Publications by authors named "Neil Murphy"

144 Publications

Testosterone, sex hormone-binding globulin, insulin-like growth factor-1 and endometrial cancer risk: observational and Mendelian randomization analyses.

Br J Cancer 2021 Aug 6. Epub 2021 Aug 6.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Background: Dysregulation of endocrine pathways related to steroid and growth hormones may modify endometrial cancer risk; however, prospective data on testosterone, sex hormone-binding globulin (SHBG) and insulin-like growth factor (IGF)-1 are limited. To elucidate the role of these hormones in endometrial cancer risk we conducted complementary observational and Mendelian randomization (MR) analyses.

Methods: The observational analyses included 159,702 women (80% postmenopausal) enrolled in the UK Biobank. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. For MR analyses, genetic variants associated with hormone levels were identified and their association with endometrial cancer (12,906 cases/108,979 controls) was examined using two-sample MR.

Results: In the observational analysis, higher circulating concentrations of total (HR per unit inverse normal scale = 1.38, 95% CI = 1.22-1.57) and free testosterone (HR per unit log scale = 2.07, 95% CI = 1.66-2.58) were associated with higher endometrial cancer risk. An inverse association was found for SHBG (HR per unit inverse normal scale = 0.76, 95% CI = 0.67-0.86). Results for testosterone and SHBG were supported by the MR analyses. No association was found between genetically predicted IGF-1 concentration and endometrial cancer risk.

Conclusions: Our results support probable causal associations between circulating concentrations of testosterone and SHBG with endometrial cancer risk.
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http://dx.doi.org/10.1038/s41416-021-01518-3DOI Listing
August 2021

Plasma concentrations of persistent organic pollutants and pancreatic cancer risk.

Int J Epidemiol 2021 Jul 14. Epub 2021 Jul 14.

Cancer Registry and Histopathology Department, "Civic-M.P. Arezzo" Hospital, ASP Ragusa, Ragusa, Italy.

Background: Findings and limitations of previous studies on persistent organic pollutants (POPs) and pancreatic cancer risk support conducting further research in prospective cohorts.

Methods: We conducted a prospective case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Participants were 513 pancreatic cancer cases and 1020 matched controls. Concentrations of 22 POPs were measured in plasma collected at baseline.

Results: Some associations were observed at higher concentrations of p, p'-DDT, trans-nonachlor, β-hexachlorocyclohexane and the sum of six organochlorine pesticides and of 16 POPs. The odds ratio (OR) for the upper quartile of trans-nonachlor was 1.55 (95% confidence interval 1.06-2.26; P for trend = 0.025). Associations were stronger in the groups predefined as most valid (participants having fasted >6 h, with microscopic diagnostic confirmation, normal weight, and never smokers), and as most relevant (follow-up ≥10 years). Among participants having fasted >6 h, the ORs were relevant for 10 of 11 exposures. Higher ORs were also observed among cases with microscopic confirmation than in cases with a clinical diagnosis, and among normal-weight participants than in the rest of participants. Among participants with a follow-up ≥10 years, estimates were higher than in participants with a shorter follow-up (for trans-nonachlor: OR = 2.14, 1.01 to 4.53, P for trend = 0.035). Overall, trans-nonachlor, three PCBs and the two sums of POPs were the exposures most clearly associated with pancreatic cancer risk.

Conclusions: Individually or in combination, most of the 22 POPs analysed did not or only moderately increased the risk of pancreatic cancer.
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http://dx.doi.org/10.1093/ije/dyab115DOI Listing
July 2021

Photoionization Loss of Mercury's Sodium Exosphere: Seasonal Observations by MESSENGER and the THEMIS Telescope.

Geophys Res Lett 2021 Apr;48(8):e2021GL092980

NASA Jet Propulsion Laboratory California Institute of Technology Pasadena CA USA.

