Publications by authors named "Graham G Giles"

914 Publications

The blood metabolome of incident kidney cancer: A case-control study nested within the MetKid consortium.

PLoS Med 2021 Sep 20;18(9):e1003786. Epub 2021 Sep 20.

Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France.

Background: Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI).

Methods And Findings: We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10-8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10-5), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10-5). BMI was also associated with increased levels of glutamate (ßBMI: 0.12, p = 1.5 × 10-3). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds.

Conclusions: This study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI-the principal modifiable risk factor of kidney cancer.
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http://dx.doi.org/10.1371/journal.pmed.1003786DOI Listing
September 2021

Smoking methylation marks for prediction of urothelial cancer risk.

Cancer Epidemiol Biomarkers Prev 2021 Sep 14. Epub 2021 Sep 14.

Precision Medicine, School of Clinical Sciences at Monash Healh, Monash University

Background: Self-reported information may not accurately capture smoking exposure. We aimed to evaluate whether smoking-associated DNA methylation markers improve urothelial cell carcinoma (UCC) risk prediction.

Methods: Conditional logistic regression was used to assess associations between blood-based methylation and UCC risk using two matched case-control samples, N=404 pairs from the Melbourne Collaborative Cohort Study (MCCS) and N=440 pairs from the Women's Health Initiative (WHI) cohort, respectively. Results were pooled using fixed-effects meta-analysis. We developed methylation-based predictors of UCC and evaluated their prediction accuracy on two replication datasets using the area under the curve (AUC).

Results: The meta-analysis identified associations (P<4.7×10-5) for 29 of 1,061 smoking-associated methylation sites, but these were substantially attenuated after adjustment for self-reported smoking. Nominally significant associations (P<0.05) were found for 387 (36%) and 86 (8%) of smoking-associated markers without/with adjustment for self-reported smoking, respectively, with same direction of association as with smoking for 387 (100%) and 79 (92%) markers. A Lasso-based predictor was associated with UCC risk in one replication dataset in MCCS (N=134, odds ratio per SD [OR]=1.37, 95%CI=1.00-1.90) after confounder adjustment; AUC=0.66, compared with AUC=0.64 without methylation information. Limited evidence of replication was found in the second testing dataset in WHI (N=440, OR=1.09, 95%CI=0.91-1.30).

Conclusions: Combination of smoking-associated methylation marks may provide some improvement to UCC risk prediction. Our findings need further evaluation using larger datasets.

Impact: DNA methylation may be associated with UCC risk beyond traditional smoking assessment and could contribute to some improvements in stratification of UCC risk in the general population.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0313DOI Listing
September 2021

Demographic and lifestyle risk factors for gastroesophageal reflux disease and Barrett's esophagus in Australia.

Dis Esophagus 2021 Aug 19. Epub 2021 Aug 19.

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.

We examined demographic and lifestyle risk factors for incidence of gastroesophageal reflux disease (GERD) and Barrett's esophagus (BE) in an Australian cohort of 20,975 participants aged 40-63 at recruitment (1990-1994). Information on GERD and BE was collected between 2007 and 2010. GERD symptoms were defined as self-reported heartburn or acid regurgitation. BE was defined as endoscopically confirmed columnar-lined esophagus. Risk factors for developing GERD symptoms, BE diagnosis, age at symptom onset, and age at BE diagnosis were quantified using regression. During a mean follow-up of 15.8 years, risk of GERD symptoms was 7.5% (n = 1,318) for daily, 7.5% (n = 1,333) for 2-6 days/week, and 4.3% (n = 751) for 1 day/week. There were 210 (1.0%) endoscopically diagnosed BE cases, of whom 141 had histologically confirmed esophageal intestinal metaplasia. Female sex, younger age, lower socioeconomic position (SEP) and educational attainment, and former smoking were associated with higher GERD risk. Male sex and smoking were associated with earlier GERD symptom onset. Men, older participants, those with higher SEP, and former smokers were at higher BE risk. There was some evidence higher SEP was associated with earlier BE diagnosis. GERD and BE had different demographic risk factors but shared similar lifestyle factors. Earlier GERD symptom onset for men and smokers might have contributed to higher BE risk. The SEP patterns observed for GERD and BE suggest potential inequity in access to care. These findings would be important in the development of clinical risk prediction models for early detection of BE.
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http://dx.doi.org/10.1093/dote/doab058DOI Listing
August 2021

Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.

Breast Cancer Res 2021 Aug 18;23(1):86. Epub 2021 Aug 18.

Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, USA.

Background: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.

Methods: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15).

Results: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy.

