Genomic Heterogeneity of Pancreatic Ductal Adenocarcinoma and Its Clinical Impact

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death due to limited advances in recent years in early diagnosis and personalized therapy capable of overcoming tumor resistance to chemotherapy. In the last decades, significant advances have been achieved in the identification of recurrent genetic and molecular alterations of PDAC including those involving the KRAS, CDKN2A, SMAD4, and TP53 driver genes. Despite these common genetic traits, PDAC are highly heterogeneous tumors at both the inter- and intra-tumoral genomic level, which might contribute to distinct tumor behavior and response to therapy, with variable patient outcomes. Despite this, genetic and genomic data on PDAC has had a limited impact on the clinical management of patients. Integration of genomic data for classification of PDAC into clinically defined entities—i.e., classical vs. squamous subtypes of PDAC—leading to different treatment approaches has the potential for significantly improving patient outcomes. In this review, we summarize current knowledge about the most relevant genomic subtypes of PDAC including the impact of distinct patterns of intra-tumoral genomic heterogeneity on the classification and clinical and therapeutic management of PDAC.

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The Emerging Role of Microbiota and Microbiome in Pancreatic Ductal Adenocarcinoma

Biomedicines ◽

10.3390/biomedicines8120565 ◽

2020 ◽

Vol 8 (12) ◽

pp. 565

Author(s):

Sona Ciernikova ◽

Maria Novisedlakova ◽

Danka Cholujova ◽

Viola Stevurkova ◽

Michal Mego

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Malignant Tumors ◽

Current Knowledge ◽

Early Stage ◽

Poor Response ◽

Response To Therapy ◽

Oral Microbiome ◽

Ductal Adenocarcinoma ◽

The Impact

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignant tumors due to the absence of biomarkers for early-stage detection and poor response to therapy. Since mounting evidence supports the role of microbiota composition in tumorigenesis and cancer treatment, the link between microbiome and PDAC has been described. In this review, we summarize the current knowledge regarding the impact of the gut and oral microbiome on the risk of PDAC development. Microenvironment-driven therapy and immune system interactions are also discussed. More importantly, we provide an overview of the clinical trials evaluating the microbiota role in the risk, prognosis, and treatment of patients suffering from PDAC and solid tumors. According to the research findings, immune tolerance might result from the microbiota-derived remodeling of pancreatic tumor microenvironment. Thus, microbiome profiling and targeting represent the potential trend to enhance antitumor immunity and improve the efficacy of PDAC treatment.

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Epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1914915116 ◽

2019 ◽

Vol 116 (52) ◽

pp. 26835-26845 ◽

Cited By ~ 7

Author(s):

Rebecca L. Porter ◽

Neelima K. C. Magnus ◽

Vishal Thapar ◽

Robert Morris ◽

Annamaria Szabolcs ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Clinical Investigation ◽

Transcriptional Profiling ◽

Response To Therapy ◽

Ductal Adenocarcinoma ◽

Transcriptional Responses ◽

In Vivo Models ◽

Functional Changes ◽

The Impact

Transcriptional profiling has defined pancreatic ductal adenocarcinoma (PDAC) into distinct subtypes with the majority being classical epithelial (E) or quasi-mesenchymal (QM). Despite clear differences in clinical behavior, growing evidence indicates these subtypes exist on a continuum with features of both subtypes present and suggestive of interconverting cell states. Here, we investigated the impact of different therapies being evaluated in PDAC on the phenotypic spectrum of the E/QM state. We demonstrate using RNA-sequencing and RNA-in situ hybridization (RNA-ISH) that FOLFIRINOX combination chemotherapy induces a common shift of both E and QM PDAC toward a more QM state in cell lines and patient tumors. In contrast, Vitamin D, another drug under clinical investigation in PDAC, induces distinct transcriptional responses in each PDAC subtype, with augmentation of the baseline E and QM state. Importantly, this translates to functional changes that increase metastatic propensity in QM PDAC, but decrease dissemination in E PDAC in vivo models. These data exemplify the importance of both the initial E/QM subtype and the plasticity of E/QM states in PDAC in influencing response to therapy, which highlights their relevance in guiding clinical trials.

