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Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer.
Laskar, RS, Qu, C, Huyghe, JR, Harrison, T, Hayes, RB, Cao, Y, Campbell, PT, Steinfelder, R, Talukdar, FR, Brenner, H, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2024
Abstract
BACKGROUND The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) β, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.
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Metabolomics of Ramadan fasting and associated risk of chronic diseases.
Al-Jafar, R, Pinto, RC, Elliott, P, Tsilidis, KK, Dehghan, A
The American journal of clinical nutrition. 2024;(4):1007-1014
Abstract
BACKGROUND The dramatic change in lifestyle associated with Ramadan fasting raises questions about its effect on metabolism and health. Metabolites, as the end product of metabolism, are excellent candidates to be studied in this regard. OBJECTIVE This study aims to investigate the effect of Ramadan fasting on the metabolic profile and risk of chronic diseases. METHODS The London Ramadan study (LORANS) is an observational study in which 2 blood samples were collected from 72 participants a few days before and after the fasting month of Ramadan. We conducted metabolomic profiling using nuclear magnetic resonance spectroscopy to assess the change in individual metabolites from before to after Ramadan. Also, we generated metabolic scores (scaled from 0 to 100) for 7 chronic diseases in the UK Biobank and assessed the association of Ramadan fasting with these scores in LORANS. RESULTS Of the 72 participants, 35 were male (48.6%); the mean (± standard deviation) age was 45.7 (±16) y. Ramadan fasting was associated with changes in 14 metabolites (1 inflammation marker, 1 amino acid, 2 glycolysis-related metabolites, 2 ketone bodies, 2 triglyceride, and 6 lipoprotein subclasses), independent of changes in body composition. Using data from 117,981 participants in the UK Biobank, we generated metabolic scores for diabetes, hypertension, coronary artery disease, renal failure, colorectal cancer, breast cancer, and lung cancer. The metabolic scores for lung cancer, colorectal cancer, and breast cancer were lower after Ramadan in LORANS (-4.74, 9.6%, 95% confidence interval -6.56, -2.91, P < 0.001), (-1.09, -2.4%, -1.69, -0. 50, P < 0.001), and (-0.48, -1.1%, -0. 81, -0.15, P = 0.006), respectively. CONCLUSIONS Ramadan fasting is associated with short-term favorable changes in the metabolic profile concerning risk of some chronic diseases. These findings should be further investigated in future, larger studies of longer follow-up with clinical outcomes.
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Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis.
Yarmolinsky, J, Robinson, JW, Mariosa, D, Karhunen, V, Huang, J, Dimou, N, Murphy, N, Burrows, K, Bouras, E, Smith-Byrne, K, et al
EBioMedicine. 2024;:104991
Abstract
BACKGROUND Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. METHODS We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 × 10-8) cis-acting SNPs (i.e., in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r2 < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P-value ("q-value") <0.05 was used as a threshold to define "strong evidence" to support associations and 0.05 ≤ q-value < 0.20 to define "suggestive evidence". A colocalisation posterior probability (PPH4) >70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. FINDINGS We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10-1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20-1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53-0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88-0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48-4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. INTERPRETATION Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. FUNDING Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).
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A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk.
Aglago, EK, Kim, A, Lin, Y, Qu, C, Evangelou, M, Ren, Y, Morrison, J, Albanes, D, Arndt, V, Barry, EL, et al
Cancer research. 2023;(15):2572-2583
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Abstract
UNLABELLED 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.
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Separating the effects of early and later life adiposity on colorectal cancer risk: a Mendelian randomization study.
Papadimitriou, N, Bull, CJ, Jenab, M, Hughes, DJ, Bell, JA, Sanderson, E, Timpson, NJ, Smith, GD, Albanes, D, Campbell, PT, et al
BMC medicine. 2023;(1):5
Abstract
BACKGROUND Observational studies have linked childhood obesity with elevated risk of colorectal cancer; however, it is unclear if this association is causal or independent from the effects of obesity in adulthood on colorectal cancer risk. METHODS We conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56.5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants. RESULTS Genetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio [OR] per category change: 1.12, 95% confidence interval [CI]: 0.98-1.27), with stronger results for colon cancer (OR: 1.16, 95% CI: 1.00-1.35), and distal colon cancer (OR: 1.25, 95% CI: 1.04-1.51). After accounting for adult body size using multivariable MR, effect estimates for early life body size were attenuated towards the null for colorectal cancer (OR: 0.97, 95% CI: 0.77-1.22) and colon cancer (OR: 0.97, 95% CI: 0.76-1.25), while the estimate for distal colon cancer was of similar magnitude but more imprecise (OR: 1.27, 95% CI: 0.90-1.77). Genetically predicted adult life body size was estimated to increase odds of colorectal (OR: 1.27, 95% CI: 1.03, 1.57), colon (OR: 1.32, 95% CI: 1.05, 1.67), and proximal colon (OR: 1.57, 95% CI: 1.21, 2.05). CONCLUSIONS Our findings suggest that the positive association between early life body size and colorectal cancer risk is likely due to large body size retainment into adulthood.