We present the first investigation and quantification of the photoionization loss process to Mercury's sodium exosphere from spacecraft and ground-based observations. We analyze plasma and neutral sodium measurements from NASA's MESSENGER spacecraft and the THEMIS telescope. We find that the sodium ion (Na) content and therefore the significance of photoionization varies with Mercury's orbit around the Sun (i.e., true anomaly angle: TAA). Na production is affected by the neutral sodium solar-radiation acceleration loss process. More Na was measured on the inbound leg of Mercury's orbit at 180°-360° TAA because less neutral sodium is lost downtail from radiation acceleration. Calculations using results from observations show that the photoionization loss process removes ∼10 atoms/s from the sodium exosphere (maxima of 4 × 10 atoms/s), showing that modeling efforts underestimate this loss process. This is an important result as it shows that photoionization is a significant loss process and larger than loss from radiation acceleration.
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http://dx.doi.org/10.1029/2021GL092980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243941PMC
April 2021

Associations between Prediagnostic Circulating Bilirubin Levels and Risk of Gastrointestinal Cancers in the UK Biobank.

Cancers (Basel) 2021 Jun 1;13(11). Epub 2021 Jun 1.

Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC-WHO), 150 Cours Albert Thomas, CEDEX 08, 69372 Lyon, France.

We investigated associations between serum levels of bilirubin, an endogenous antioxidant, and gastrointestinal cancer risk. In the UK Biobank, prediagnostic serum levels of total bilirubin were measured in blood samples collected from 440,948 participants. In multivariable-adjusted Cox proportional hazard regression, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for associations between bilirubin levels and gastrointestinal cancer risk (colorectum, esophagus, stomach, mouth, pancreas, and liver). After a median follow-up of 7.1 years (interquartile range: 1.4), 5033 incident gastrointestinal cancer cases were recorded. In multivariable-adjusted models, bilirubin levels were negatively associated with risk of esophageal adenocarcinoma (EAC, HR per 1-SD increment in log-total bilirubin levels 0.72, 95%CI 0.56-0.92, = 0.01). Weak and less robust negative associations were observed for colorectal cancer (CRC, HR per 1-SD increment in log-total bilirubin levels 0.95, 95%CI 0.88-1.02, = 0.14). Bilirubin levels were positively associated with risk of hepatocellular carcinoma (HCC, HR per 1-SD increment in log-total bilirubin levels 2.07, 95%CI 1.15-3.73, = 0.02) and intrahepatic bile duct (IBD) cancer (HR per 1-SD increment 1.67, 95%CI 1.07-2.62, = 0.03). We found no associations with risks of stomach, oral, and pancreatic cancers. Prediagnostic serum levels of bilirubin were negatively associated with risk of EAC and positively associated with HCC and IBD cancer. Further studies are warranted to replicate our findings for specific GI cancers.
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http://dx.doi.org/10.3390/cancers13112749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198711PMC
June 2021

Circulating tryptophan metabolites and risk of colon cancer: Results from case-control and prospective cohort studies.

Int J Cancer 2021 Nov 12;149(9):1659-1669. Epub 2021 Jul 12.

International Agency for Research on Cancer, Lyon, France.

Dysregulation of tryptophan metabolism has been linked to colorectal tumorigenesis; however, epidemiological studies investigating tryptophan metabolites in relation to colorectal cancer risk are limited. We studied associations of plasma tryptophan, serotonin and kynurenine with colon cancer risk in two studies with cancer patients and controls, and in one prospective cohort: ColoCare Study (110 patients/153 controls), the Colorectal Cancer Study of Austria (CORSA; 46 patients/390 controls) and the European Prospective Investigation into Cancer and Nutrition (EPIC; 456 matched case-control pairs). Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for colon cancer risk. Tryptophan was inversely associated with colon cancer risk in ColoCare (OR per 1-SD = 0.44; 95% CI, 0.31-0.64) and EPIC (OR per 1-SD = 0.86; 95% CI, 0.74-0.99). Comparing detectable vs nondetectable levels, serotonin was positively associated with colon cancer in CORSA (OR = 6.39; 95% CI, 3.61-11.3) and EPIC (OR = 2.03; 95% CI, 1.20-3.40). Kynurenine was inversely associated with colon cancer in ColoCare (OR per 1-SD = 0.74; 95% CI, 0.55-0.98), positively associated in CORSA (OR per 1-SD = 1.79; 95% CI, 1.27-2.52), while no association was observed in EPIC. The kynurenine-to-tryptophan ratio was positively associated with colon cancer in ColoCare (OR per 1-SD = 1.38; 95% CI, 1.03-1.84) and CORSA (OR per 1-SD = 1.44; 95% CI, 1.06-1.96), but not in EPIC. These results suggest that higher plasma tryptophan may be associated with lower colon cancer risk, while increased serotonin may be associated with a higher risk of colon cancer. The kynurenine-to-tryptophan ratio may also reflect altered tryptophan catabolism during colon cancer development.
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http://dx.doi.org/10.1002/ijc.33725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429124PMC
November 2021