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Comprehensive characterisation of compartment-specific long non-coding RNAs associated with pancreatic ductal adenocarcinoma

Gut ◽

10.1136/gutjnl-2017-314353 ◽

2018 ◽

Vol 68 (3) ◽

pp. 499-511 ◽

Cited By ~ 19

Author(s):

Luis Arnes ◽

Zhaoqi Liu ◽

Jiguang Wang ◽

Carlo Maurer ◽

Irina Sagalovskiy ◽

...

Keyword(s):

Clinical Outcome ◽

Pancreatic Ductal Adenocarcinoma ◽

Ductal Adenocarcinoma ◽

Nucleotide Polymorphisms ◽

Rna Seq ◽

Driver Genes ◽

Cross Sectional ◽

Genetic Traits ◽

Cancer Driver ◽

Non Coding Rnas

ObjectivePancreatic ductal adenocarcinoma (PDA) is a highly metastatic disease with limited therapeutic options. Genome and transcriptome analyses have identified signalling pathways and cancer driver genes with implications in patient stratification and targeted therapy. However, these analyses were performed in bulk samples and focused on coding genes, which represent a small fraction of the genome.DesignWe developed a computational framework to reconstruct the non-coding transcriptome from cross-sectional RNA-Seq, integrating somatic copy number alterations (SCNA), common germline variants associated to PDA risk and clinical outcome. We validated the results in an independent cohort of paired epithelial and stromal RNA-Seq derived from laser capture microdissected human pancreatic tumours, allowing us to annotate the compartment specificity of their expression. We employed systems and experimental biology approaches to interrogate the function of epithelial long non-coding RNAs (lncRNAs) associated with genetic traits and clinical outcome in PDA.ResultsWe generated a catalogue of PDA-associated lncRNAs. We showed that lncRNAs define molecular subtypes with biological and clinical significance. We identified lncRNAs in genomic regions with SCNA and single nucleotide polymorphisms associated with lifetime risk of PDA and associated with clinical outcome using genomic and clinical data in PDA. Systems biology and experimental functional analysis of two epithelial lncRNAs (LINC00673andFAM83H-AS1) suggest they regulate the transcriptional profile of pancreatic tumour samples and PDA cell lines.ConclusionsOur findings indicate that lncRNAs are associated with genetic marks of pancreatic cancer risk, contribute to the transcriptional regulation of neoplastic cells and provide an important resource to design functional studies of lncRNAs in PDA.

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MicroRNA-Regulated Signaling Pathways: Potential Biomarkers for Pancreatic Ductal Adenocarcinoma

Stresses ◽

10.3390/stresses1010004 ◽

2021 ◽

Vol 1 (1) ◽

pp. 30-47

Author(s):

