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      Identification and Validation of a Biomarker Signature in Patients With Resectable Pancreatic Cancer via Genome-Wide Screening for Functional Genetic Variants

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          Abstract

          Can genetic polymorphisms serve as biomarkers of prognosis and direct therapy outcomes in patients with pancreatic cancer amenable to resection? This study used 2 independent cohorts of patients with pancreatic ductal adenocarcinoma who underwent resection of their tumors to perform a genome-wide screening for functional single-nucleotide polymorphisms that affect pancreatic cancer survival. Two single-nucleotide polymorphisms in known cancer-associated genes that were associated with tumor-associated survival after pancreatic resection were identified and validated. These common polymorphisms may be used as a noninvasive biomarker signature in a clinical setting that is readily available at the time of diagnosis to identify patients with a very low probability of survival, guide personalized treatment decisions, and direct patient stratification in clinical trials. This study assesses 2 datasets on cohorts of patients with pancreatic ductal adenocarcinoma to identify and validate functional genetic variants that can serve as biomarkers for prospective treatment response and survival. Surgery currently offers the only chance for a cure in pancreatic ductal adenocarcinoma (PDAC), but it carries a significant morbidity and mortality risk and results in varying oncologic outcomes. At present, to our knowledge, there are no tests available before surgical resection to identify tumors with an aggressive biological phenotype that could guide personalized treatment strategies. Identification of noninvasive genetic biomarkers that could direct therapy in patients whose cases are amenable to pancreatic cancer resection. This multicenter study combined a prospective European cohort of patients with PDAC who underwent pancreatic resection (from University Hospital of Zurich, Zurich, Switzerland; Cantonal Hospital of Winterthur, Winterthur, Switzerland; and University Clinic of Ulm, Ulm, Germany) with data from the Cancer Genome Atlas database in the United States, which includes prospectively registered patients with PDAC. A genome-wide screening for functional single-nucleotide polymorphisms (SNPs) that affect PDAC survival was conducted using the European cohort for identification and the Cancer Genome Atlas cohort for validation. We used Cox proportional hazards models to screen for high-frequency polymorphic variants that are associated with allelic differences in tumor-associated survival and either result in an altered protein structure and function or reside in known regulatory noncoding genomic regions. The false-discovery rate method was applied for multiple hypothesis-testing corrections. Data analysis occurred from November 2017 to May 2018. Pancreatic resection. Tumor-associated survival. A total of 195 patients in the European cohort were included, as well as 136 patients in the Cancer Genome Atlas cohort (overall median [range] age, 66 [19-87] years; 156 [47.1%] were women, and 175 [52.9%] were men). Two SNPs in noncoding, functional regions of genes that regulate cancer progression, invasion, and metastasis were identified ( CHI3L2 SNP rs684559 and CD44 SNP rs353630 ). These were associated with survival after PDAC resection; patients who carry the risk alleles at 1 of both SNP loci had a 2.63-fold increased risk for tumor-associated death compared with those with protective genotypes (hazard ratio for survival, 0.38 [95% CI, 0.27-0.53]; P  = 1.0 × 10 −8 ). The identified polymorphisms may serve as a noninvasive biomarker signature of prospective survival after pancreatic resection that is readily available at the time of PDAC diagnosis. This signature can be used to identify a subset of high-risk patients with PDAC with very low survival probability who might be eligible for inclusion in clinical trials of new therapeutic strategies, including neoadjuvant chemotherapy protocols. In addition, the biological knowledge about these SNPs could help guide the development of individualized genomic strategies for PDAC therapies.

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          Most cited references29

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          Identification of pancreatic cancer stem cells.

          Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. Although data have been provided to support this theory in human blood, brain, and breast cancers, the identity of pancreatic cancer stem cells has not been determined. Using a xenograft model in which primary human pancreatic adenocarcinomas were grown in immunocompromised mice, we identified a highly tumorigenic subpopulation of pancreatic cancer cells expressing the cell surface markers CD44, CD24, and epithelial-specific antigen (ESA). Pancreatic cancer cells with the CD44(+)CD24(+)ESA(+) phenotype (0.2-0.8% of pancreatic cancer cells) had a 100-fold increased tumorigenic potential compared with nontumorigenic cancer cells, with 50% of animals injected with as few as 100 CD44(+)CD24(+)ESA(+) cells forming tumors that were histologically indistinguishable from the human tumors from which they originated. The enhanced ability of CD44(+)CD24(+)ESA(+) pancreatic cancer cells to form tumors was confirmed in an orthotopic pancreatic tail injection model. The CD44(+)CD24(+)ESA(+) pancreatic cancer cells showed the stem cell properties of self-renewal, the ability to produce differentiated progeny, and increased expression of the developmental signaling molecule sonic hedgehog. Identification of pancreatic cancer stem cells and further elucidation of the signaling pathways that regulate their growth and survival may provide novel therapeutic approaches to treat pancreatic cancer, which is notoriously resistant to standard chemotherapy and radiation.
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            Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma

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            We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.
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              CD44: from adhesion molecules to signalling regulators.

              Cell-adhesion molecules, once believed to function primarily in tethering cells to extracellular ligands, are now recognized as having broader functions in cellular signalling cascades. The CD44 transmembrane glycoprotein family adds new aspects to these roles by participating in signal-transduction processes--not only by establishing specific transmembrane complexes, but also by organizing signalling cascades through association with the actin cytoskeleton. CD44 and its associated partner proteins monitor changes in the extracellular matrix that influence cell growth, survival and differentiation.
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                Author and article information

                Journal
                JAMA Surgery
                JAMA Surg
                American Medical Association (AMA)
                2168-6254
                June 01 2019
                June 19 2019
                : 154
                : 6
                : e190484
                Affiliations
                [1 ]Computational Biology Group, Department of Biosystems Science and Engineering, ETH Zurich, Zurich, Switzerland
                [2 ]Swiss Institute of Bioinformatics, Basel, Switzerland
                [3 ]Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
                [4 ]Institute for Pathology, Cantonal Hospital of Winterthur, Winterthur, Switzerland
                [5 ]Department of General and Visceral Surgery, Ulm University Hospital, Ulm, Germany
                [6 ]Senckenberg Institute for Pathology, Goethe University Hospital Frankfurt, Frankfurt, Germany
                [7 ]Institute for Regenerative Medicine, University of Zurich, Zurich, Switzerland
                [8 ]Department of General, Visceral and Thoracic Surgery, Klinikum Dessau, Dessau, Germany
                [9 ]Department of Visceral and Transplantation Surgery, University Hospital Zurich, Zurich, Switzerland
                [10 ]Department of Visceral and Thoracic Surgery, Cantonal Hospital of Winterthur, Winterthur, Switzerland
                [11 ]Ludwig Institute for Cancer Research, University of Oxford, Oxford, United Kingdom
                Article
                10.1001/jamasurg.2019.0484
                6583393
                30942874
                0f839094-08fe-4476-a220-e6769d992738
                © 2019
                History

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