Nongenetic Determinants of Risk for Early-Onset Colorectal Cancer.

JNCI Cancer Spectr 2021 Jun 20;5(3):pkab029. Epub 2021 May 20.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Background: Incidence of early-onset (younger than 50 years of age) colorectal cancer (CRC) is increasing in many countries. Thus, elucidating the role of traditional CRC risk factors in early-onset CRC is a high priority. We sought to determine whether risk factors associated with late-onset CRC were also linked to early-onset CRC and whether association patterns differed by anatomic subsite.

Methods: Using data pooled from 13 population-based studies, we studied 3767 CRC cases and 4049 controls aged younger than 50 years and 23 437 CRC cases and 35 311 controls aged 50 years and older. Using multivariable and multinomial logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to assess the association between risk factors and early-onset CRC and by anatomic subsite.

Results: Early-onset CRC was associated with not regularly using nonsteroidal anti-inflammatory drugs (OR = 1.43, 95% CI = 1.21 to 1.68), greater red meat intake (OR = 1.10, 95% CI = 1.04 to 1.16), lower educational attainment (OR = 1.10, 95% CI = 1.04 to 1.16), alcohol abstinence (OR = 1.23, 95% CI = 1.08 to 1.39), and heavier alcohol use (OR = 1.25, 95% CI = 1.04 to 1.50). No factors exhibited a greater excess in early-onset compared with late-onset CRC. Evaluating risks by anatomic subsite, we found that lower total fiber intake was linked more strongly to rectal (OR = 1.30, 95% CI = 1.14 to 1.48) than colon cancer (OR = 1.14, 95% CI = 1.02 to 1.27;  = .04).

Conclusion: In this large study, we identified several nongenetic risk factors associated with early-onset CRC, providing a basis for targeted identification of those most at risk, which is imperative in mitigating the rising burden of this disease.
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http://dx.doi.org/10.1093/jncics/pkab029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134523PMC
June 2021

Are sugar-sweetened beverages contributing to the rising occurrence of colorectal cancer in young adults?

Gut 2021 May 20. Epub 2021 May 20.

Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France

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http://dx.doi.org/10.1136/gutjnl-2021-324614DOI Listing
May 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

Metabolic signatures of greater body size and their associations with risk of colorectal and endometrial cancers in the European Prospective Investigation into Cancer and Nutrition.

BMC Med 2021 Apr 30;19(1):101. Epub 2021 Apr 30.

International Agency for Research on Cancer, World Health Organization, Lyon, France.

Background: The mechanisms underlying the obesity-cancer relationship are incompletely understood. This study aimed to characterise metabolic signatures of greater body size and to investigate their association with two obesity-related malignancies, endometrial and colorectal cancers, and with weight loss within the context of an intervention study.

Methods: Targeted mass spectrometry metabolomics data from 4326 participants enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort and 17 individuals from a single-arm pilot weight loss intervention (Intercept) were used in this analysis. Metabolic signatures of body size were first determined in discovery (N = 3029) and replication (N = 1297) sets among EPIC participants by testing the associations between 129 metabolites and body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) using linear regression models followed by partial least squares analyses. Conditional logistic regression models assessed the associations between the metabolic signatures with endometrial (N = 635 cases and 648 controls) and colorectal (N = 423 cases and 423 controls) cancer risk using nested case-control studies in EPIC. Pearson correlation between changes in the metabolic signatures and weight loss was tested among Intercept participants.

