Genetic polymorphisms in inflammatory genes and pancreatic cancer risk: a two-phase study on more than 14 000 individuals.

There is overwhelming evidence that inflammation plays a key role in the pathogenesis of cancer and its progression. Inflammation is regulated through a complex network of genes and polymorphic variants in these genes have been found to be associated to risk of various human cancers, alone or in combination with environmental variables. Despite this, not much is known on the genetic variability of genes that regulate inflammation and risk of pancreatic ductal adenocarcinoma (PDAC). We performed a two-phase association study considering the genetic variability of 76 genes that are key players in inflammatory response. We analysed tagging single nucleotide polymorphisms (SNPs) and regulatory SNPs on 7207 PDAC cases and 7063 controls and observed several associations with PDAC risk. The most significant association was between the carriers of the A allele of the CCL4-rs1719217 polymorphism, which was reported to be also associated with the expression level of the CCL4 gene, and increased risk of developing PDAC (odds ratio = 1.12, 95% confidence interval = 1.06-1.18, P = 3.34 × 10-5). This association was significant also after correction for multiple testing, highlighting the importance of using potentially functional SNPs in order to discover more genetic variants associated with PDAC risk.

[1]  U. Boggi,et al.  Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma , 2019, International journal of cancer.

[2]  J. Xue,et al.  Inflammation and development of pancreatic ductal adenocarcinoma. , 2019, Chinese clinical oncology.

[3]  M. Plebani,et al.  Inflammation and Pancreatic Cancer: Focus on Metabolism, Cytokines, and Immunity , 2019, International journal of molecular sciences.

[4]  J. D'haese,et al.  Prognostic Impact of Tumor-Infiltrating Lymphocytes and Neutrophils on Survival of Patients with Upfront Resection of Pancreatic Cancer , 2019, Cancers.

[5]  Diego Romero,et al.  The relationship between chemokines CCL2, CCL3, and CCL4 with the tumor microenvironment and tumor-associated macrophage markers in colorectal cancer , 2018, Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine.

[6]  Yan Wang,et al.  Correlation between CCL4 gene polymorphisms and clinical aspects of breast cancer , 2018, International journal of medical sciences.

[7]  E. Platz,et al.  Polymorphisms in genes related to inflammation and obesity and colorectal adenoma risk , 2018, Molecular Carcinogenesis.

[8]  Chien-Chung Huang,et al.  Chemokine C-C Motif Ligand 4 Gene Polymorphisms Associated with Susceptibility to Rheumatoid Arthritis , 2018, BioMed research international.

[9]  Yan Li,et al.  High levels of CCL2 or CCL4 in the tumor microenvironment predict unfavorable survival in lung adenocarcinoma , 2018, Thoracic cancer.

[10]  Peter Kraft,et al.  Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer , 2018, Nature Communications.

[11]  M. Shimada,et al.  High STAT4 Expression Indicates Better Disease-free Survival in Patients with Gastric Cancer. , 2017, Anticancer research.

[12]  V. Weaver,et al.  Development of Aggressive Pancreatic Ductal Adenocarcinomas Depends on Granulocyte Colony Stimulating Factor Secretion in Carcinoma Cells , 2017, Cancer Immunology Research.

[13]  Shun-Fa Yang,et al.  Impacts of CCL4 gene polymorphisms on hepatocellular carcinoma susceptibility and development , 2017, International journal of medical sciences.

[14]  N. Funel,et al.  Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study , 2017, International journal of cancer.

[15]  W. Lau,et al.  An integrated analysis identifies STAT4 as a key regulator of ovarian cancer metastasis , 2017, Oncogene.

[16]  Shun-Fa Yang,et al.  Impact of CCL4 gene polymorphisms and environmental factors on oral cancer development and clinical characteristics , 2017, Oncotarget.

[17]  G. Hotamışlıgil.  Inflammation, metaflammation and immunometabolic disorders , 2017, Nature.

[18]  William J. Astle,et al.  Allelic Landscape of Human Blood Cell Trait Variation and Links , 2016 .

[19]  Jiang Chang,et al.  A single nucleotide polymorphism in the 3′-UTR of STAT3 regulates its expression and reduces risk of pancreatic cancer in a Chinese population , 2016, Oncotarget.

[20]  Alison P. Klein,et al.  Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21 , 2016, Oncotarget.

[21]  Krzysztof Jamroziak,et al.  Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk , 2016, Oncotarget.

[22]  R. Bloigu,et al.  The relationships between serum cytokine levels and tumor infiltrating immune cells and their clinical significance in colorectal cancer , 2016, International journal of cancer.

[23]  L. Amundadottir.  Pancreatic Cancer Genetics , 2016, International journal of biological sciences.

[24]  N. Funel,et al.  TERT gene harbors multiple variants associated with pancreatic cancer susceptibility , 2015, International journal of cancer.

[25]  Manal M. Hassan,et al.  Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer , 2015, Nature Genetics.