Conclusions: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.
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http://dx.doi.org/10.1186/s13058-021-01450-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371820PMC
August 2021

Association Between Smoking and Molecular Subtypes of Colorectal Cancer.

JNCI Cancer Spectr 2021 Aug 14;5(4):pkab056. Epub 2021 Jun 14.

Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.

Background: Smoking is associated with colorectal cancer (CRC) risk. Previous studies suggested this association may be restricted to certain molecular subtypes of CRC, but large-scale comprehensive analysis is lacking.

Methods: A total of 9789 CRC cases and 11 231 controls of European ancestry from 11 observational studies were included. We harmonized smoking variables across studies and derived sex study-specific quartiles of pack-years of smoking for analysis. Four somatic colorectal tumor markers were assessed individually and in combination, including mutation, mutation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. A multinomial logistic regression analysis was used to assess the association between smoking and risk of CRC subtypes by molecular characteristics, adjusting for age, sex, and study. All statistical tests were 2-sided and adjusted for Bonferroni correction.

Results: Heavier smoking was associated with higher risk of CRC overall and stratified by individual markers ( < .001). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and . Compared with never-smokers, smokers in the fourth quartile of pack-years had a 90% higher risk of CIMP-positive CRC (odds ratio = 1.90, 95% confidence interval = 1.60 to 2.26) but only 35% higher risk for CIMP-negative CRC (odds ratio = 1.35, 95% confidence interval = 1.22 to 1.49; = 2.1 x 10). The association was also stronger in tumors that were positive, MSI high, or wild type when combined ( < .001).

Conclusion: Smoking was associated with differential risk of CRC subtypes defined by molecular characteristics. Heavier smokers had particularly higher risk of CRC subtypes that were CIMP positive and MSI high in combination, suggesting that smoking may be involved in the development of colorectal tumors via the serrated pathway.
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http://dx.doi.org/10.1093/jncics/pkab056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346704PMC
August 2021

Genetic insights into biological mechanisms governing human ovarian ageing.

Nature 2021 08 4;596(7872):393-397. Epub 2021 Aug 4.

Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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http://dx.doi.org/10.1038/s41586-021-03779-7DOI Listing
August 2021

Mendelian randomisation study of smoking exposure in relation to breast cancer risk.

Br J Cancer 2021 Aug 2. Epub 2021 Aug 2.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.

Background: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk.

Methods: We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy.

Results: Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect.

Conclusion: Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.
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http://dx.doi.org/10.1038/s41416-021-01432-8DOI Listing
August 2021

Inflammation-Related Marker Profiling of Dietary Patterns and All-cause Mortality in the Melbourne Collaborative Cohort Study.

J Nutr 2021 Jul 28. Epub 2021 Jul 28.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Background: Nutritional epidemiology research using self-reported dietary intake is prone to measurement error. Objective methods are being explored to overcome this limitation.

Objectives: We aimed to examine 1) the association between plasma markers related to inflammation and derive marker scores for dietary patterns [Mediterranean dietary score (MDS), energy-adjusted Dietary Inflammatory Index (E-DIITM), Alternative Healthy Eating Index 2010 (AHEI)] and 2) the associations of these marker scores with mortality.

Methods: Weighted marker scores were derived from the cross-sectional association between 30 plasma markers and each dietary score (assessed using food-frequency questionnaires) using linear regression for 770 participants in the Melbourne Collaborative Cohort Study (aged 50-82 y). Prospective associations between marker scores and mortality (n = 249 deaths) were assessed using Cox regression (median follow-up: 14.4 y).

Results: The MDS, E-DII, and AHEI were associated (P < 0.05) with 9, 14, and 11 plasma markers, respectively. Healthier diets (higher MDS and AHEI, and lower anti-inflammatory, E-DII) were associated with lower concentrations of kynurenines, neopterin, IFN-γ, cytokines, and C-reactive protein. Five of 6 markers common to the 3 dietary scores were components of the kynurenine pathway. The 3 dietary-based marker scores were highly correlated (Spearman ρ: -0.74, -0.82, and 0.93). Inverse associations (for 1-SD increment) were observed with all-cause mortality for the MDS marker score (HR: 0.84; 95% CI: 0.72-0.98) and the AHEI marker score (HR: 0.76; 95% CI: 0.66-0.89), whereas a positive association was observed with the E-DII marker score (HR: 1.18; 95% CI: 1.01-1.39). The same magnitude of effect was not observed for the respective dietary patterns.

