Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate ...levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol–CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case‐control and 11 nested case‐control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study‐specific results were pooled using fixed‐effects meta‐analysis. Compared to non‐/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio OR: 0.92, 95% confidence interval CI: 0.88–0.98, p = 0.005), heavy drinking (2–3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99–1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11–1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J‐shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.
What's new?
Heavy drinking is associated with increased colorectal cancer (CRC) risk, but there's debate about the impact of moderate drinking. Here, the authors conducted a combined analysis of 16 studies comprising 14,276 cases and 15,802 controls. By their analysis, drinking 1‐2 alcoholic beverages per day was associated with a reduced risk of CRC, compared with rare or no alcohol consumption. With 3 or more drinks per day, CRC risk rises. The authors suggest that moderate alcohol consumption may reduce inflammation and DNA damage, although they acknowledge that more research is needed to understand the biochemical mechanism at work.
Associations between selenium and cancer have directed attention to role of selenoproteins in the carcinogenic process.
We used data from two population-based case-control studies of colon (n = 1555 ...cases, 1956 controls) and rectal (n = 754 cases, 959 controls) cancer. We evaluated the association between genetic variation in TXNRD1, TXNRD2, TXNRD3, C11orf31 (SelH), SelW, SelN1, SelS, SepX, and SeP15 with colorectal cancer risk.
After adjustment for multiple comparisons, several associations were observed. Two SNPs in TXNRD3 were associated with rectal cancer (rs11718498 dominant OR 1.42 95% CI 1.16,1.74 pACT 0.0036 and rs9637365 recessive 0.70 95% CI 0.55,0.90 pACT 0.0208). Four SNPs in SepN1 were associated with rectal cancer (rs11247735 recessive OR 1.30 95% CI 1.04,1.63 pACT 0.0410; rs2072749 GGvsAA OR 0.53 95% CI 0.36,0.80 pACT 0.0159; rs4659382 recessive OR 0.58 95% CI 0.39,0.86 pACT 0.0247; rs718391 dominant OR 0.76 95% CI 0.62,0.94 pACT 0.0300). Interaction between these genes and exposures that could influence these genes showed numerous significant associations after adjustment for multiple comparisons. Two SNPs in TXNRD1 and four SNPs in TXNRD2 interacted with aspirin/NSAID to influence colon cancer; one SNP in TXNRD1, two SNPs in TXNRD2, and one SNP in TXNRD3 interacted with aspirin/NSAIDs to influence rectal cancer. Five SNPs in TXNRD2 and one in SelS, SeP15, and SelW1 interacted with estrogen to modify colon cancer risk; one SNP in SelW1 interacted with estrogen to alter rectal cancer risk. Several SNPs in this candidate pathway influenced survival after diagnosis with colon cancer (SeP15 and SepX1 increased HRR) and rectal cancer (SepX1 increased HRR).
Findings support an association between selenoprotein genes and colon and rectal cancer development and survival after diagnosis. Given the interactions observed, it is likely that the impact of cancer susceptibility from genotype is modified by lifestyle.
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.
Toll‐like receptors (TLRs) are mediators of inflammation in the gut and potentially important modulators of colon and rectal cancer risk. We use data from a population‐based study of incident colon ...cancer cases (n = 1,555) and controls (n = 1,956) and rectal cancer cases (n = 754) and controls (n = 959). We evaluate genetic variation in TLR2 (six SNPs), TLR3 (four SNPs) and TLR4 (eight SNPs) with risk of developing colon or rectal cancer and survival after diagnosis. TLR3 rs11721827 was associated with rectal cancer (odds ratio OR 1.27, 95% confidence interval CI 1.02, 1.58 for AC/CC vs. AA genotype, Wald p = 0.035; adjusted p = 0.126); TLR3 rs3775292 and TLR4 rs11536898 were associated with colon cancer (OR 0.68, 95% CI 0.49, 0.95 for GG vs. CC/CG and OR 0.50. 95% CI 0.29, 0.87 for AA vs. CA/CC, respectively; Wald p = 0.023 and 0.015; adjusted p = 0.085 and 0.101, respectively). TLR2 rs7656411 and rs3804099, respectively, interacted with nonsteroidal anti‐inflammatory drug (NSAID) use and cigarette smoking to alter risk of colon cancer (adjusted p = 0.034 and 0.077); TLR3 rs11721827 interacted with NSAID use to alter risk of colon cancer (adjusted p = 0.071). TLR3 rs3775292 interacted with dietary carbohydrates to alter colon cancer risk and with dietary carbohydrates and saturated fat to alter rectal cancer risk (adjusted p = 0.064, 0.0035 and 0.025, respectively). Multiple SNPs in TLR2 and TLR4 were associated with colon cancer survival. Although few independent associations with TLR genes were observed, we observed significant interaction of TLR2 and TLR3 with hypothesized lifestyle factors. Interaction with dietary factors remained significant for rectal cancer after adjustment for multiple comparisons.
