prognostic marker(s) and therapeutic target(s) for its better management. Trefoil factors (TFF 1/2/3) are a family of small, stable molecules observed to co-express with mucin and secreted by mucus-producing cells that facilitate mucosal repair after injury. Recent studies have shown that TFF1 and TFF3 can differentiate between molecular subtypes of PC. Based on this, we hypothesized that differential expression of TFF1 and TFF3 could predict pancreatic intraepithelial neoplasia (PanIN) as well as the early stage of PC. The present study explores the diagnostic and functional significance of TFF in PC. Material and Methods: Immunohistochemistry was used to determine the expression status of TFF1 and TFF3 in PC tissue microarray containing normal pancreatic (n=40), pancreatic intraepithelial lesion 1, 2, 3 (PanIN 1- 3, n=13) and well, moderately and poorly differentiated PC tissues (n=149). Sandwich ELISA was used to detect TFF1 levels in serum. The diagnostic significance of TFF1 was evaluated in the sample set (n=331) comprising of benign control (BC, n=104), chronic pancreatitis (CP, n=47), early stage PC (EPC, Stage 1 and 2, n=78) and late PC (LPC, Stage 2-3, n=69). RT-PCR and ELISA were carried out to profile levels of TFF1 and TFF3 in PC cell lines and cell supernatants respectively. Recombinant treatment with TFF3 was performed to observe the impact on of transmembrane (MUC4) and secreted mucins (MUC5AC) stability and expression. Results: Differential expression of TFF3 was observed in PanIN precursor lesion, pancreatic cancer tissue in comparison to normal pancreatic tissue (p < 0.0003). Furthermore, the TFF3 expression was significantly higher for well-differentiated tumor in comparison to poorly differentiated cases (p = 0.006). For TFF1, expression was significantly higher in PanIN lesions compared to normal pancreas (p < 0.0001), and PC versus normal pancreatic tissue (p < 0.0001). In serum, significantly increased expression of TFF1 was observed in EPC serum samples compared to BC (p-value = 0.035) and CP (p-value=0.0058) cases. RT-PCR analysis revealed positive expression of TFF1 and TFF3 in the majority of the PC cell lines. Treatment of PC cells with recombinant TFF3 lead to differential expression of MUC4 and MUC5AC. Conclusion: Overall, both tissue and serum based studies show that TFF1 and TFF3 are differentially expressed in early PanIN lesions as well early stage of PC tissues compared to normal pancreas. Overall, these results suggest a potential implication of TFF1 and TFF3 in PC pathogenesis and provide a basis for functional impact of TFF 1 and 3 on mucins stability and downstream signaling in PC pathogenesis. Citation Format: Rahat Jahan, Sukhwinder Kaur, Muzafar A. Macha, Yuri Sheinin, Lynette Smith, Jane Meza, Surinder K. Batra. Pathobiological implications of Trefoil Factors in the progression and metastasis of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 719. doi:10.1158/1538-7445.AM2017-719

Genome-wide DNA methylation analysis reveals molecular subtypes of pancreatic cancer.