Conclusions: Markers involved in inflammation-related processes are associated with dietary quality, including a substantial overlap between markers associated with the MDS, the E-DII, and the AHEI, especially kynurenines. Unfavorable marker scores, reflecting poorer-quality diets, were associated with increased mortality.
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http://dx.doi.org/10.1093/jn/nxab231DOI Listing
July 2021

Factors Explaining Socio-Economic Inequalities in Survival from Colon Cancer: A Causal Mediation Analysis.

Cancer Epidemiol Biomarkers Prev 2021 Jul 16. Epub 2021 Jul 16.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Background: Socio-economic inequalities in colon cancer survival exist in high-income countries, but the reasons are unclear. We assessed the mediating effects of stage at diagnosis, comorbidities, and treatment (surgery and intravenous chemotherapy) on survival from colon cancer.

Methods: We identified 2,203 people aged 15 to 79 years with first primary colon cancer diagnosed in Victoria, Australia, between 2008 and 2011. Colon cancer cases were identified through the Victorian Cancer Registry (VCR), and clinical information was obtained from hospital records. Deaths till December 31, 2016 ( = 807), were identified from Victorian and national death registries. Socio-economic disadvantage was based on residential address at diagnosis. For stage III disease, we decomposed its total effect into direct and indirect effects using interventional mediation analysis.

Results: Socio-economic inequalities in colon cancer survival were not explained by stage and were greater for men than women. For men with stage III disease, there were 161 [95% confidence interval (CI), 67-256] additional deaths per 1,000 cases in the 5 years following diagnosis for the most disadvantaged compared with the least disadvantaged. The indirect effects through comorbidities and intravenous chemotherapy explained 6 (95% CI, -10-21) and 15 (95% CI, -14-44) per 1,000 of these additional deaths, respectively. Surgery did not explain the observed gap in survival.

Conclusions: Disadvantaged men have lower survival from stage III colon cancer that is only modestly explained by having comorbidities or not receiving chemotherapy after surgery.

Impact: Future studies should investigate the potential mediating role of factors occurring beyond the first year following diagnosis, such as compliance with surveillance for recurrence and supportive care services.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0222DOI Listing
July 2021

Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies.

Am J Clin Nutr 2021 Jul 13. Epub 2021 Jul 13.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Background: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis.

Objectives: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC.

Methods: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs.

Results: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association.

Conclusions: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.
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http://dx.doi.org/10.1093/ajcn/nqab217DOI Listing
July 2021

Smoking, alcohol consumption, body fatness, and risk of myelodysplastic syndromes: A prospective study.

Leuk Res 2021 Apr 24;109:106593. Epub 2021 Apr 24.

Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, Melbourne, Victoria, 3004, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, 3010, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, 3168, Australia.

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http://dx.doi.org/10.1016/j.leukres.2021.106593DOI Listing
April 2021

Epidemiology of 40 blood biomarkers of one-carbon metabolism, vitamin status, inflammation, and renal and endothelial function among cancer-free older adults.

Sci Rep 2021 Jul 5;11(1):13805. Epub 2021 Jul 5.

Duke - NUS Medical School, Singapore, Singapore.

Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40-80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was - 0.91 standard-deviations lower in women than men (95%CI - 0.98; - 0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p < 0.05) association with time since smoking cessation was observed for 8 markers, including C-reactive protein, kynurenine, choline, and total homocysteine. We conclude that most blood biomarkers show small variations across demographic characteristics. Patterns by smoking status point to normalization of multiple physiological processes after smoking cessation.
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http://dx.doi.org/10.1038/s41598-021-93214-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257595PMC
July 2021

Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.

Am J Hum Genet 2021 07 18;108(7):1190-1203. Epub 2021 Jun 18.

Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10).
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http://dx.doi.org/10.1016/j.ajhg.2021.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322933PMC
July 2021

Association of markers of inflammation, the kynurenine pathway and B vitamins with age and mortality, and a signature of inflammaging.

J Gerontol A Biol Sci Med Sci 2021 Jun 12. Epub 2021 Jun 12.

Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.

Background: Inflammation is a key feature of aging. We aimed to i) investigate the association of 34 blood markers potentially involved in inflammatory processes with age and mortality, ii) develop a signature of 'inflammaging'.

Methods: Thirty-four blood markers relating to inflammation, B vitamin status and the kynurenine pathway were measured in 976 participants in the Melbourne Collaborative Cohort Study at baseline (median age=59 years) and follow-up (median age=70 years). Associations with age and mortality were assessed using linear and Cox regression, respectively. A parsimonious signature of inflammaging was developed and its association with mortality was compared with two marker scores calculated across all markers associated with age and mortality, respectively.

