Pathway‐analysis of published genome‐wide association studies of lung cancer: A potential role for the CYP4F3 locus

The fatty acids (FAs) metabolism is suggested to play a pivotal role in the development of lung cancer, and we explored that by conducting a pathway‐based analysis. We performed a meta‐analysis of published datasets of six genome wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium, which included 12 160 cases with lung cancer and 16 838 cancer‐free controls. A total of 30 722 single‐nucleotide polymorphisms (SNPs) from 317 genes relevant to FA metabolic pathways were identified. An additional dataset from the Harvard Lung Cancer Study with 984 cases and 970 healthy controls was also added to the final meta‐analysis. In the initial meta‐analysis, 26 of 28 SNPs that passed false discovery rate multiple tests were mapped to the CYP4F3 gene. Among the 26 top ranked hits was a proxy SNP, CYP4F3 rs4646904 (P = 8.65 × 10−6, FDR = 0.018), which is suggested to change splicing pattern/efficiency and to be associated with gene expression levels. However, after adding data of rs4646904 from the Harvard GWAS, the significance in the combined analysis was reduced to P = 3.52 × 10−3 [odds ratio (OR) = 1.07, 95% confidence interval (95%CI) = 1.03–1.12]. Interestingly, the small Harvard dataset also pointed to the same direction of the association in subgroups of smokers (OR = 1.07) and contributed to a combined OR of 1.13 (95% CI = 1.06–1.20, P = 6.70 × 10−5). The results suggest that a potentially functional SNP in CYP4F3 (rs4646904) may contribute to the etiology of lung cancer, especially in smokers. Additional mechanistic studies are warranted to unravel the potential biological significance of the finding.

[1]  Sathesh Bhat,et al.  Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small cell lung cancer in preclinical models , 2016, Nature Medicine.

[2]  A. Zajdel,et al.  Toxic effects of n-3 polyunsaturated fatty acids in human lung A549 cells. , 2015, Toxicology in vitro : an international journal published in association with BIBRA.

[3]  J. Mesirov,et al.  The Molecular Signatures Database Hallmark Gene Set Collection , 2015 .

[4]  Yuqi Wang,et al.  Role of autophagy in the ω-3 long chain polyunsaturated fatty acid-induced death of lung cancer A549 cells. , 2015, Oncology letters.

[5]  J. Sánchez-Yagüe,et al.  Identification of potential erythrocyte phospholipid fatty acid biomarkers of advanced lung adenocarcinoma, squamous cell lung carcinoma, and small cell lung cancer , 2015, Tumor Biology.

[6]  J. Mesirov,et al.  The Molecular Signatures Database (MSigDB) hallmark gene set collection. , 2015, Cell systems.

[7]  L. Qiu,et al.  Serum Unsaturated Free Fatty Acids: Potential Biomarkers for Early Detection and Disease Progression Monitoring of Non-Small Cell Lung Cancer , 2014, Journal of Cancer.

[8]  E. Mascha,et al.  Serum free fatty acid biomarkers of lung cancer. , 2014, Chest.

[9]  Vicenta S Martínez-Zorzano,et al.  Erythrocyte fatty acids as potential biomarkers in the diagnosis of advanced lung adenocarcinoma, lung squamous cell carcinoma, and small cell lung cancer. , 2014, American journal of clinical pathology.

[10]  William Wheeler,et al.  Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer , 2014, Nature Genetics.

[11]  Wei Chen,et al.  Pleiotropic Associations of Risk Variants Identified for Other Cancers With Lung Cancer Risk: The PAGE and TRICL Consortia , 2014, Journal of the National Cancer Institute.

[12]  R. Zhai,et al.  Smoking and smoking cessation in relation to the development of co‐existing non‐small cell lung cancer with chronic obstructive pulmonary disease , 2014, International journal of cancer.

[13]  A. Jemal,et al.  Cancer statistics, 2014 , 2014, CA: a cancer journal for clinicians.

[14]  Mark I. McCarthy,et al.  Global analysis of DNA methylation variation in adipose tissue from twins reveals links to disease-associated variants in distal regulatory elements. , 2013, American journal of human genetics.

[15]  Pedro G. Ferreira,et al.  Transcriptome and genome sequencing uncovers functional variation in humans , 2013, Nature.

[16]  Christopher Y. Kang,et al.  Differential Expression of Cytochrome P450 Omega-hydroxylase Isoforms and Their Association with Clinicopathological Features in Pancreatic Ductal Adenocarcinoma , 2013, Annals of Surgical Oncology.

[17]  David Haussler,et al.  ENCODE Data in the UCSC Genome Browser: year 5 update , 2012, Nucleic Acids Res..

[18]  Yang Zhao,et al.  Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls , 2012, Human molecular genetics.

[19]  D. Berry,et al.  Benefits and harms of CT screening for lung cancer: a systematic review. , 2012, JAMA.

[20]  B. Simon,et al.  Human cytochrome P450 4F3: structure, functions, and prospects , 2012, Drug metabolism and drug interactions.

[21]  R. Deberardinis,et al.  Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? , 2012, Cell.

[22]  M. Roizen.  Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening , 2012 .