Results: After adjustment for multiple comparisons, greater BMI, WC, and WHR were associated with higher levels of valine, isoleucine, glutamate, PC aa C38:3, and PC aa C38:4 and with lower levels of asparagine, glutamine, glycine, serine, lysoPC C17:0, lysoPC C18:1, lysoPC C18:2, PC aa C42:0, PC ae C34:3, PC ae C40:5, and PC ae C42:5. The metabolic signature of BMI (OR 1.50, 95% CI 1.30-1.74), WC (OR 1.46, 95% CI 1.27-1.69), and WHR (OR 1.54, 95% CI 1.33-1.79) were each associated with endometrial cancer risk. Risk of colorectal cancer was positively associated with the metabolic signature of WHR (OR: 1.26, 95% CI 1.07-1.49). In the Intercept study, a positive correlation was observed between weight loss and changes in the metabolic signatures of BMI (r = 0.5, 95% CI 0.06-0.94, p = 0.03), WC (r = 0.5, 95% CI 0.05-0.94, p = 0.03), and WHR (r = 0.6, 95% CI 0.32-0.87, p = 0.01).

Conclusions: Obesity is associated with a distinct metabolic signature comprising changes in levels of specific amino acids and lipids which is positively associated with both colorectal and endometrial cancer and is potentially reversible following weight loss.
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http://dx.doi.org/10.1186/s12916-021-01970-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086283PMC
April 2021

Dietary intake and plasma phospholipid concentrations of saturated, monounsaturated and trans fatty acids and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort.

Int J Cancer 2021 Apr 28. Epub 2021 Apr 28.

Department of Public Health and Clinical Medicine, Section of Sustainable Health, Umeå University, Umeå, Sweden.

Epidemiologic studies examining the association between specific fatty acids and colorectal cancer (CRC) risk are inconclusive. We investigated the association between dietary estimates and plasma levels of individual and total saturated (SFA), monounsaturated (MUFA), industrial-processed trans (iTFA), and ruminant-sourced trans (rTFA) fatty acids, and CRC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Baseline fatty acid intakes were estimated in 450 112 participants (6162 developed CRC, median follow-up = 15 years). In a nested case-control study, plasma phospholipid fatty acids were determined by gas chromatography in 433 colon cancer cases and 433 matched controls. Multivariable-adjusted hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were computed using Cox and conditional logistic regression, respectively. Dietary total SFA (highest vs lowest quintile, HR  = 0.80; 95%CI:0.69-0.92), myristic acid (HR  = 0.83, 95%CI:0.74-0.93) and palmitic acid (HR  = 0.81, 95%CI:0.70-0.93) were inversely associated with CRC risk. Plasma myristic acid was also inversely associated with colon cancer risk (highest vs lowest quartile, OR  = 0.51; 95%CI:0.32-0.83), whereas a borderline positive association was found for plasma stearic acid (OR  = 1.63; 95%CI:1.00-2.64). Dietary total MUFA was inversely associated with colon cancer (per 1-SD increment, HR  = 0.92, 95%CI: 0.85-0.98), but not rectal cancer (HR  = 1.04, 95%CI:0.95-1.15, P  = 0.027). Dietary iTFA, and particularly elaidic acid, was positively associated with rectal cancer (HR  = 1.07, 95%CI:1.02-1.13). Our results suggest that total and individual saturated fatty acids and fatty acids of industrial origin may be relevant to the aetiology of CRC. Both dietary and plasma myristic acid levels were inversely associated with colon cancer risk, which warrants further investigation.
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http://dx.doi.org/10.1002/ijc.33615DOI Listing
April 2021

Circulating Levels of Testosterone, Sex Hormone Binding Globulin and Colorectal Cancer Risk: Observational and Mendelian Randomization Analyses.

Cancer Epidemiol Biomarkers Prev 2021 Jul 20;30(7):1336-1348. Epub 2021 Apr 20.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Background: Epidemiologic studies evaluating associations between sex steroid hormones and colorectal cancer risk have yielded inconsistent results. To elucidate the role of circulating levels of testosterone, and sex hormone-binding globulin (SHBG) in colorectal cancer risk, we conducted observational and Mendelian randomization (MR) analyses.