Results: The majority of markers (30/34) were associated with age, with stronger associations observed for neopterin, cystatin C, IL-6, TNF-α, several markers of the kynurenine pathway and derived indices KTR (kynurenine/tryptophan ratio), PAr index (ratio of 4-pyridoxic acid and the sum of pyridoxal 5´-phosphate and pyridoxal), and HK:XA (3-hydroxykynurenine/xanthurenic acid ratio). Many markers (17/34) showed an association with mortality, in particular IL-6, neopterin, CRP, quinolinic acid, PAr index, and KTR. The inflammaging signature included ten markers and was strongly associated of mortality (HR per SD=1.40, 95%CI:1.24-1.57, P=2x10 -8), similar to scores based on all age-associated (HR=1.38, 95%CI:1.23-1.55, P=4x10 -8) and mortality-associated markers (HR=1.43, 95%CI:1.28-1.60, P=1x10 -10), respectively. Strong evidence of replication of the inflammaging signature association with mortality was found in the Hordaland Health Study.

Conclusion: Our study highlights the key role of the kynurenine pathway and vitamin B6 catabolism in aging, along with other well-established inflammation-related markers. A signature of inflammaging based on ten markers was strongly associated with mortality.
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http://dx.doi.org/10.1093/gerona/glab163DOI Listing
June 2021

DNA Methylation Signatures and the Contribution of Age-Associated Methylomic Drift to Carcinogenesis in Early-Onset Colorectal Cancer.

Cancers (Basel) 2021 May 25;13(11). Epub 2021 May 25.

Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia.

We investigated aberrant DNA methylation (DNAm) changes and the contribution of ageing-associated methylomic drift and age acceleration to early-onset colorectal cancer (EOCRC) carcinogenesis. Genome-wide DNAm profiling using the Infinium HM450K on 97 EOCRC tumour and 54 normal colonic mucosa samples was compared with: (1) intermediate-onset CRC (IOCRC; diagnosed between 50-70 years; 343 tumour and 35 normal); and (2) late-onset CRC (LOCRC; >70 years; 318 tumour and 40 normal). CpGs associated with age-related methylation drift were identified using a public dataset of 231 normal mucosa samples from people without CRC. DNAm-age was estimated using epiTOC2. Common to all three age-of-onset groups, 88,385 (20% of all CpGs) CpGs were differentially methylated between tumour and normal mucosa. We identified 234 differentially methylated genes that were unique to the EOCRC group; 13 of these DMRs/genes were replicated in EOCRC compared with LOCRCs from TCGA. In normal mucosa from people without CRC, we identified 28,154 CpGs that undergo ageing-related DNAm drift, and of those, 65% were aberrantly methylated in EOCRC tumours. Based on the mitotic-based DNAm clock epiTOC2, we identified age acceleration in normal mucosa of people with EOCRC compared with normal mucosa from the IOCRC, LOCRC groups ( = 3.7 × 10) and young people without CRC ( = 5.8 × 10). EOCRC acquires unique DNAm alterations at 234 loci. CpGs associated with ageing-associated drift were widely affected in EOCRC without needing the decades-long accrual of DNAm drift as commonly seen in intermediate- and late-onset CRCs. Accelerated ageing in normal mucosa from people with EOCRC potentially underlies the earlier age of diagnosis in CRC carcinogenesis.
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http://dx.doi.org/10.3390/cancers13112589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199056PMC
May 2021

The Future Burden of Head and Neck Cancers Attributable to Modifiable Behaviors in Australia: A Pooled Cohort Study.

Cancer Epidemiol Biomarkers Prev 2021 Aug 21;30(8):1566-1574. Epub 2021 May 21.

Centre for Big Data Research in Health, University of New South Wales, Sydney, Australia.

Background: Estimates of future burden of cancer attributable to current modifiable causal exposures can guide cancer prevention. We quantified future head and neck cancer burden in Australia attributable to individual and joint causal exposures, and assessed whether these burdens differ between population subgroups.

Methods: We estimated the strength of the associations between exposures and head and neck cancer using adjusted proportional hazards models from pooled data from seven Australian cohorts ( = 367,058) linked to national cancer and death registries and estimated exposure prevalence from the 2017 to 2018 Australian National Health Survey. We calculated population attributable fractions (PAF) with 95% confidence intervals (CI), accounting for competing risk of death, and compared PAFs for population subgroups.