Maria Mortoglou ◽

David Wallace ◽

Aleksandra Buha Buha Djordjevic ◽

Vladimir Djordjevic ◽

E. Damla Arisan ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Metabolic Stress ◽

Resistance Mechanisms ◽

Current Data ◽

Cellular Damage ◽

Ductal Adenocarcinoma ◽

Aberrant Expression ◽

Metabolic Alterations ◽

Limited Effectiveness ◽

The Impact

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and invasive type of pancreatic cancer (PCa) and is expected to be the second most common cause of cancer-associated deaths. The high mortality rate is due to the asymptomatic progression of the clinical features until the advanced stages of the disease and the limited effectiveness of the current therapeutics. Aberrant expression of several microRNAs (miRs/miRNAs) has been related to PDAC progression and thus they could be potential early diagnostic, prognostic, and/or therapeutic predictors for PDAC. miRs are small (18 to 24 nucleotides long) non-coding RNAs, which regulate the expression of key genes by targeting their 3′-untranslated mRNA region. Increased evidence has also suggested that the chemoresistance of PDAC cells is associated with metabolic alterations. Metabolic stress and the dysfunctionality of systems to compensate for the altered metabolic status of PDAC cells is the foundation for cellular damage. Current data have implicated multiple systems as hallmarks of PDAC development, such as glutamine redox imbalance, oxidative stress, and mitochondrial dysfunction. Hence, both the aberrant expression of miRs and dysregulation in metabolism can have unfavorable effects in several biological processes, such as apoptosis, cell proliferation, growth, survival, stress response, angiogenesis, chemoresistance, invasion, and migration. Therefore, due to these dismal statistics, it is crucial to develop beneficial therapeutic strategies based on an improved understanding of the biology of both miRs and metabolic mediators. This review focuses on miR-mediated pathways and therapeutic resistance mechanisms in PDAC and evaluates the impact of metabolic alterations in the progression of PDAC.

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The Emerging Role of Cyclin-Dependent Kinases (CDKs) in Pancreatic Ductal Adenocarcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms19103219 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3219 ◽

Cited By ~ 11

Author(s):

Balbina García-Reyes ◽

Anna-Laura Kretz ◽

Jan-Philipp Ruff ◽

Silvia von Karstedt ◽

Andreas Hillenbrand ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Therapeutic Potential ◽

Current Knowledge ◽

Ductal Adenocarcinoma ◽

Transcriptional Elongation ◽

Cyclin Dependent Kinases ◽

Dismal Prognosis ◽

The Family ◽

Cycle Regulation

The family of cyclin-dependent kinases (CDKs) has critical functions in cell cycle regulation and controlling of transcriptional elongation. Moreover, dysregulated CDKs have been linked to cancer initiation and progression. Pharmacological CDK inhibition has recently emerged as a novel and promising approach in cancer therapy. This idea is of particular interest to combat pancreatic ductal adenocarcinoma (PDAC), a cancer entity with a dismal prognosis which is owed mainly to PDAC’s resistance to conventional therapies. Here, we review the current knowledge of CDK biology, its role in cancer and the therapeutic potential to target CDKs as a novel treatment strategy for PDAC.

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Repression of MUC1 promotes expansion and suppressive function of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma and breast cancer murine models

10.1101/2020.12.07.415299 ◽

2020 ◽

Author(s):

S. Mahnaz ◽

L. Das Roy ◽

M. Bose ◽

C. De ◽

S. Nath ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Pancreatic Ductal Adenocarcinoma ◽

Signaling Pathways ◽

Suppressor Cells ◽

Ductal Adenocarcinoma ◽

Myeloid Derived Suppressor Cells ◽

Mucin 1 ◽

Transmembrane Glycoprotein ◽

The Impact

ABSTRACTMyeloid-derived suppressor cells (MDSCs) are immature myeloid cells that are responsible for immunosuppression in tumor microenvironment. Here we report the impact of mucin 1 (MUC1), a transmembrane glycoprotein, on proliferation and functional activity of MDSCs. To determine the role of MUC1 in MDSC phenotype, we analyzed MDSCs derived from wild type (WT) and MUC1-knockout (MUC1KO) mice bearing pancreatic ductal adenocarcinoma KCKO and breast cancer C57MG xenografts. We observed enhanced tumor growth in MUC1KO mice compared to WT mice in both pancreatic KCKO and breast C57MG cancer models due to increased MDSC population and enrichment of Tregs in tumor microenvironment. Our current study shows that knockdown of MUC1 in MDSCs promotes proliferation and immature suppressive phenotype indicated by increased level of iNOS, ARG1 activity and TGF-β secretion under cancer conditions. Increased activity of MDSCs leads to repression of IL-2 and IFN-ɣ production by T-cells. We were able to find that MDSCs from MUC1KO mice have higher levels of c-Myc and activated pSTAT3 as compared to MUC1 WT mice, that are signaling pathways leading to increased survival, proliferation and prevention of maturation. In summary, MUC1 regulates signaling pathways that maintain immunosuppressive properties of MDSCs. Thus, immunotherapy must target only tumor associated MUC1 on epithelial cells and not MUC1 on hematopoietic cells to avoid expansion and suppressive functions of MDSC.