[26]  T. Hudson,et al.  Association between Variants in Atopy-Related Immunologic Candidate Genes and Pancreatic Cancer Risk , 2015, PloS one.

[27]  G. Wang,et al.  Decreased STAT4 indicates poor prognosis and enhanced cell proliferation in hepatocellular carcinoma. , 2015, World journal of gastroenterology.

[28]  P. Maisonneuve,et al.  Risk factors for pancreatic cancer: a summary review of meta-analytical studies. , 2015, International journal of epidemiology.

[29]  Carson C Chow,et al.  Second-generation PLINK: rising to the challenge of larger and richer datasets , 2014, GigaScience.

[30]  Yusuke Nakamura,et al.  Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer , 2014, Nature Genetics.

[31]  Benjamin D. Smith,et al.  Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. , 2014, Cancer research.

[32]  J. Chitra,et al.  CCL2, CCL3 and CCL4 gene polymorphisms in pulmonary tuberculosis patients of South India , 2014, International journal of immunogenetics.

[33]  J. Richmond,et al.  Regulation of Cellular Processes by Interleukin‐16 in Homeostasis and Cancer , 2014, Journal of cellular physiology.

[34]  Ellen T. Gelfand,et al.  The Genotype-Tissue Expression (GTEx) project , 2013, Nature Genetics.

[35]  Martha L Slattery,et al.  JAK/STAT/SOCS‐signaling pathway and colon and rectal cancer , 2013, Molecular carcinogenesis.

[36]  N. Funel,et al.  Genetic susceptibility to pancreatic cancer and its functional characterisation: the PANcreatic Disease ReseArch (PANDoRA) consortium. , 2013, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[37]  M. Beckmann,et al.  Polymorphisms in Inflammation Pathway Genes and Endometrial Cancer Risk , 2012, Cancer Epidemiology, Biomarkers & Prevention.

[38]  K. Hemminki,et al.  Interaction between functional polymorphic variants in cytokine genes, established risk factors and susceptibility to basal cell carcinoma of skin. , 2011, Carcinogenesis.

[39]  J. Mulenga,et al.  Genetic variations and heterosexual HIV-1 infection: analysis of clustered genes encoding CC-motif chemokine ligands , 2011, Genes and Immunity.

[40]  M. Juan,et al.  CCL4L polymorphisms and CCL4/CCL4L serum levels are associated with psoriasis severity. , 2011, The Journal of investigative dermatology.

[41]  B. Fridley,et al.  Inflammation-Related Gene Variants as Risk Factors for Pancreatic Cancer , 2011, Cancer Epidemiology, Biomarkers & Prevention.

[42]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[43]  Wei Zheng,et al.  A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33 , 2010, Nature Genetics.

[44]  Geoffrey S. Tobias,et al.  Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer , 2009, Nature Genetics.

[45]  Alberto Mantovani,et al.  Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. , 2009, Carcinogenesis.

[46]  R. Rad,et al.  Interleukin 1 beta gene promoter SNPs are associated with risk of pancreatic cancer. , 2009, Cytokine.

[47]  P. Allavena,et al.  Cancer-related inflammation , 2008, Nature.

[48]  D. Reich,et al.  Population Structure and Eigenanalysis , 2006, PLoS genetics.

[49]  E. Guinó,et al.  Polymorphisms within inflammatory genes and colorectal cancer , 2006, Journal of Negative Results in BioMedicine.

[50]  M. Gazouli,et al.  Relation between common polymorphisms in genes related to inflammatory response and colorectal cancer. , 2006, World journal of gastroenterology.

[51]  J. Goedert,et al.  Genetic variation in the CCL18-CCL3-CCL4 chemokine gene cluster influences HIV Type 1 transmission and AIDS disease progression. , 2006, American journal of human genetics.

[52]  E. Holly,et al.  Inflammation, Genetic Polymorphisms in Proinflammatory Genes TNF-A, RANTES, and CCR5, and Risk of Pancreatic Adenocarcinoma , 2006, Cancer Epidemiology Biomarkers & Prevention.

[53]  H. Nagawa,et al.  Beta-chemokine, macrophage inflammatory protein-1beta (MIP-1beta), is highly expressed in diffuse type human gastric cancers. , 2003, Journal of experimental & clinical cancer research : CR.

[54]  Maíra R. Rodrigues,et al.  Population, Epidemiological, and Functional Genetics of Gastric Cancer Candidate Genes in Peruvians with Predominant Amerindian Ancestry , 2015, Digestive Diseases and Sciences.

[55]  W. Tan,et al.  Silencing of stat4 gene inhibits cell proliferation and invasion of colorectal cancer cells. , 2015, Journal of Biological Regulators and Homeostatic Agents.

[56]  J. Chang-Claude,et al.  Polymorphisms of Helicobacter pylori signaling pathway genes and gastric cancer risk in the European prospective investigation into cancer‐eurgast cohort , 2014, International journal of cancer.