Results: Contemporary levels of current and former smoking contribute 30.6% (95% CI, 22.7%-37.8%), alcohol consumption exceeding two standard drinks per day 12.9% (95% CI, 7.6%-17.9%), and these exposures jointly 38.5% (95% CI, 31.1%-45.0%) to the future head and neck cancer burden. Alcohol-attributable burden is triple and smoking-attributable burden is double for men compared with women. Smoking-attributable burden is also at least double for those consuming more than two alcoholic drinks daily or doing less than 150 minutes of moderate or 75 minutes of vigorous activity weekly, and for those aged under 65 years, unmarried, with low or intermediate educational attainment or lower socioeconomic status, compared with their counterparts.

Conclusions: Two-fifths of head and neck cancers in Australia are preventable by investment in tobacco and alcohol control.

Impact: Targeting men and other identified high-burden subgroups can help to reduce head and neck cancer burden disparities.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0003DOI Listing
August 2021

Prospective Evaluation of the Addition of Polygenic Risk Scores to Breast Cancer Risk Models.

JNCI Cancer Spectr 2021 Jun 2;5(3):pkab021. Epub 2021 Mar 2.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Background: The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm and the International Breast Cancer Intervention Study breast cancer risk models are used to provide advice on screening intervals and chemoprevention. We evaluated the performance of these models, which now incorporate polygenic risk scores (PRSs), using a prospective cohort study.

Methods: We used a case-cohort design, involving women in the Melbourne Collaborative Cohort Study aged 50-75 years when surveyed in 2003-2007, of whom 408 had a first primary breast cancer diagnosed within 10 years (cases), and 2783 were from the subcohort. Ten-year risks were calculated based on lifestyle factors, family history data, and a 313-variant PRS. Discrimination was assessed using a C-statistic compared with 0.50 and calibration using the ratio of expected to observed number of cases (E/O).

Results: When the PRS was added to models with lifestyle factors and family history, the C-statistic (95% confidence interval [CI]) increased from 0.57 (0.54 to 0.60) to 0.62 (0.60 to 0.65) using IBIS and from 0.56 (0.53 to 0.59) to 0.62 (0.59 to 0.64) using BOADICEA. IBIS underpredicted risk (E/O = 0.62, 95% CI = 0.48 to 0.80) for women in the lowest risk category (<1.7%) and overpredicted risk (E/O = 1.40, 95% CI = 1.18 to 1.67) in the highest risk category (≥5%), using the Hosmer-Lemeshow test for calibration in quantiles of risk and a 2-sided value less than.001. BOADICEA underpredicted risk (E/O = 0.82, 95% CI = 0.67 to 0.99) in the second highest risk category (3.4%-5%); the Hosmer-Lemeshow test and a 2-sided valuewas equal to .02.

Conclusions: Although the inclusion of a 313 genetic variant PRS doubles discriminatory accuracy (relative to reference 0.50), models with and without this PRS have relatively modest discrimination and might require recalibration before their clinical and wider use are promoted.
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http://dx.doi.org/10.1093/jncics/pkab021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099999PMC
June 2021

Genetically Predicted Circulating C-Reactive Protein Concentration and Colorectal Cancer Survival: A Mendelian Randomization Consortium Study.

Cancer Epidemiol Biomarkers Prev 2021 Jul 10;30(7):1349-1358. Epub 2021 May 10.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: A positive association between circulating C-reactive protein (CRP) and colorectal cancer survival was reported in observational studies, which are susceptible to unmeasured confounding and reverse causality. We used a Mendelian randomization approach to evaluate the association between genetically predicted CRP concentrations and colorectal cancer-specific survival.

Methods: We used individual-level data for 16,918 eligible colorectal cancer cases of European ancestry from 15 studies within the International Survival Analysis of Colorectal Cancer Consortium. We calculated a genetic-risk score based on 52 CRP-associated genetic variants identified from genome-wide association studies. Because of the non-collapsibility of hazard ratios from Cox proportional hazards models, we used the additive hazards model to calculate hazard differences (HD) and 95% confidence intervals (CI) for the association between genetically predicted CRP concentrations and colorectal cancer-specific survival, overall and by stage at diagnosis and tumor location. Analyses were adjusted for age at diagnosis, sex, body mass index, genotyping platform, study, and principal components.

Results: Of the 5,395 (32%) deaths accrued over up to 10 years of follow-up, 3,808 (23%) were due to colorectal cancer. Genetically predicted CRP concentration was not associated with colorectal cancer-specific survival (HD, -1.15; 95% CI, -2.76 to 0.47 per 100,000 person-years; = 0.16). Similarly, no associations were observed in subgroup analyses by stage at diagnosis or tumor location.

Conclusions: Despite adequate power to detect moderate associations, our results did not support a causal effect of circulating CRP concentrations on colorectal cancer-specific survival.