Few risk factors have been identified for triple negative breast cancer (TNBC) which lacks expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor ...2 (HER2). This more aggressive subtype disproportionately affects some racial/ethnic minorities and is associated with lower survival. We pooled data from three population‐based studies (558 TNBC and 5,111 controls) and examined associations of TNBC risk with reproductive history and breast‐feeding. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression. For younger women, aged <50 years, TNBC risk was increased two‐fold for parous women who never breast‐fed compared to nulliparous women (OR = 2.02, 95% CI = 1.12–3.63). For younger parous women, longer duration of lifetime breast‐feeding was associated with a borderline reduced risk (≥24 vs. 0 months: OR = 0.52, 95% CI = 0.26–1.04, Ptrend = 0.06). Considering the joint effect of parity and breast‐feeding, risk was increased two‐fold for women with ≥3 full‐term pregnancies (FTPs) and no or short‐term (<12 months) breast‐feeding compared to women with 1–2 FTPs and breast‐feeding ≥12 months (OR = 2.56, 95% CI = 1.22–5.35). None of these associations were observed among older women (≥50 years). Differences in reproductive patterns possibly contribute to the ethnic differences in TNBC incidence. Among controls aged <50 years, the prevalence of no or short‐term breast‐feeding and ≥3 FTPs was highest for Hispanics (22%), followed by African Americans (18%), Asian Americans (15%) and non‐Hispanic whites (6%). Breast‐feeding is a modifiable behavioral factor that may lower TNBC risk and mitigate the effect of FTPs in women under age 50 years.
What's new?
Triple negative breast cancer (TNBC) is an aggressive subtype with few known risk factors. In this pooled multiethnic population, the authors found that among younger women, aged <50 years, TNBC risk was increased two‐fold for parous women who never breast‐fed compared to nulliparous women. TNBC risk was increased two‐fold for women with high parity (≥3 full‐term pregnancies) and short‐term (<12 months) breast‐feeding, whereas no increase in risk was seen for women with high parity and long‐term breast‐feeding. The findings suggest that breast‐feeding, a modifiable behavioral risk factor, mitigates the elevated risk of TNBC associated with full‐term pregnancies among younger women.
The popular Genome-wide Complex Trait Analysis (GCTA) software uses the random-effects models for estimating the narrow-sense heritability based on GWAS data of unrelated individuals without knowing ...and identifying the causal loci. Many methods have since extended this approach to various situations. However, since the proportion of causal loci among the variants is typically very small and GCTA uses all variants to calculate the similarities among individuals, the estimation of heritability may be unstable, resulting in a large variance of the estimates. Moreover, if the causal SNPs are not genotyped, GCTA sometimes greatly underestimates the true heritability. We present a novel narrow-sense heritability estimator, named HERRA, using well-developed ultra-high dimensional machine-learning methods, applicable to continuous or dichotomous outcomes, as other existing methods. Additionally, HERRA is applicable to time-to-event or age-at-onset outcome, which, to our knowledge, no existing method can handle. Compared to GCTA and LDAK for continuous and binary outcomes, HERRA often has a smaller variance, and when causal SNPs are not genotyped, HERRA has a much smaller empirical bias. We applied GCTA, LDAK and HERRA to a large colorectal cancer dataset using dichotomous outcome (4,312 cases, 4,356 controls, genotyped using Illumina 300K), the respective heritability estimates of GCTA, LDAK and HERRA are 0.068 (SE = 0.017), 0.072 (SE = 0.021) and 0.110 (SE = 5.19 x 10-3). HERRA yields over 50% increase in heritability estimate compared to GCTA or LDAK.
The BRAF V600E mutation has been associated with microsatellite instability and the CpG island methylator phenotype (CIMP) in colon cancer. We evaluated a large population-based sample of individuals ...with colon cancer to determine its relationship to survival and other clinicopathologic variables. The V600E BRAF mutation was seen in 5% (40 of 803) of microsatellite-stable tumors and 51.8% (43 of 83) of microsatellite-unstable tumors. In microsatellite-stable tumors, this mutation was related to poor survival, CIMP high, advanced American Joint Committee on Cancer (AJCC) stage, and family history of colorectal cancer odds ratio, 4.23; 95% confidence interval (95% CI), 1.65-10.84. The poor survival was observed in a univariate analysis of 5-year survival (16.7% versus 60.0%; P < 0.01); in an analysis adjusted for age, stage, and tumor site hazard rate ratio (HRR), 2.97; 95% CI, 2.05-4.32; in stage-specific, age-adjusted analyses for AJCC stages 2 to 4 (HRR, 4.88, 3.60, and 2.04, respectively); and in Kaplan-Meier survival estimates for AJCC stages 2 to 4 (P < 0.01 for all three stages). Microsatellite-unstable tumors were associated with an excellent 5-year survival whether the V600E mutation was present or absent (76.2% and 75.0%, respectively). We conclude that the BRAF V600E mutation in microsatellite-stable colon cancer is associated with a significantly poorer survival in stages 2 to 4 colon cancer but has no effect on the excellent prognosis of microsatellite-unstable tumors.
