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      Transcriptional Profiling of Peripheral Blood Mononuclear Cells in Pancreatic Cancer Patients Identifies Novel Genes with Potential Diagnostic Utility

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          Abstract

          Background

          It is well known that many malignancies, including pancreatic cancer (PC), possess the ability to evade the immune system by indirectly downregulating the mononuclear cell machinery necessary to launch an effective immune response. This knowledge, in conjunction with the fact that the trancriptome of peripheral blood mononuclear cells has been shown to be altered in the context of many diseases, including renal cell carcinoma, lead us to study if any such alteration in gene expression exists in PC as it may have diagnostic utility.

          Methods and Findings

          PBMC samples from 26 PC patients and 33 matched healthy controls were analyzed by whole genome cDNA microarray. Three hundred eighty-three genes were found to be significantly different between PC and healthy controls, with 65 having at least a 1.5 fold change in expression. Pathway analysis revealed that many of these genes fell into pathways responsible for hematopoietic differentiation, cytokine signaling, and natural killer (NK) cell and CD8+ T-cell cytotoxic response. Unsupervised hierarchical clustering analysis identified an eight-gene predictor set, consisting of SSBP2, Ube2b-rs1, CA5B, F5, TBC1D8, ANXA3, ARG1, and ADAMTS20, that could distinguish PC patients from healthy controls with an accuracy of 79% in a blinded subset of samples from treatment naïve patients, giving a sensitivity of 83% and a specificity of 75%.

          Conclusions

          In summary, we report the first in-depth comparison of global gene expression profiles of PBMCs between PC patients and healthy controls. We have also identified a gene predictor set that can potentially be developed further for use in diagnostic algorithms in PC. Future directions of this research should include analysis of PBMC expression profiles in patients with chronic pancreatitis as well as increasing the number of early-stage patients to assess the utility of PBMCs in the early diagnosis of PC.

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          Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse.

          Sunil R Hingorani, Emanuel Petricoin, Anirban Maitra … (2003)
          To evaluate the role of oncogenic RAS mutations in pancreatic tumorigenesis, we directed endogenous expression of KRAS(G12D) to progenitor cells of the mouse pancreas. We find that physiological levels of Kras(G12D) induce ductal lesions that recapitulate the full spectrum of human pancreatic intraepithelial neoplasias (PanINs), putative precursors to invasive pancreatic cancer. The PanINs are highly proliferative, show evidence of histological progression, and activate signaling pathways normally quiescent in ductal epithelium, suggesting potential therapeutic and chemopreventive targets for the cognate human condition. At low frequency, these lesions also progress spontaneously to invasive and metastatic adenocarcinomas, establishing PanINs as definitive precursors to the invasive disease. Finally, mice with PanINs have an identifiable serum proteomic signature, suggesting a means of detecting the preinvasive state in patients.
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            Gene-expression profiles in hereditary breast cancer.

            I Hedenfalk, D. Duggan, Y. Chen … (2001)
            Many cases of hereditary breast cancer are due to mutations in either the BRCA1 or the BRCA2 gene. The histopathological changes in these cancers are often characteristic of the mutant gene. We hypothesized that the genes expressed by these two types of tumors are also distinctive, perhaps allowing us to identify cases of hereditary breast cancer on the basis of gene-expression profiles. RNA from samples of primary tumor from seven carriers of the BRCA1 mutation, seven carriers of the BRCA2 mutation, and seven patients with sporadic cases of breast cancer was compared with a microarray of 6512 complementary DNA clones of 5361 genes. Statistical analyses were used to identify a set of genes that could distinguish the BRCA1 genotype from the BRCA2 genotype. Permutation analysis of multivariate classification functions established that the gene-expression profiles of tumors with BRCA1 mutations, tumors with BRCA2 mutations, and sporadic tumors differed significantly from each other. An analysis of variance between the levels of gene expression and the genotype of the samples identified 176 genes that were differentially expressed in tumors with BRCA1 mutations and tumors with BRCA2 mutations. Given the known properties of some of the genes in this panel, our findings indicate that there are functional differences between breast tumors with BRCA1 mutations and those with BRCA2 mutations. Significantly different groups of genes are expressed by breast cancers with BRCA1 mutations and breast cancers with BRCA2 mutations. Our results suggest that a heritable mutation influences the gene-expression profile of the cancer.
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              Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer.