Impact: Future research evaluating genetically determined levels of other circulating inflammatory biomarkers (i.e., IL6) with colorectal cancer survival outcomes is needed.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254760PMC
July 2021

Dairy foods, calcium, and risk of breast cancer overall and for subtypes defined by estrogen receptor status: a pooled analysis of 21 cohort studies.

Am J Clin Nutr 2021 08;114(2):450-461

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.

Background: Epidemiologic studies examining the relations between dairy product and calcium intakes and breast cancer have been inconclusive, especially for tumor subtypes.

Objective: To evaluate the associations between intakes of specific dairy products and calcium and risk of breast cancer overall and for subtypes defined by estrogen receptor (ER) status.

Method: We pooled the individual-level data of over 1 million women who were followed for a maximum of 8-20 years across studies. Associations were evaluated for dairy product and calcium intakes and risk of incident invasive breast cancer overall (n = 37,861 cases) and by subtypes defined by ER status. Study-specific multivariable hazard ratios (HRs) were estimated and then combined using random-effects models.

Results: Overall, no clear association was observed between the consumption of specific dairy foods, dietary (from foods only) calcium, and total (from foods and supplements) calcium, and risk of overall breast cancer. Although each dairy product showed a null or very weak inverse association with risk of overall breast cancer (P, test for trend >0.05 for all), differences by ER status were suggested for yogurt and cottage/ricotta cheese with associations observed for ER-negative tumors only (pooled HR = 0.90, 95% CI: 0.83, 0.98 comparing ≥60 g/d with <1 g/d of yogurt and 0.85, 95% CI: 0.76, 0.95 comparing ≥25 g/d with <1 g/d of cottage/ricotta cheese). Dietary calcium intake was only weakly associated with breast cancer risk (pooled HR = 0.98, 95% CI: 0.97, 0.99 per 350 mg/d).

Conclusion: Our study shows that adult dairy or calcium consumption is unlikely to associate with a higher risk of breast cancer and that higher yogurt and cottage/ricotta cheese intakes were inversely associated with the risk of ER-negative breast cancer, a less hormonally dependent subtype with poor prognosis. Future studies on fermented dairy products, earlier life exposures, ER-negative breast cancer, and different racial/ethnic populations may further elucidate the relation.
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http://dx.doi.org/10.1093/ajcn/nqab097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326053PMC
August 2021

KLK3 SNP-SNP interactions for prediction of prostate cancer aggressiveness.

Sci Rep 2021 04 29;11(1):9264. Epub 2021 Apr 29.

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA.

Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP-SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 (P < 3.5 × 10) and 3145 (P < 1 × 10) SNP-SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved KLK3. The 3 most common gene-gene interactions were KLK3-COL4A1:COL4A2, KLK3-CDH13, and KLK3-TGFBR3. Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified KLK3 SNP-SNP interactions were supported by gene expression and protein-protein interaction results. Our findings suggest KLK3 SNP interactions may play an important role in PCa aggressiveness.
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http://dx.doi.org/10.1038/s41598-021-85169-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084951PMC
April 2021

Epigenetic Drift Association with Cancer Risk and Survival, and Modification by Sex.

Cancers (Basel) 2021 Apr 14;13(8). Epub 2021 Apr 14.

Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia.

To investigate age- and sex-specific DNA methylation alterations related to cancer risk and survival, we used matched case-control studies of colorectal ( = 835), gastric ( = 170), kidney ( = 143), lung ( = 332), prostate ( = 869) and urothelial ( = 428) cancers, and mature B-cell lymphoma ( = 438). Linear mixed-effects models were conducted to identify age-, sex- and age-by-sex-associated methylation markers using a discovery (controls)-replication (cases) strategy. Replication was further examined using summary statistics from Generation Scotland (GS). Associations between replicated markers and risk of and survival from cancer were assessed using conditional logistic regression and Cox models (hazard ratios (HR)), respectively. We found 32,659, 23,141 and 48 CpGs with replicated associations for age, sex and age-by-sex, respectively. The replication rates for these CpGs using GS summary data were 94%, 86% and 91%, respectively. Significant associations for cancer risk and survival were identified at some individual age-related CpGs. Opposite to previous findings using epigenetic clocks, there was a strong negative trend in the association between epigenetic drift and risk of colorectal cancer. Methylation at two CpGs overlapping and genes was associated with survival of overall (HR = 0.91, = 7.7 × 10) and colorectal (HR = 1.52, = 1.8 × 10) cancer, respectively, with significant age-by-sex interaction. Our results may provide markers for cancer early detection and prognosis prediction.
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http://dx.doi.org/10.3390/cancers13081881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070898PMC
April 2021

Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies.