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Postdiagnosis body fatness, weight change and breast cancer prognosis: Global Cancer Update Program (CUP global) systematic literature review and meta-analysis.
Chan, DSM, Vieira, R, Abar, L, Aune, D, Balducci, K, Cariolou, M, Greenwood, DC, Markozannes, G, Nanu, N, Becerra-Tomás, N, et al
International journal of cancer. 2023;(4):572-599
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Previous evidence on postdiagnosis body fatness and mortality after breast cancer was graded as limited-suggestive. To evaluate the evidence on body mass index (BMI), waist circumference, waist-hip-ratio and weight change in relation to breast cancer prognosis, an updated systematic review was conducted. PubMed and Embase were searched for relevant studies published up to 31 October, 2021. Random-effects meta-analyses were conducted to estimate summary relative risks (RRs). The evidence was judged by an independent Expert Panel using pre-defined grading criteria. One randomized controlled trial and 225 observational studies were reviewed (220 publications). There was strong evidence (likelihood of causality: probable) that higher postdiagnosis BMI was associated with increased all-cause mortality (64 studies, 32 507 deaths), breast cancer-specific mortality (39 studies, 14 106 deaths) and second primary breast cancer (11 studies, 5248 events). The respective summary RRs and 95% confidence intervals per 5 kg/m2 BMI were 1.07 (1.05-1.10), 1.10 (1.06-1.14) and 1.14 (1.04-1.26), with high between-study heterogeneity (I2 = 56%, 60%, 66%), but generally consistent positive associations. Positive associations were also observed for waist circumference, waist-hip-ratio and all-cause and breast cancer-specific mortality. There was limited-suggestive evidence that postdiagnosis BMI was associated with higher risk of recurrence, nonbreast cancer deaths and cardiovascular deaths. The evidence for postdiagnosis (unexplained) weight or BMI change and all outcomes was graded as limited-no conclusion. The RCT showed potential beneficial effect of intentional weight loss on disease-free-survival, but more intervention trials and well-designed observational studies in diverse populations are needed to elucidate the impact of body composition and their changes on breast cancer outcomes.
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Association between adiposity after diagnosis of prostate cancer and mortality: systematic review and meta-analysis.
Cariolou, M, Markozannes, G, Becerra-Tomás, N, Vieira, R, Balducci, K, Aune, D, Muller, DC, Chan, DSM, Tsilidis, KK
BMJ medicine. 2023;(1):e000339
Abstract
OBJECTIVE To explore the associations between adiposity indices, assessed at or after a diagnosis of prostate cancer, and mortality. DESIGN Systematic review and meta-analysis. DATA SOURCES PubMed and Embase, from inception to 16 November 2022. ELIGIBILITY CRITERIA FOR SELECTING STUDIES Cohort studies or randomised controlled trials of men with a diagnosis of prostate cancer that investigated the associations between adiposity (body mass index, waist and hip circumference, waist-to-hip ratio, and subcutaneous and visceral adipose tissue) after diagnosis and mortality outcomes. A modified version of the risk of bias for nutrition observational studies tool was used to assess risk of bias. RESULTS 79 studies were identified that investigated adiposity indices after a diagnosis of prostate cancer in relation to mortality. No randomised controlled trials were found. A non-linear dose-response meta-analysis indicated a J shaped association between body mass index and all cause mortality (33 910 men, 11 095 deaths, 17 studies). The highest rate of all cause mortality was found at the lowest and upper range of the distribution: 11-23% higher rate for a body mass index of 17-21 and 4-43% higher rate for a body mass index of 30-40. The association between body mass index and mortality specific to prostate cancer was flat until body mass index reached 26-27, and then increased linearly by 8-66% for a body mass index of 30-40 (33 137 men, 2947 deaths, 13 studies), but the 95% confidence intervals were wide. These associations did not differ in most predefined subgroups by study design, number of deaths, anthropometric assessment, follow-up time, geographical location, prostate cancer risk group, and adjustment variables. No associations were found in meta-analyses between 10 cm increases in waist circumference and all cause mortality or mortality specific to prostate cancer, but only three studies were available. The few studies with data on change in weight, waist-to-hip ratio, and subcutaneous and visceral adipose tissue reported conflicting results. CONCLUSIONS This review suggests that patients with prostate cancer might benefit from maintaining a healthy weight and avoiding obesity. Future studies should investigate adiposity across different stages of cancer survivorship and use various parameters for distribution of adipose tissue. SYSTEMATIC REVIEW REGISTRATION Open Science Framework https://osf.io/qp3c4.