Methods: The observational analyses included 333,530 participants enrolled in the UK Biobank with testosterone and SHBG measured. HRs and 95% confidence intervals (CI) were estimated using multivariable Cox proportional hazards models. For MR analyses, genetic variants robustly associated with hormone levels were identified and their association with colorectal cancer (42,866 cases/42,752 controls) was examined using two-sample MR.

Results: In the observational analysis, there was little evidence that circulating levels of total testosterone were associated with colorectal cancer risk; the MR analyses showed a greater risk for women (OR per 1-SD = 1.09; 95% CI, 1.01-1.17), although pleiotropy may have biased this result. Higher SHBG concentrations were associated with greater colorectal cancer risk for women (HR per 1-SD = 1.16; 95% CI, 1.05-1.29), but was unsupported by the MR analysis. There was little evidence of associations between free testosterone and colorectal cancer in observational and MR analyses.

Conclusions: Circulating concentrations of sex hormones are unlikely to be causally associated with colorectal cancer. Additional experimental studies are required to better understand the possible role of androgens in colorectal cancer development.

Impact: Our results from large-scale analyses provide little evidence for sex hormone pathways playing a causal role in colorectal cancer development..
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1690DOI Listing
July 2021

Association of the Age at Menarche with Site-Specific Cancer Risks in Pooled Data from Nine Cohorts.

Cancer Res 2021 04 5;81(8):2246-2255. Epub 2021 Apr 5.

Division of Cancer Epidemiology and Genetics, National Institutes of Health, Rockville, Maryland.

The average age at menarche declined in European and U.S. populations during the 19th and 20th centuries. The timing of pubertal events may have broad implications for chronic disease risks in aging women. Here we tested for associations of recalled menarcheal age with risks of 19 cancers in 536,450 women [median age, 60 years (range, 31-39 years)] in nine prospective U.S. and European cohorts that enrolled participants from 1981 to 1998. Cox regression estimated multivariable-adjusted HRs and 95% confidence intervals (CI) for associations of the age at menarche with risk of each cancer in each cohort and random-effects meta-analysis was used to generate summary estimates for each cancer. Over a median 10 years of follow-up, 60,968 women were diagnosed with a first primary incident cancer. Inverse linear associations were observed for seven of 19 cancers studied. Each additional year in the age at menarche was associated with reduced risks of endometrial cancer (HR = 0.91; 95% CI, 0.89-0.94), liver cancer (HR = 0.92; 95% CI, 0.85-0.99), melanoma (HR = 0.95; 95% CI, 0.93-0.98), bladder cancer (HR = 0.96; 95% CI, 0.93-0.99), and cancers of the colon (HR = 0.97; 95% CI, 0.96-0.99), lung (HR = 0.98; 95% CI, 0.96-0.99), and breast (HR = 0.98; 95% CI, 0.93-0.99). All but one of these associations remained statistically significant following adjustment for baseline body mass index. Similarities in the observed associations between menarche and seven cancers suggest shared underlying causes rooted early in life. We propose as a testable hypothesis that early exposure to sex hormones increases mid-life cancer risks by altering functional capacities of stem cells with roles in systemic energy balance and tissue homeostasis. SIGNIFICANCE: Age at menarche is associated with risk for seven cancers in middle-aged women, and understanding the shared underlying causal pathways across these cancers may suggest new avenues for cancer prevention.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137527PMC
April 2021

Dietary intake of trans fatty acids and breast cancer risk in 9 European countries.

BMC Med 2021 Mar 30;19(1):81. Epub 2021 Mar 30.

Clinical Sciences Lund, Oncology, Lund University and Skåne University Hospital, Lund, Sweden.

Background: Trans fatty acids (TFAs) have been hypothesised to influence breast cancer risk. However, relatively few prospective studies have examined this relationship, and well-powered analyses according to hormone receptor-defined molecular subtypes, menopausal status, and body size have rarely been conducted.