Nat Commun 2021 04 22;12(1):2329. Epub 2021 Apr 22.

MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.
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http://dx.doi.org/10.1038/s41467-021-22370-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062567PMC
April 2021

Prediagnosis alcohol intake and metachronous cancer risk in cancer survivors: A prospective cohort study.

Int J Cancer 2021 Apr 19. Epub 2021 Apr 19.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Alcohol consumption is a known cause of cancer, but its role in the etiology of second primary (metachronous) cancer is uncertain. Associations between alcohol intake up until study enrollment (prediagnosis) and risk of metachronous cancer were estimated using 9435 participants in the Melbourne Collaborative Cohort Study who were diagnosed with their first invasive cancer after enrollment (1990-1994). Follow-up was from date of first invasive cancer until diagnosis of metachronous cancer, death or censor date (February 2018), whichever came first. Alcohol intake for 10-year periods from age 20 until decade encompassing baseline using recalled beverage-specific frequency and quantity was used to calculate baseline and lifetime intakes, and group-based intake trajectories. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for potential confounders. After a mean follow-up of 7 years, 1512 metachronous cancers were identified. A 10 g/d increment in prediagnosis lifetime alcohol intake (HR = 1.03, 95% CI = 1.00-1.06; P = .02) and an intake of ≥60 g/d (HR = 1.32, 95% CI = 1.01-1.73) were associated with increased metachronous cancer risk. We observed positive associations (per 10 g/d increment) for metachronous colorectal (HR = 1.07, 95% CI = 1.00-1.14), upper aero-digestive tract (UADT) (HR = 1.16, 95% CI = 1.00-1.34) and kidney cancer (HR = 1.24, 95% CI = 1.10-1.39). Although these findings were partly explained by effects of smoking, the association for kidney cancer remained unchanged when current smokers or obese individuals were excluded. Alcohol intake trajectories over the life course confirmed associations with metachronous cancer risk. Prediagnosis long-term alcohol intake, and particularly heavy drinking, may increase the risk of metachronous cancer, particularly of the colorectum, UADT and kidney.
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http://dx.doi.org/10.1002/ijc.33603DOI Listing
April 2021

Rare Germline Pathogenic Variants Identified by Multigene Panel Testing and the Risk of Aggressive Prostate Cancer.

Cancers (Basel) 2021 Mar 24;13(7). Epub 2021 Mar 24.

Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, VIC 3168, Australia.

While gene panel sequencing is becoming widely used for cancer risk prediction, its clinical utility with respect to predicting aggressive prostate cancer (PrCa) is limited by our current understanding of the genetic risk factors associated with predisposition to this potentially lethal disease phenotype. This study included 837 men diagnosed with aggressive PrCa and 7261 controls (unaffected men and men who did not meet criteria for aggressive PrCa). Rare germline pathogenic variants (including likely pathogenic variants) were identified by targeted sequencing of 26 known or putative cancer predisposition genes. We found that 85 (10%) men with aggressive PrCa and 265 (4%) controls carried a pathogenic variant ( < 0.0001). Aggressive PrCa odds ratios (ORs) were estimated using unconditional logistic regression. Increased risk of aggressive PrCa (OR (95% confidence interval)) was identified for pathogenic variants in (5.8 (2.7-12.4)), (5.5 (1.8-16.6)), and (3.8 (1.6-9.1)). Our study provides further evidence that rare germline pathogenic variants in these genes are associated with increased risk of this aggressive, clinically relevant subset of PrCa. These rare genetic variants could be incorporated into risk prediction models to improve their precision to identify men at highest risk of aggressive prostate cancer and be used to identify men with newly diagnosed prostate cancer who require urgent treatment.
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http://dx.doi.org/10.3390/cancers13071495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036662PMC
March 2021

Population-Based Estimates of the Age-Specific Cumulative Risk of Breast Cancer for Pathogenic Variants in : Findings from the Australian Breast Cancer Family Registry.

Cancers (Basel) 2021 Mar 18;13(6). Epub 2021 Mar 18.

Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Victoria 3168, Australia.