[23]  C. Holland,et al.  Peroxisome Proliferator–Activated Receptors Modulate Proliferation and Angiogenesis in Human Endometrial Carcinoma , 2011, Molecular Cancer Research.

[24]  M. Weiser-Evans,et al.  Activation of PPARγ in Myeloid Cells Promotes Lung Cancer Progression and Metastasis , 2011, PloS one.

[25]  A. Pozzi,et al.  EET signaling in cancer , 2011, Cancer and Metastasis Reviews.

[26]  C. Kimchi-Sarfaty,et al.  Understanding the contribution of synonymous mutations to human disease , 2011, Nature Reviews Genetics.

[27]  J. Antoun,et al.  CYP4F3B Expression Is Associated with Differentiation of HepaRG Human Hepatocytes and Unaffected by Fatty Acid Overload , 2011, Drug Metabolism and Disposition.

[28]  J. McClung,et al.  Hepcidin: A Critical Regulator of Iron Metabolism during Hypoxia , 2011, Advances in hematology.

[29]  C. Gatsonis,et al.  Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening , 2012 .

[30]  K. Stefánsson,et al.  Association of a novel functional promoter variant (rs2075533 C>T) in the apoptosis gene TNFSF8 with risk of lung cancer--a finding from Texas lung cancer genome-wide association study. , 2011, Carcinogenesis.

[31]  Mostafa Ronaghi,et al.  pfSNP: An integrated potentially functional SNP resource that facilitates hypotheses generation through knowledge syntheses , 2011, Human mutation.

[32]  H. Hakonarson,et al.  Analysing biological pathways in genome-wide association studies , 2010, Nature Reviews Genetics.

[33]  M. Loda,et al.  Fatty acid synthase polymorphisms, tumor expression, body mass index, prostate cancer risk, and survival. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  Tsviya Olender,et al.  GeneCards Version 3: the human gene integrator , 2010, Database J. Biol. Databases Curation.

[35]  Michael Boehnke,et al.  LocusZoom: regional visualization of genome-wide association scan results , 2010, Bioinform..

[36]  F. Clavel-Chapelon,et al.  Polymorphisms in fatty-acid-metabolism-related genes are associated with colorectal cancer risk. , 2010, Carcinogenesis.

[37]  J. Seagrave,et al.  Effects of 10 cigarette smoke condensates on primary human airway epithelial cells by comparative gene and cytokine expression studies. , 2010, Toxicological sciences : an official journal of the Society of Toxicology.

[38]  R. Crystal,et al.  Disparate oxidant gene expression of airway epithelium compared to alveolar macrophages in smokers , 2009, Respiratory research.

[39]  M. Paige,et al.  HPLC quantification of 5-hydroxyeicosatetraenoic acid in human lung cancer tissues. , 2009, Biomedical chromatography : BMC.

[40]  Jack A. Taylor,et al.  SNPinfo: integrating GWAS and candidate gene information into functional SNP selection for genetic association studies , 2009, Nucleic Acids Res..

[41]  J. Witte,et al.  Dietary Omega-3 Fatty Acids, Cyclooxygenase-2 Genetic Variation, and Aggressive Prostate Cancer Risk , 2009, Clinical Cancer Research.

[42]  Christopher I Amos,et al.  Common 5p15.33 and 6p21.33 variants influence lung cancer risk , 2008, Nature Genetics.

[43]  J. Hardwick.  Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases. , 2008, Biochemical pharmacology.

[44]  M. McCarthy,et al.  Genome-wide association studies for complex traits: consensus, uncertainty and challenges , 2008, Nature Reviews Genetics.

[45]  Paolo Vineis,et al.  A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25 , 2008, Nature.

[46]  Julie E. Zeskind,et al.  Smoking-induced gene expression changes in the bronchial airway are reflected in nasal and buccal epithelium , 2008, BMC Genomics.

[47]  E. Papaemmanuil,et al.  National study of colorectal cancer genetics , 2007, British Journal of Cancer.

[48]  Yoshihiko Hamamoto,et al.  Patterns of expression of cytochrome P450 genes in progression of hepatitis C virus-associated hepatocellular carcinoma. , 2005, International journal of oncology.

[49]  M. Raponi,et al.  Synonymous mutations in CFTR exon 12 affect splicing and are not neutral in evolution. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[50]  C. Agostoni,et al.  Cigarette smoke negatively and dose-dependently affects the biosynthetic pathway of the n−3 polyunsaturated fatty acid series in human mammary epithelial cells , 2004, Lipids.

[51]  Douglas G Altman,et al.  Interaction revisited: the difference between two estimates , 2003, BMJ : British Medical Journal.

[52]  C. Li,et al.  Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[53]  F. Kuhajda.  Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. , 2000, Nutrition.

[54]  Jack L. Vevea,et al.  Fixed- and random-effects models in meta-analysis. , 1998 .

[55]  H. Horstmann,et al.  Influence of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) on the localization of cathepsin B and cathepsin L in human lung tumor cells. , 1997, European journal of cell biology.

[56]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[57]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[58]  O. Warburg.  [Origin of cancer cells]. , 1956, Oncologia.

[59]  Bernard Maitre,et al.  Screening by Chest Radiograph and Lung Cancer Mortality : The Prostate , Lung , Colorectal , and Ovarian ( PLCO ) Randomized Trial , 2022 .