Methods: In the European Prospective Investigation into Cancer and Nutrition (EPIC), we investigated the associations between dietary intakes of TFAs (industrial trans fatty acids [ITFAs] and ruminant trans fatty acids [RTFAs]) and breast cancer risk among 318,607 women. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, adjusted for other breast cancer risk factors.

Results: After a median follow-up of 8.1 years, 13,241 breast cancer cases occurred. In the multivariable-adjusted model, higher total ITFA intake was associated with elevated breast cancer risk (HR for highest vs lowest quintile, 1.14, 95% CI 1.06-1.23; P trend = 0.001). A similar positive association was found between intake of elaidic acid, the predominant ITFA, and breast cancer risk (HR for highest vs lowest quintile, 1.14, 95% CI 1.06-1.23; P trend = 0.001). Intake of total RTFAs was also associated with higher breast cancer risk (HR for highest vs lowest quintile, 1.09, 95% CI 1.01-1.17; P trend = 0.015). For individual RTFAs, we found positive associations with breast cancer risk for dietary intakes of two strongly correlated fatty acids (Spearman correlation r = 0.77), conjugated linoleic acid (HR for highest vs lowest quintile, 1.11, 95% CI 1.03-1.20; P trend = 0.001) and palmitelaidic acid (HR for highest vs lowest quintile, 1.08, 95% CI 1.01-1.16; P trend = 0.028). Similar associations were found for total ITFAs and RTFAs with breast cancer risk according to menopausal status, body mass index, and breast cancer subtypes.

Conclusions: These results support the hypothesis that higher dietary intakes of ITFAs, in particular elaidic acid, are associated with elevated breast cancer risk. Due to the high correlation between conjugated linoleic acid and palmitelaidic acid, we were unable to disentangle the positive associations found for these fatty acids with breast cancer risk. Further mechanistic studies are needed to identify biological pathways that may underlie these associations.
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http://dx.doi.org/10.1186/s12916-021-01952-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008592PMC
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

Genetically Raised Circulating Bilirubin Levels and Risk of Ten Cancers: A Mendelian Randomization Study.

Cells 2021 02 15;10(2). Epub 2021 Feb 15.

Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC-WHO), 69008 Lyon, France.

Bilirubin, an endogenous antioxidant, may play a protective role in cancer development. We applied two-sample Mendelian randomization to investigate whether genetically raised bilirubin levels are causally associated with the risk of ten cancers (pancreas, kidney, endometrium, ovary, breast, prostate, lung, Hodgkin's lymphoma, melanoma, and neuroblastoma). The number of cases and their matched controls of European descent ranged from 122,977 and 105,974 for breast cancer to 1200 and 6417 for Hodgkin's lymphoma, respectively. A total of 115 single-nucleotide polymorphisms (SNPs) associated ( < 5 × 10) with circulating total bilirubin, extracted from a genome-wide association study in the UK Biobank, were used as instrumental variables. One SNP (rs6431625) in the promoter region of the uridine-diphosphoglucuronate glucuronosyltransferase1A1 ( gene explained 16.9% and the remaining 114 SNPs (non- SNPs) explained 3.1% of phenotypic variance in circulating bilirubin levels. A one-standarddeviation increment in circulating bilirubin (≈ 4.4 µmol/L), predicted by non- SNPs, was inversely associated with risk of squamous cell lung cancer and Hodgkin's lymphoma (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.73-0.99, 0.04 and OR 0.64, 95% CI 0.42-0.99, 0.04, respectively), which was confirmed after removing potential pleiotropic SNPs. In contrast, a positive association was observed with the risk of breast cancer after removing potential pleiotropic SNPs (OR 1.12, 95% CI 1.04-1.20, 0.002). There was little evidence for robust associations with the other seven cancers investigated. Genetically raised bilirubin levels were inversely associated with risk of squamous cell lung cancer as well as Hodgkin's lymphoma and positively associated with risk of breast cancer. Further studies are required to investigate the utility of bilirubin as a low-cost clinical marker to improve risk prediction for certain cancers.
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http://dx.doi.org/10.3390/cells10020394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918902PMC
February 2021

Causal Effects of Lifetime Smoking on Breast and Colorectal Cancer Risk: Mendelian Randomization Study.

