title: A pathway approach to evaluating the association between the CHIEF pathway and risk of colorectal cancer.
abstract: Inflammation, hormones and energy-related factors have been associated with colorectal cancer (CRC) and it has been proposed that convergence and interactions of these factors importantly influence CRC risk. We have previously hypothesized that genetic variation in the CHIEF (convergence of hormones, inflammation and energy-related factors) pathway would influence risk of CRC. In this paper, we utilize an Adaptive Rank Truncation Product (ARTP) statistical method to determine the overall pathway significance and then use that method to identify the key elements within the pathway associated with disease risk. Data from two population-based case-control studies of colon (n = 1555 cases and 1956 controls) and rectal (n = 754 cases and 959 controls) cancer were used. We use ARTP to estimate pathway and gene significance and polygenic scores based on ARTP findings to further estimate the risk associated with the pathway. Associations were further assessed based on tumor molecular phenotype. The CHIEF pathway was statistically significant for colon cancer (P(ARTP)= 0.03) with the most significant interferons (P(ARTP) = 0.0253), JAK/STAT/SOCS (P(ARTP) = 0.0111), telomere (P(ARTP) = 0.0399) and transforming growth factor β (P(ARTP) = 0.0043) being the most significant subpathways for colon cancer. For rectal cancer, interleukins (P(ARTP) = 0.0235) and selenoproteins (P ARTP = 0.0047) were statistically significant although the pathway overall was of borderline significance (P(ARTP) = 0.06). Interleukins (P(ARTP) = 0.0456) and mitogen-activated protein kinase (P(ARTP) = 0.0392) subpathways were uniquely significant for CpG island methylator phenotype-positive colon tumors. Increasing number of at-risk alleles was significantly associated with both colon [odds ratio (OR) = 6.21, 95% confidence interval (CI): 4.72, 8.16] and rectal (OR = 7.82, 95% CI: 5.26, 11.62) cancer. We conclude that elements of the CHIEF pathway are important for CRC risk.
authors.affiliation: Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT 84108, USA marty.slattery@hsc.utah.edu.
authors.forename: Martha L
authors.initials: ML
authors.lastname: Slattery
authors.affiliation: Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT 84108, USA.
authors.forename: Roger K
authors.initials: RK
authors.lastname: Wolff
authors.affiliation: Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT 84108, USA.
authors.forename: Abbie
authors.initials: A
authors.lastname: Lundgreen
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007372:Interferons / Q000235:genetics; D053613:Janus Kinase 1 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors; D050794:STAT1 Transcription Factor / Q000235:genetics; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics; D016615:Telomere / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D014481:United States / Q000453:epidemiology
chemical_list: D014408:Biomarkers, Tumor; C108944:SOCS1 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016212:Transforming Growth Factor beta; D007372:Interferons; C507904:JAK1 protein, human; D053613:Janus Kinase 1