Description: MiRNAs are small, non-protein-coding RNA molecules that regulate gene expression either by post-transcriptionally suppressing mRNA translation or by mRNA degradation. We examine differentially expressed miRNAs in colorectal carcinomas, adenomas and normal colonic mucosa. Data come from population-based studies of colorectal cancer conducted in Utah and the Kaiser Permanente Medical Care Program. A total of 1893 carcinoma/normal-paired samples and 290 adenoma tissue samples were run on the Agilent Human miRNA Microarray V19.0 which contained 2006 miRNAs. We tested for significant differences in miRNA expression between paired carcinoma/adenoma/normal colonic tissue samples. Fewer than 600 miRNAs were expressed in 〉80% of people for colonic tissue; of these 86.5% were statistically differentially expressed between carcinoma and normal colonic mucosa using a false discovery rate of 0.05. Roughly half of these differentially expressed miRNAs showed a progression in levels of expression from normal to adenoma to carcinoma tissue. Other miRNAs appeared to be altered at the normal to adenoma stage, while others were only altered at the adenoma to carcinoma stage or only at the normal to carcinoma stage. Evaluation of the Agilent platform showed a high degree of repeatability ( r = 0.98) and reasonable agreement with the NanoString platform. Our data suggest that miRNAs are highly dysregulated in colorectal tissue among individuals with colorectal cancer; the pattern of disruption varies by miRNA as tissue progresses from normal to adenoma to carcinoma.

Description: Mitogen-activated protein kinase (MAPK) pathways regulate many cellular functions including cell proliferation, differentiation, migration and apoptosis. We evaluate genetic variation in the c-Jun-N-terminal kinases, p38, and extracellular regulated kinases 1/2 MAPK-signaling pathways and colon and rectal cancer risk using data from population-based case-control studies (colon: n = 1555 cases, 1956 controls; rectal: n = 754 cases, 959 controls). We assess 19 genes ( DUSP1, DUSP2, DUSP4, DUSP6, DUSP7, MAP2K1, MAP3K1, MAP3K2, MAP3K3, MAP3K7, MAP3K9, MAP3K10, MAP3K11, MAPK1, MAPK3, MAPK8, MAPK12, MAPK14 and RAF1 ). MAP2K1 rs8039880 [odds ratio (OR) = 0.57, 95% confidence interval (CI) = 0.38, 0.83; GG versus AA genotype] and MAP3K9 rs11625206 (OR = 1.41, 95% CI = 1.14, 1.76; recessive model) were associated with colon cancer ( P adj value 〈 0.05). DUSP1 rs322351 (OR = 1.43, 95% CI = 1.09, 1.88; TT versus CC) and MAPK8 rs10857561 (OR = 1.48, 95% CI 1.08, 2.03; AA versus GG/GA) were associated with rectal cancer ( P adj 〈 0.05). Aspirin/non-steroidal anti-inflammatory drug, cigarette smoking and body mass index interacted with several genes to alter cancer risk. Genetic variants had unique associations with KRAS , TP53 and CIMP+ tumors. DUSP2 rs1724120 [hazard rate ratio (HRR) = 0.72, 95%CI = 0.54, 0.96; AA versus GG/GA), MAP3K10 rs112956 (HRR = 1.40, 95% CI = 1.10, 1.76; CT/TT versus CC) and MAP3K11 (HRR = 1.76, 95% CI 1.18, 2.62 TT versus GG/GT) influenced survival after diagnosis with colon cancer; MAP2K1 rs8039880 (HRR = 2.53, 95% CI 1.34, 4.79 GG versus AG/GG) and Raf1 rs11923427 (HRR = 0.59 95% CI = 0.40, 0.86; AA versus TT/TA) were associated with rectal cancer survival. These data suggest that genetic variation in the MAPK-signaling pathway influences colorectal cancer risk and survival after diagnosis. Associations may be modified by lifestyle factors that influence inflammation and oxidative stress.

Description: Interleukins (ILs) are key regulators of immune response. Genetic variation in IL genes may influence breast cancer risk and mortality given their role in cell growth, angiogenesis and regulation of inflammatory process. We examined 16 IL genes with breast cancer risk and mortality in an admixed population of Hispanic/Native American (NA) (2111 cases and 2597 controls) and non-Hispanic white (NHW) (1481 cases and 1585 controls) women. Adaptive Rank Truncated Product (ARTP) analysis was conducted to determine gene significance and lasso (least absolute shrinkage and selection operator) was used to identify potential gene by gene and gene by lifestyle interactions. The pathway was statistically significant for breast cancer risk overall ( P ARTP = 0.0006), for women with low NA ancestry ( P ARTP = 0.01), for premenopausal women ( P ARTP = 0.02), for estrogen receptor (ER)+/progesterone receptor (PR)+ tumors ( P ARTP = 0.03) and ER–/PR– tumors ( P ARTP = 0.02). Eight of the 16 genes evaluated were associated with breast cancer risk ( IL1A , IL1B , IL1RN , IL2 , IL2RA , IL4 , IL6 and IL10 ); four genes were associated with breast cancer risk among women with low NA ancestry ( IL1B , IL6 , IL6R and IL10 ), two were associated with breast cancer risk among women with high NA ancestry ( IL2 and IL2RA ) and four genes were associated with premenopausal breast cancer risk ( IL1A , IL1B , IL2 and IL3 ). IL4 , IL6R , IL8 and IL17A were associated with breast cancer-specific mortality. We confirmed associations with several functional polymorphisms previously associated with breast cancer risk and provide support that their combined effect influences the carcinogenic process.

Description: Breast cancer incidence rates are characterized by unique racial and ethnic differences. Native American ancestry has been associated with reduced breast cancer risk. We explore the biological basis of disparities in breast cancer risk in Hispanic and non-Hispanic white women by evaluating genetic variation in genes involved in inflammation, insulin and energy homeostasis in conjunction with genetic ancestry. Hispanic (2111 cases, 2597 controls) and non-Hispanic white (1481 cases, 1586 controls) women enrolled in the 4-Corner’s Breast Cancer Study, the Mexico Breast Cancer Study and the San Francisco Bay Area Breast Cancer Study were included. Genetic admixture was determined from 104 ancestral informative markers that discriminate between European and Native American ancestry. Twenty-one genes in the CHIEF candidate pathway were evaluated. Higher Native American ancestry was associated with reduced risk of breast cancer (odds ratio = 0.79, 95% confidence interval 0.65, 0.95) but was limited to postmenopausal women (odds ratio = 0.66, 95% confidence interval 0.52, 0.85). After adjusting for genetic ancestry and multiple comparisons, four genes were significantly associated with breast cancer risk, NFB1, NFB1A, PTEN and STK11 . Within admixture strata, breast cancer risk among women with low Native American ancestry was associated with IkBKB, NFB1, PTEN and RPS6KA2, whereas among women with high Native American ancestry, breast cancer risk was associated with IkBKB, mTOR, PDK2, PRKAA1, RPS6KA2 and TSC1 . Higher Native American ancestry was associated with reduced breast cancer risk. Breast cancer risk differed by genetic ancestry along with genetic variation in genes involved in inflammation, insulin, and energy homeostasis.

Description: 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.