Cancer Epidemiol Biomarkers Prev 2021 05 2;30(5):953-964. Epub 2021 Mar 2.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Background: Observational evidence has shown that smoking is a risk factor for breast and colorectal cancer. We used Mendelian randomization (MR) to examine causal associations between smoking and risks of breast and colorectal cancer.

Methods: Genome-Wide Association Study summary data were used to identify genetic variants associated with lifetime amount of smoking ( = 126 variants) and ever having smoked regularly ( = 112 variants). Using two-sample MR, we examined these variants in relation to incident breast (122,977 cases/105,974 controls) and colorectal cancer (52,775 cases/45,940 controls).

Results: In inverse-variance weighted models, a genetic predisposition to higher lifetime amount of smoking was positively associated with breast cancer risk [OR per 1-SD increment: 1.13; 95% confidence interval (CI): 1.00-1.26; = 0.04]; although heterogeneity was observed. Similar associations were found for estrogen receptor-positive and estrogen receptor-negative tumors. Higher lifetime amount of smoking was positively associated with colorectal cancer (OR per 1-SD increment, 1.21; 95% CI, 1.04-1.40; = 0.01), colon cancer (OR, 1.31; 95% CI, 1.11-1.55; < 0.01), and rectal cancer (OR, 1.36; 95% CI, 1.07-1.73; = 0.01). Ever having smoked regularly was not associated with risks of breast (OR, 1.01; 95% CI, 0.90-1.14; = 0.85) or colorectal cancer (OR, 0.97; 95% CI, 0.86-1.10; = 0.68).

Conclusions: These findings are consistent with prior observational evidence and support a causal role of higher lifetime smoking amount in the development of breast and colorectal cancer.

Impact: The results from this comprehensive MR analysis indicate that lifetime smoking is a causal risk factor for these common malignancies.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611442PMC
May 2021

Genetic architectures of proximal and distal colorectal cancer are partly distinct.

Gut 2021 Jul 25;70(7):1325-1334. Epub 2021 Feb 25.

Cancer Prevention and Control Program, Catalan Institute of Oncology - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.

Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.

Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.

Results: We identified 13 loci that reached genome-wide significance (p<5×10) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.

Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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http://dx.doi.org/10.1136/gutjnl-2020-321534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223655PMC
July 2021

Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study.

BMC Med 2020 12 17;18(1):396. Epub 2020 Dec 17.

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

Background: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood.

Methods: We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models.

Results: In sex-specific MR analyses, higher BMI (per 4.2 kg/m) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles.

Conclusions: Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.
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http://dx.doi.org/10.1186/s12916-020-01855-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745469PMC
December 2020

Metabolic Signatures of Healthy Lifestyle Patterns and Colorectal Cancer Risk in a European Cohort.

Clin Gastroenterol Hepatol 2020 Dec 29. Epub 2020 Dec 29.

CIBER Epidemiología y Salud Pública, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain; Department of Preventive Medicine and Public Health, University of Granada, Granada, Spain.

Background & Aims: Colorectal cancer risk can be lowered by adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guidelines. We derived metabolic signatures of adherence to these guidelines and tested their associations with colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort.

Methods: Scores reflecting adherence to the WCRF/AICR recommendations (scale, 1-5) were calculated from participant data on weight maintenance, physical activity, diet, and alcohol among a discovery set of 5738 cancer-free European Prospective Investigation into Cancer and Nutrition participants with metabolomics data. Partial least-squares regression was used to derive fatty acid and endogenous metabolite signatures of the WCRF/AICR score in this group. In an independent set of 1608 colorectal cancer cases and matched controls, odds ratios (ORs) and 95% CIs were calculated for colorectal cancer risk per unit increase in WCRF/AICR score and per the corresponding change in metabolic signatures using multivariable conditional logistic regression.