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Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response.
Carreras-Torres, R, Kim, AE, Lin, Y, Díez-Obrero, V, Bien, SA, Qu, C, Wang, J, Dimou, N, Aglago, EK, Albanes, D, et al
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2023;(3):315-328
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BACKGROUND Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer. METHODS A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia. RESULTS Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10-8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20-1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10-8) and 8q24.23 (rs7005722, P = 2.88 × 10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09-1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07-1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33). CONCLUSIONS Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response. IMPACT These findings can guide potential prevention treatments.
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Circulating amino acid levels and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition and UK Biobank cohorts.
Rothwell, JA, Bešević, J, Dimou, N, Breeur, M, Murphy, N, Jenab, M, Wedekind, R, Viallon, V, Ferrari, P, Achaintre, D, et al
BMC medicine. 2023;(1):80
Abstract
BACKGROUND Amino acid metabolism is dysregulated in colorectal cancer patients; however, it is not clear whether pre-diagnostic levels of amino acids are associated with subsequent risk of colorectal cancer. We investigated circulating levels of amino acids in relation to colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank cohorts. METHODS Concentrations of 13-21 amino acids were determined in baseline fasting plasma or serum samples in 654 incident colorectal cancer cases and 654 matched controls in EPIC. Amino acids associated with colorectal cancer risk following adjustment for the false discovery rate (FDR) were then tested for associations in the UK Biobank, for which measurements of 9 amino acids were available in 111,323 participants, of which 1221 were incident colorectal cancer cases. RESULTS Histidine levels were inversely associated with colorectal cancer risk in EPIC (odds ratio [OR] 0.80 per standard deviation [SD], 95% confidence interval [CI] 0.69-0.92, FDR P-value=0.03) and in UK Biobank (HR 0.93 per SD, 95% CI 0.87-0.99, P-value=0.03). Glutamine levels were borderline inversely associated with colorectal cancer risk in EPIC (OR 0.85 per SD, 95% CI 0.75-0.97, FDR P-value=0.08) and similarly in UK Biobank (HR 0.95, 95% CI 0.89-1.01, P=0.09) In both cohorts, associations changed only minimally when cases diagnosed within 2 or 5 years of follow-up were excluded. CONCLUSIONS Higher circulating levels of histidine were associated with a lower risk of colorectal cancer in two large prospective cohorts. Further research to ascertain the role of histidine metabolism and potentially that of glutamine in colorectal cancer development is warranted.
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Postdiagnosis body fatness, recreational physical activity, dietary factors and breast cancer prognosis: Global Cancer Update Programme (CUP Global) summary of evidence grading.
Tsilidis, KK, Cariolou, M, Becerra-Tomás, N, Balducci, K, Vieira, R, Abar, L, Aune, D, Markozannes, G, Nanu, N, Greenwood, DC, et al
International journal of cancer. 2023;(4):635-644
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Based on the Global Cancer Update Programme, formally known as the World Cancer Research Fund/American Institute for Cancer Research Continuous Update Project, we performed systematic reviews and meta-analyses to investigate the association of postdiagnosis body fatness, physical activity and dietary factors with breast cancer prognosis. We searched PubMed and Embase for randomised controlled trials and longitudinal observational studies from inception to 31 October 2021. We calculated summary relative risks (RRs) and 95% confidence intervals (CIs) using random-effects meta-analyses. An independent Expert Panel graded the quality of evidence according to predefined criteria. The evidence on postdiagnosis body fatness and higher all-cause mortality (RR per 5 kg/m2 in body mass index: 1.07, 95% CI: 1.05-1.10), breast cancer-specific mortality (RR: 1.10, 95% CI: 1.06-1.14) and second primary breast cancer (RR: 1.14, 95% CI: 1.04-1.26) was graded as strong (likelihood of causality: probable). The evidence for body fatness and breast cancer recurrence and other nonbreast cancer-related mortality was graded as limited (likelihood of causality: limited-suggestive). The evidence on recreational physical activity and lower risk of all-cause (RR per 10 metabolic equivalent of task-hour/week: 0.85, 95% CI: 0.78-0.92) and breast cancer-specific mortality (RR: 0.86, 95% CI: 0.77-0.96) was judged as limited-suggestive. Data on dietary factors was limited, and no conclusions could be reached except for healthy dietary patterns, isoflavone and dietary fibre intake and serum 25(OH)D concentrations that were graded with limited-suggestive evidence for lower risk of the examined outcomes. Our results encourage the development of lifestyle recommendations for breast cancer patients to avoid obesity and be physically active.