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Evolving Role of Genomics in Genitourinary Neoplasms

Acta Medica Academica ◽

10.5644/ama2006-124.243 ◽

2019 ◽

Vol 48 (1) ◽

pp. 68

Author(s):

Michael E. Devitt ◽

Robert Dreicer

Keyword(s):

Dna Damage ◽

Genomic Data ◽

Treatment Decisions ◽

Response To Therapy ◽

Genomic Alterations ◽

Dna Damage And Repair ◽

Genitourinary Cancer ◽

Genitourinary Cancers ◽

The Impact

The aim of this article is to review the current role of genomic testing in the risk, prognosis, and treatment of genitourinary malignancies. The authors selected guidelines, publications, and abstracts relevant to the current and emerging role of genomics in genitourinary cancers. The risk of developing genitourinary cancer can be stratified based on genomic data. Prostate cancer has the strongest degree of heritability, with BRCA1/2 and HOXB13 mutations playing a role in familial disease. Genomic data is on the verge of informing treatment decisions across genitourinary cancers. mCRPC has diverse genomic alterations that represent potential therapeutic targets, including alterations in the AR pathway, DNA damage and repair pathways, cell cycle pathways, PI3K pathway, and Wnt signaling. Genomic alterations in clear cell renal cell carcinoma can inform prognosis and mutations in mTOR pathways predict response to mTOR inhibitors. Urothelial carcinoma can be classified into different subtypes based on gene expression profiling, which provides prognostic information and predicts response to chemotherapy and immunotherapy. Specific mutations have been identified that predict response to therapy including ERCC2 mutations and cisplatin, DNA damage and repair mutations and checkpoint inhibitors, and FGFR3 mutations and FGFR tyrosine kinase inhibitors such as erdafitinib.Conclusion. Genitourinary malignancies have not felt the impact of genomic data as greatly as other cancer types. The majority of benefit lies in identifying patients at high risk of genitourinary cancer. Fortunately, breakthroughs are on the horizon that will result in a greater incorporation of genomic information into treatment decisions for patients with genitourinary cancer.

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P-P13 Long-term outcome after portal vein resection during pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: a propensity score matched analysis

British Journal of Surgery ◽

10.1093/bjs/znab430.236 ◽

2021 ◽

Vol 108 (Supplement_9) ◽

Author(s):

James Russell ◽

Claire Stevens ◽

Rahul Bhome ◽

Dimitrios Karavias ◽

Ali Arshad ◽

...

Keyword(s):