              Orlando Gutiérrez, Gary Allred, Gary Chamness … (2003)
              Systemic chemotherapy for operable breast cancer substantially decreases the risk of death. Patients often have de novo resistance or incomplete response to docetaxel, one of the most active agents in this disease. We postulated that gene expression profiles of the primary breast cancer can predict the response to docetaxel. We took core biopsy samples from primary breast tumours in 24 patients before treatment and then assessed tumour response to neoadjuvant docetaxel (four cycles, 100 mg/m2 daily for 3 weeks) by cDNA analysis of RNA extracted from biopsy samples using HgU95-Av2 GeneChip. From the core biopsy samples, we extracted sufficient total RNA (3-6 microg) for cDNA array analysis using HgU95-Av2 GeneChip. Differential patterns of expression of 92 genes correlated with docetaxel response (p=0.001). Sensitive tumours had higher expression of genes involved in cell cycle, cytoskeleton, adhesion, protein transport, protein modification, transcription, and stress or apoptosis; whereas resistant tumours showed increased expression of some transcriptional and signal transduction genes. In leave-one-out cross-validation analysis, ten of 11 sensitive tumours (90% specificity) and 11 of 13 resistant tumours (85% sensitivity) were correctly classified, with an accuracy of 88%. This 92-gene predictor had positive and negative predictive values of 92% and 83%, respectively. Correlation between RNA expression measured by the arrays and semiquantitative RT-PCR was also ascertained, and our results were validated in an independent set of six patients. If validated, these molecular profiles could allow development of a clinical test for docetaxel sensitivity, thus reducing unnecessary treatment for women with breast cancer.
              Article 0 comments Cited 143 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2011
                Publication date (Electronic): 10 February 2011
                Volume: 6
                Issue: 2
                Electronic Location Identifier: e17014
                Affiliations
                [1 ]Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center Omaha, Omaha, Nebraska, United States of America
                [2 ]Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
                [3 ]Department of Biostatistics, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
                [4 ]Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
                [5 ]Division of Gastroenterology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
                Institut Pasteur, France
                Author notes

                Conceived and designed the experiments: MJB, SC, SKB. Performed the experiments: MJB, SC, KM. Analyzed the data: MJB, SC, LS. Contributed reagents/materials/analysis tools: SKB, AS. Wrote the paper: MJB, SC, KM, LS, AS, RB, SKB. Provided clinical insight and information: ARS REB.

                Article
                Publisher ID: PONE-D-10-06253
                DOI: 10.1371/journal.pone.0017014
                PMC ID: 3037404
                PubMed ID: 21347333
                SO-VID: a1b487b4-2a33-4408-9938-06deaa281373
                Copyright © Baine et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 7 December 2010
                Date accepted : 19 January 2011
                Page count
                Pages: 10
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Computational Biology
                Subject: Genomics
                Subject: Genome Expression Analysis
                Subject: Microarrays
                Subject: Genomics
                Subject: Genome Expression Analysis
                Subject: Immunology
                Subject: Immunity
                Subject: Immune Deficiency
                Subject: Immune Suppression
                Subject: Immunologic Subspecialties
                Subject: Tumor Immunology
                Subject: Immune Cells
                Subject: Immune Response
                Subject: Molecular Cell Biology
                Subject: Cellular Types
                Subject: Blood Cells
                Subject: Medicine
                Subject: Diagnostic Medicine
                Subject: Pathology
                Subject: General Pathology
                Subject: Biomarkers
                Subject: Gastroenterology and Hepatology
                Subject: Gastrointestinal Cancers
                Subject: Pancreas
                Subject: Oncology
                Subject: Cancer Detection and Diagnosis
                Subject: Cancer Screening
                Subject: Early Detection
                Subject: Cancers and Neoplasms
                Subject: Gastrointestinal Tumors
                Subject: Pancreatic Cancer

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