Pancreatic cancer (PC) is the fourth leading cause of cancer deaths in the United States with a five-year patient survival rate of only 6%. Early detection and treatment of this disease is hampered due to lack of reliable diagnostic and prognostic markers. Recent studies have shown that dynamic changes in the global DNA methylation and gene expression patterns play key roles in the PC development; hence, provide valuable insights for better understanding the initiation and progression of PC. In the current study, we used DNA methylation, gene expression, copy number, mutational and clinical data from pancreatic patients. We independently investigated the DNA methylation and differential gene expression profiles between normal and tumor samples and correlated methylation levels with gene expression patterns. We observed a total of ~23-thousand differentially methylated CpG sites (Δβ≥0.1) between normal and tumor samples, where majority of the CpG sites are hypermethylated in PC, and this phenomenon is more prominent in the 5′UTRs and promoter regions compared to the gene bodies. Differential methylation is observed in genes associated with the homeobox domain, cell division and differentiation, cytoskeleton, epigenetic regulation and development, pancreatic development and pancreatic signaling and pancreatic cancer core signaling pathways. Correlation analysis suggests that methylation in the promoter region and 5′UTR has mostly negative correlations with gene expression while gene body and 3′UTR associated methylation has positive correlations. Regulatory element analysis suggests that HOX cluster and histone core proteins are upstream regulators of hypomethylation, while SMAD4, STAT4, STAT5B and zinc finger proteins (ZNF) are upstream regulators of hypermethylation. Non-negative matrix factorization (NMF) clustering of differentially methylated sites generated three clusters in PCs suggesting the existence of distinct molecular subtypes. Cluster 1 and cluster 2 showed samples enriched with clinical phenotypes like neoplasm histological grade and pathologic T-stage T3, respectively, while cluster 3 showed the enrichment of samples with neoplasm histological grade G1. To the best of our knowledge, this is the first genome-scale methylome analysis of PC data from TCGA. Our clustering analysis provides a strong basis for future work on the molecular subtyping of epigenetic regulation in pancreatic cancer.

Molecular Subtyping of Pancreatic Cancer: Translating Genomics and Transcriptomics into the Clinic.

Pancreatic cancer remains one of the most lethal malignancies, and insights into both personalized diagnosis and intervention of this disease are urgently needed. The rapid development of sequencing technologies has enabled the successive completion of a series of genetic and epigenetic sequencing studies of pancreatic cancer. The mutational landscape of pancreatic cancer is generally portrayed in terms of somatic mutations, structural variations, epigenetic alterations and the core signaling pathways. In recent years, four significant molecular subtype classifications of pancreatic cancer have been proposed based on the expression of transcription factors and downstream targets or the distribution of structural rearrangements. Increasing researches focus on the identification of somatic mutations and other genetic aberrations that drive pancreatic cancer has led to a new era of precision medicine based on molecular subtyping. However, few known molecular classifications are used to guide clinical strategies. Specific scientific, regulatory and ethical challenges must be overcome before genomic and transcriptomic discoveries can be translated into the clinic.

Molecular subtypes of pancreatic cancer based on miRNA expression profiles have independent prognostic value.

Altered microRNAs (miRNA) expression, a typical feature of many cancers, is reportedly associated with prognosis according to several studies. Although numerous studies on miRNAs in pancreatic ductal adenocarcinoma have also attempted to identify prognostic biomarkers, more large-scale clinical studies are needed to establish the clinical significance of the results. Present study aimed to identify prognosis-related molecular subtypes of primary pancreas tumors using miRNA expression profiling. Expression profiles of 1733 miRNAs were obtained by using microarray analysis of 104 pancreatic tumors of Korean patients. To detect subgroups informative in predicting the patient's prognosis, we applied unsupervised clustering methods and then analyzed the association of the molecular subgroups with survival time. Then, we constructed a classifier to predict the subgroup using penalized regression models. We have determined three pancreatic ductal adenocarcinoma tumor subtypes associated with prognosis based on miRNA expression profiles. These subtypes showed significantly different survival time for patients with the same clinical conditions. This demonstrates that our prognostic molecular subgroup has independent prognostic utility. The molecular subtypes can be predicted with a classifier of 19 miRNAs. Of the 19 signature miRNAs, miR-106b-star, miR-324-3p, and miR-615 were related to a p53 canonical pathway, and miR-324, miR-145-5p, miR-26b-5p, and miR-574-3p were related to a Cox-2 centered pathway. Our prognostic molecular subtypes demonstrated that miRNA profiles could be used as prognostic markers. Additionally, we have constructed a classifier that may be used to determine the molecular subgroup of new patient sample data. Further studies are needed for validation.

Molecular subtypes of pancreatic cancer based on miRNA expression profiles have independent prognostic value

Molecular subtypes of pancreatic cancer based on miRNA expression profiles have independent prognostic value

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Molecular subtypes of pancreatic cancer

Molecular subtypes of pancreatic cancer