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Background: Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis.
Methods: We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test).
Results: Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 – ORAA: 1.62, 95% CI: 1.34–1.96; ORAG: 1.41, 95% CI: 1.30–1.54; ORGG: 1.22, 95% CI: 1.13–1.31; p-value3-d.f.: 5.46 × 10−11) and 13q14.13 (rs9526201, LRCH1 – ORGG: 2.11, 95% CI: 1.56–2.83; ORGA: 1.52, 95% CI: 1.38–1.68; ORAA: 1.13, 95% CI: 1.06–1.21; p-value2-d.f.: 7.84 × 10−09).
Discussion: These results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.
Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer.
Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk
(2024)
Background: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk.
Methods: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated.
Results: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10−8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%–4.0%) vs 6.1% (5.7%–6.5%) (difference 2.4%, P-value = 1.83 × 10−14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%–1.8%) vs 2.2% (1.9%–2.4%) (difference 0.6%, P-value = 1.01 × 10−3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk.
Conclusions: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.
Background: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate’s role in CRC.
Objectives: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk.
Methods: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO).
Results: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate.
Conclusions: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.
Background & Aims: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development.
Methods: Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls])
Results: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05–1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03–1.12; P = 3.3 × 10–4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06–1.18; P = 4.2 × 10–5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2.
Conclusions: In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.
Early-onset colorectal cancer has been on the rise in Western populations. Here, we compare patient characteristics between those with early- (<50 years) vs. late-onset (≥50 years) disease in a large multinational cohort of colorectal cancer patients (n = 2193). We calculated descriptive statistics and assessed associations of clinicodemographic factors with age of onset using mutually-adjusted logistic regression models. Patients were on average 60 years old, with BMI of 29 kg/m2, 52% colon cancers, 21% early-onset, and presented with stage II or III (60%) disease. Early-onset patients presented with more advanced disease (stages III–IV: 63% vs. 51%, respectively), and received more neo and adjuvant treatment compared to late-onset patients, after controlling for stage (odds ratio (OR) (95% confidence interval (CI)) = 2.30 (1.82–3.83) and 2.00 (1.43–2.81), respectively). Early-onset rectal cancer patients across all stages more commonly received neoadjuvant treatment, even when not indicated as the standard of care, e.g., during stage I disease. The odds of early-onset disease were higher among never smokers and lower among overweight patients (1.55 (1.21–1.98) and 0.56 (0.41–0.76), respectively). Patients with early-onset colorectal cancer were more likely to be diagnosed with advanced stage disease, to have received systemic treatments regardless of stage at diagnosis, and were less likely to be ever smokers or overweight.
Background: Physical activity and BMI have been individually associated with cancer survivorship but have not yet been studied in combinations in colorectal cancer patients. Here, we investigate individual and combined associations of physical activity and BMI groups with colorectal cancer survival outcomes.
Methods: Self-reported physical activity levels (MET hrs/wk) were assessed using an adapted version of the International Physical Activity Questionnaire (IPAQ) at baseline in 931 patients with stage I-III colorectal cancer and classified into ‘highly active’ and ’not-highly active’ (≥/ < 18 MET hrs/wk). BMI (kg/m2) was categorized into ‘normal weight’, ‘overweight’, and ‘obese’. Patients were further classified into combined physical activity and BMI groups. Cox-proportional hazard models with Firth correction were computed to assess associations [hazard ratio (HR), 95% profile HR likelihood confidence interval (95% CI) between individual and combined physical activity and BMI groups with overall and disease-free survival in colorectal cancer patients.
Results: ‘Not-highly active’ compared to ‘highly active’ and ‘overweight’/‘obese’ compared to ‘normal weight’ patients had a 40–50% increased risk of death or recurrence (HR: 1.41 (95% CI: 0.99–2.06), p=0.03; HR: 1.49 (95% CI: 1.02–2.21) and HR: 1.51 (95% CI: 1.02–2.26), p= 0.04, respectively). ‘Not-highly active’ patients had worse disease-free survival outcomes, regardless of their BMI, compared to ‘highly active/normal weight’ patients. ‘Not-highly active/obese’ patients had a 3.66 times increased risk of death or recurrence compared to ‘highly active/normal weight’ patients (HR: 4.66 (95% CI: 1.75–9.10), p=0.002). Lower activity thresholds yielded smaller effect sizes.
Conclusion: Physical activity and BMI were individually associated with disease-free survival among colorectal cancer patients. Physical activity seems to improve survival outcomes in patients regardless of their BMI.
A major gap impeding development of new treatments for cancer-related fatigue is an inadequate understanding of the complex biological, clinical, demographic, and lifestyle mechanisms underlying fatigue. In this paper, we describe a new application of a comprehensive model for cancer-related fatigue: the predisposing, precipitating, and perpetuating (3P) factors model. This model framework outlined herein, which incorporates the emerging field of metabolomics, may help to frame a more in-depth analysis of the etiology of cancer-related fatigue as well as a broader and more personalized set of approaches to the clinical treatment of fatigue in oncology care. Included within this review paper is an in-depth description of the proposed biological mechanisms of cancer-related fatigue, as well as a presentation of the 3P model’s application to this phenomenon. We conclude that a clinical focus on organization risk stratification and treatment around the 3P model may be warranted, and future research may benefit from expanding the 3P model to understand fatigue not only in oncology, but also across a variety of chronic conditions.
Cancer-related fatigue (CRF) is considered one of the most frequent and distressing symptoms for cancer survivors. Despite its high prevalence, factors that predispose, precipitate, and perpetuate CRF are poorly understood. Emerging research focuses on cancer and treatment-related nutritional complications, changes in body composition, and nutritional deficiencies that can compound CRF. Nutritional metabolomics, the novel study of diet-related metabolites in cells, tissues, and biofluids, offers a promising tool to further address these research gaps. In this position paper, we examine CRF risk factors, summarize metabolomics studies of CRF, outline dietary recommendations for the prevention and management of CRF in cancer survivorship, and identify knowledge gaps and challenges in applying nutritional metabolomics to understand dietary contributions to CRF over the cancer survivorship trajectory.
Background: Cachexia accounts for about 20% of all cancer‐related deaths and indicates poor prognosis. The impact of Fusobacterium nucleatum (Fn), a microbial risk factor for colorectal cancer (CRC), on the development of cachexia in CRC has not been established.
Methods: We evaluated the association between Fn abundance in pre‐surgical stool samples and onset of cachexia at 6 months post‐surgery in n = 87 patients with stages I–III CRC in the ColoCare Study.
Results: High fecal Fn abundance compared to negative/low fecal Fn abundance was associated with 4‐fold increased risk of cachexia onset at 6 months post‐surgery (OR = 4.82, 95% CI = 1.15, 20.10, p = 0.03).
Conclusion: Our findings suggest that high fecal Fn abundance was associated with an increased risk of cachexia at 6 months post‐surgery in CRC patients. This is the first study to link Fn abundance with cachexia in CRC patients, offering novel insights into biological mechanisms and potential management of cancer cachexia. Due to the small sample size, our results should be interpreted with caution. Future studies with larger sample sizes are needed to validate these findings.