Propensity Score ◽

Portal Vein ◽

Pancreatic Ductal Adenocarcinoma ◽

Perineural Invasion ◽

Nodal Metastasis ◽

Ductal Adenocarcinoma ◽

Safe Procedure ◽

Portal Vein Resection ◽

Vein Resection ◽

The Impact

Abstract Background Portal vein resection (PVR) with pancreaticoduodenectomy (PD) is often performed to achieve clear margins for patients with vascular involvement in pancreatic ductal adenocarcinoma (PDAC). However, there is evidence to suggest that patients undergoing PVR often have more advanced cancers, therefore the impact of PVR on survival and recurrence remains unclear. The aim of this study is to assess overall (OS) and recurrence free (RFS) survival in patients who underwent PVR during PD, with particular attention to margin positivity. Methods A retrospective analysis was performed on 638 patients who underwent PD during a 12-year period. Exclusion criteria included PD for non-PDAC tumours, neoadjuvant chemotherapy or intra-operative radiotherapy. 374 patients were included in the study (90 PVR and 284 non-PVR). Patient characteristics and histopathological factors associated with OS and RFS were then evaluated using univariate and multivariate Cox regression analyses. 270 patients (90 PVR and 180 non-PVR), were matched by propensity score based on perineural invasion, pT and pN staging. The Kaplan-Meier method was used to calculate survival and log-rank tests. Results Resection margin positivity was associated with shorter OS and RFS (p < 0.0001), and the superior mesenteric vein (SMV) margin was the most significant risk factor for survival on competing risks analysis. Absent adjuvant chemotherapy, nodal metastasis and margin positivity were independent risk factors for OS and RFS on multivariate analysis. PVR was associated with higher intra-operative blood loss (p = 0.009), but was not associated with increased length of stay, complications or readmissions. PVR patients had increased pT staging, nodal metastasis and perineural invasion, however, there was no difference in OS (p = 0.551) or RFS (p = 0.256) between PVR and non-PVR after propensity matching. Conclusions Positive resection margins are associated with shorter survival times, and the SMV margin is the most significant prognostic indicator for overall survival and recurrence compared to other margins. PVR is a relatively safe procedure, however, it does not achieve the intended survival benefits of complete margin clearance. The impact on survival for margin positivity, particularly the SMV margin, and nodal metastasis should be considered when making decisions with regards to vein resection and adjuvant treatments.

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Homologous Recombination Deficiency in Patients With Pancreatic Ductal Adenocarcinoma and Response to Chemotherapy

JCO Precision Oncology ◽

10.1200/po.17.00087 ◽

2018 ◽

pp. 1-11 ◽

Cited By ~ 5

Author(s):

Safi Shahda ◽

Kirsten M. Timms ◽

Ashley A. Ibrahim ◽

Julia E. Reid ◽

Harvey M. Cramer ◽

...

Keyword(s):

Homologous Recombination ◽

Pancreatic Ductal Adenocarcinoma ◽

Locally Advanced ◽

Progression Free Survival ◽

Needle Aspiration ◽

Response To Therapy ◽

Ductal Adenocarcinoma ◽

Response To Chemotherapy ◽

Formalin Fixed Paraffin Embedded ◽

Mutation Data

Purpose Mutations or copy number abnormalities of genes involved in homologous recombination (HR) occur in pancreatic ductal adenocarcinoma (PDAC). DNA-based measures of HR deficiency (HRD) have been developed and may help identify tumors with better response to DNA-damaging agents. This study aimed to describe the HR pathway mutations and HRD status and determine their association with treatment response and outcome in patients with PDAC. Patients and Methods We performed a retrospective analysis of tumor samples from patients treated at Indiana University for locally advanced or metastatic PDAC. Patients were included if they received gemcitabine plus nanoparticle albumin-bound paclitaxel (control) or fluorouracil, oxaliplatin, leucovorin, and irinotecan (FOLFIRINOX) and had adequate follow-up to assess survival and response to therapy. Tumor analysis generated a three-biomarker HRD score and mutation data for 44 genes. Results Ninety-one samples met inclusion criteria, and 78 samples (formalin-fixed paraffin-embedded, n = 15; fine-needle aspiration, n = 63) generated mutation data. HRD analysis was successful for 57 samples (HRD score: median, 18; range, 5 to 61); the primary cause of failure was low tumor cellularity. Six BRCA1/ 2 mutations were detected, four with HRD scores in the top decile ( P = .011). There was no statistically significant correlation between HRD score and radiographic response (odds ratio per interquartile range, 1.40; P = .32 adjusted for treatment) in either treatment group. In patients treated with FOLFIRINOX, HRD score dichotomized at the median was not associated with progression-free survival (median, 5.3 v 9.4 months for low v high HRD score, respectively; P = .083) or overall survival (median, 11.9 v 10.7 months for low v high HRD score, respectively; P = .76). Conclusion Mutations in DNA repair genes occur in PDAC, and HRD scores can be generated in the majority of patients. The HRD score was not significantly associated with higher response rate or prolonged survival in patients treated with FOLFIRINOX.

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