Objective We examined the association between body mass index (BMI) around the time of diagnosis, weight change post-diagnosis, and breast cancer prognosis in a prospective cohort study of 1,692 ...breast cancer survivors. Methods Pre-diagnosis weight, weight at study entry, and height was obtained from mailed questionnaires and then weight change and BMI were calculated. After approximately seven years of follow-up, 207 recurrences, 99 deaths due to breast cancer, and 162 deaths due to any cause were reported. Delayed entry Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI), controlling for treatment and known prognostic factors. Results Being obese one year before diagnosis was associated with an increased risk of death from any cause (HR = 1.6; 95% CI: 1.1-2.3) and a suggestion of increased risk of death from breast cancer (HR = 1.6; 95% CI: 0.9-2.7). However, weight gain up to four years after a breast cancer diagnosis was not associated with an increased risk of recurrence or death from any cause nor did moderate weight loss (5-10%) decrease risk of these outcomes. There was some evidence that women who had larger weight losses (>=10%) between pre-diagnosis and study entry had an increased risk of recurrence (HR = 1.7; 95% CI 1.0-2.6) and death due to any cause (HR = 2.1; 95% CI 1.3-3.4) compared to being weight stable. This elevated risk was more pronounced among women who were obese before diagnosis (BMI >= 30 kg/m²) or who had ER- or PR- tumors. Conclusion We found that being obese before breast cancer diagnosis was associated with increased risk of recurrence and poorer survival, corroborating results from previous studies. However, weight gain after diagnosis did not confer additional risk. Body weight pre-diagnosis appears to be the strongest predictor of an adverse breast cancer prognosis.
Interleukins are a group of cytokines that contribute to growth and differentiation, cell migration, and inflammatory and anti‐inflammatory responses by the immune system. In our study, we examined ...genetic variation in genes from various anti‐inflammatory and proinflammatory interleukins to determine association with colon and rectal cancer risk and overall survival. Data from two population‐based incident studies of colon cancer (1,555 cases and 1,956 controls) and rectal cancer (754 cases and 954 controls) were used. After controlling for multiple comparisons, single nucleotide polymorphisms (SNPs) from four genes, IL3, IL6R, IL8, IL15, were associated with increased colon cancer risk, and CXCR1 and CXCR2 were significantly associated with increased rectal cancer risk. Only SNPs from genes within the IL‐8 pathway (IL8, CXCR1 and CXCR2) showed a significant association with both colon and rectal cancer risk. Several SNPs interacted significantly with IL8 and IFNG SNPs and with aspirin/non‐steroidal anti‐inflammatory drug (NSAID), cigarette smoking, estrogen use and BMI. For both colon and rectal cancer, increasing numbers of risk alleles were associated with increased hazard of death from cancer; the estimated hazard of death for colon cancer for the highest category of risk alleles was 1.74 (95% confidence interval CI 1.18–2.56) and 1.96 (95% CI 1.28–2.99) for rectal cancer. These data suggest that interleukin genes play a role in risk and overall survival for colon and rectal cancer.
What's new?
This research describes the association of genetic variation in interleukin genes with risk for colon or rectal cancer, as well as with survival from these diseases. Few of these associations were modified by lifestyle factors such as obesity, smoking, or NSAID/aspirin use, although several associations were modified by current estrogen use. As a whole, the data suggest that interleukins play a role in both risk and survival for colon and rectal cancers, and set the stage for future studies of specific mechanisms involved.
Mitogen-activated protein kinase (MAPK) pathways regulate many cellular functions including cell proliferation and apoptosis. We examined associations of differential gene and microRNA (miRNA) ...expression between carcinoma and paired normal mucosa for 241 genes in the KEGG-identified MAPK-signaling pathway among 217 colorectal cancer (CRC) cases. Gene expression data (RNA-Seq) and miRNA expression data (Agilent Human miRNA Microarray V19.0; Agilent Technologies Inc., Santa Clara, CA, USA) were analyzed. We first identified genes most strongly associated with CRC using a fold change (FC) of >1.50 or <0.67) that were statistically significant after adjustment for multiple comparisons. We then determined miRNAs associated with dysregulated genes and through miRNA:mRNA (messenger RNA) seed region matches discerned genes with a greater likelihood of having a direct biological association. Ninety-nine genes had a meaningful FC for all CRC, microsatellite unstable–specific tumors, or microsatellite stable–specific tumors. Thirteen dysregulated genes were associated with miRNAs, totaling 68 miRNA:mRNA associations. Thirteen of the miRNA:mRNA associations had seed region matches where the differential expression between the miRNA and mRNA was inversely related suggesting a direct association as a result of their binding. Several direct associations, upstream of ERK1/ERK2, JNK, and p38, were found for PDGFRA with 7 miRNAs; RASGRP3 and PRKCB with miR-203a; and TGFBR1 with miR-6071 and miR-2117. Other associations between miRNAs and mRNAs are most likely indirect, resulting from feedback and feed forward loops. Our results suggest that miRNAs may alter MAPK signaling through direct binding with key genes in this pathway. We encourage others to validate results in targeted CRC experiments that can help solidify important therapeutic targets.
PDF