Case-control studies of breast cancer have consistently shown that pathogenic variants in are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein-truncating variant c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all pathogenic (including likely pathogenic) variants combined. We conducted a population-based case-control-family study of pathogenic variants (26 families, 1071 relatives) and estimated the age-specific cumulative risk of breast cancer using segregation analysis. The estimated hazard ratio for carriers of pathogenic variants (combined) was 4.9 (95% CI 2.5-9.5) relative to non-carriers. The HR for carriers of the c.1100delC variant was estimated to be 3.5 (95% CI 1.02-11.6) and the HR for carriers of all other variants combined was estimated to be 5.7 (95% CI 2.5-12.9). The age-specific cumulative risk of breast cancer was estimated to be 18% (95% CI 11-30%) and 33% (95% CI 21-48%) to age 60 and 80 years, respectively. These findings provide important information for the clinical management of breast cancer risk for women carrying pathogenic variants in .
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http://dx.doi.org/10.3390/cancers13061378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003064PMC
March 2021

: Genetic Variation, Heritable Methylation and Disease Association.

Int J Mol Sci 2021 Mar 3;22(5). Epub 2021 Mar 3.

Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia.

is a metastable epiallele with accumulating evidence that methylation at this region is heritable, modifiable and associated with disease including risk and progression of cancer. This study investigated the influence of genetic variation and other factors such as age and adult lifestyle on blood DNA methylation in this region. We first sequenced the gene region in multiple-case breast cancer families in which methylation was identified as heritable and associated with breast cancer risk. Methylation quantitative trait loci (mQTL) were investigated using a prospective cohort study (4500 participants with genotyping and methylation data). The -mQTL analysis (334 variants ± 50 kb of the most heritable CpG site) identified 43 variants associated with methylation ( < 1.5 × 10); however, these explained little of the methylation variation (R < 0.5% for each of these variants). No genetic variants elsewhere in the genome were found to strongly influence methylation. SNP-based heritability estimates were consistent with the mQTL findings (h = 0, 95%CI: -0.14 to 0.14). We found no evidence that age, sex, country of birth, smoking, body mass index, alcohol consumption or diet influenced blood DNA methylation at . Genetic factors and adult lifestyle play a minimal role in explaining methylation variability at the heritable cluster.
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http://dx.doi.org/10.3390/ijms22052535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961504PMC
March 2021

Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study.

Am J Clin Nutr 2021 06;113(6):1490-1502

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited.

Objectives: To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR).

Methods: Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions.

Results: Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk.

Conclusions: These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.
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http://dx.doi.org/10.1093/ajcn/nqab003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168352PMC
June 2021

Vegetable intake and the risk of bladder cancer in the BLadder Cancer Epidemiology and Nutritional Determinants (BLEND) international study.

BMC Med 2021 Mar 9;19(1):56. Epub 2021 Mar 9.

Department of Complex Genetics and Epidemiology, School of Nutrition and Translational Research in Metabolism, Maastricht University, Universiteitssingel 40 (Room C5.570), 6229 ER, Maastricht, the Netherlands.

Background: Although a potential inverse association between vegetable intake and bladder cancer risk has been reported, epidemiological evidence is inconsistent. This research aimed to elucidate the association between vegetable intake and bladder cancer risk by conducting a pooled analysis of data from prospective cohort studies.

Methods: Vegetable intake in relation to bladder cancer risk was examined by pooling individual-level data from 13 cohort studies, comprising 3203 cases among a total of 555,685 participants. Pooled multivariate hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), were estimated using Cox proportional hazards regression models stratified by cohort for intakes of total vegetable, vegetable subtypes (i.e. non-starchy, starchy, green leafy and cruciferous vegetables) and individual vegetable types. In addition, a diet diversity score was used to assess the association of the varied types of vegetable intake on bladder cancer risk.

Results: The association between vegetable intake and bladder cancer risk differed by sex (P-interaction = 0.011) and smoking status (P-interaction = 0.038); therefore, analyses were stratified by sex and smoking status. With adjustment of age, sex, smoking, energy intake, ethnicity and other potential dietary factors, we found that higher intake of total and non-starchy vegetables were inversely associated with the risk of bladder cancer among women (comparing the highest with lowest intake tertile: HR = 0.79, 95% CI = 0.64-0.98, P = 0.037 for trend, HR per 1 SD increment = 0.89, 95% CI = 0.81-0.99; HR = 0.78, 95% CI = 0.63-0.97, P = 0.034 for trend, HR per 1 SD increment = 0.88, 95% CI = 0.79-0.98, respectively). However, no evidence of association was observed among men, and the intake of vegetable was not found to be associated with bladder cancer when stratified by smoking status. Moreover, we found no evidence of association for diet diversity with bladder cancer risk.

Conclusion: Higher intakes of total and non-starchy vegetable are associated with reduced risk of bladder cancer for women. Further studies are needed to clarify whether these results reflect causal processes and potential underlying mechanisms.
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http://dx.doi.org/10.1186/s12916-021-01931-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942172PMC
March 2021
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