Results: Higher WCRF/AICR scores were characterized by metabolic signatures of increased odd-chain fatty acids, serine, glycine, and specific phosphatidylcholines. Signatures were inversely associated more strongly with colorectal cancer risk (fatty acids: OR, 0.51 per unit increase; 95% CI, 0.29-0.90; endogenous metabolites: OR, 0.62 per unit change; 95% CI, 0.50-0.78) than the WCRF/AICR score (OR, 0.93 per unit change; 95% CI, 0.86-1.00) overall. Signature associations were stronger in male compared with female participants.

Conclusions: Metabolite profiles reflecting adherence to WCRF/AICR guidelines and additional lifestyle or biological risk factors were associated with colorectal cancer. Measuring a specific panel of metabolites representative of a healthy or unhealthy lifestyle may identify strata of the population at higher risk of colorectal cancer.
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http://dx.doi.org/10.1016/j.cgh.2020.11.045DOI Listing
December 2020

Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200 000 men in UK Biobank.

Int J Cancer 2021 05 11;148(9):2274-2288. Epub 2020 Dec 11.

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Insulin-like growth factor-I (IGF-I) and testosterone have been implicated in prostate cancer aetiology. Using data from a large prospective full-cohort with standardised assays and repeat blood measurements, and genetic data from an international consortium, we investigated the associations of circulating IGF-I, sex hormone-binding globulin (SHBG), and total and calculated free testosterone concentrations with prostate cancer incidence and mortality. For prospective analyses, risk was estimated using multivariable-adjusted Cox regression in 199 698 male UK Biobank participants. Hazard ratios (HRs) were corrected for regression dilution bias using repeat hormone measurements from a subsample. Two-sample Mendelian randomisation (MR) analysis of IGF-I and risk used genetic instruments identified from UK Biobank men and genetic outcome data from the PRACTICAL consortium (79 148 cases and 61 106 controls). We used cis- and all (cis and trans) SNP MR approaches. A total of 5402 men were diagnosed with and 295 died from prostate cancer (mean follow-up 6.9 years). Higher circulating IGF-I was associated with elevated prostate cancer diagnosis (HR per 5 nmol/L increment = 1.09, 95% CI 1.05-1.12) and mortality (HR per 5 nmol/L increment = 1.15, 1.02-1.29). MR analyses also supported the role of IGF-I in prostate cancer diagnosis (cis-MR odds ratio per 5 nmol/L increment = 1.34, 1.07-1.68). In observational analyses, higher free testosterone was associated with a higher risk of prostate cancer (HR per 50 pmol/L increment = 1.10, 1.05-1.15). Higher SHBG was associated with a lower risk (HR per 10 nmol/L increment = 0.95, 0.94-0.97), neither was associated with prostate cancer mortality. Total testosterone was not associated with prostate cancer. These findings implicate IGF-I and free testosterone in prostate cancer development and/or progression.
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http://dx.doi.org/10.1002/ijc.33416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048461PMC
May 2021

Unraveling the Etiology of Early-Onset Colorectal Cancer.

J Natl Cancer Inst 2021 May;113(5):505-506

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

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http://dx.doi.org/10.1093/jnci/djaa165DOI Listing
May 2021

Anthropometry, body fat composition and reproductive factors and risk of oesophageal and gastric cancer by subtype and subsite in the UK Biobank cohort.

PLoS One 2020 20;15(10):e0240413. Epub 2020 Oct 20.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.

Background: Obesity has been positively associated with upper gastrointestinal cancers, but prospective data by subtype/subsite are limited. Obesity influences hormonal factors, which may play a role in these cancers. We examined anthropometry, body fat and reproductive factors in relation to oesophageal and gastric cancer by subtype/subsite in the UK Biobank cohort.

Methods: Among 458,713 UK Biobank participants, 339 oesophageal adenocarcinomas, 124 oesophageal squamous cell carcinomas, 137 gastric cardia and 92 gastric non-cardia cancers were diagnosed during a mean of 6.5 years follow-up. Cox models estimated multivariable hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: Body mass index (BMI), hip circumference, waist circumference, waist-to-hip ratio, waist-to-height ratio, total body fat and trunk fat were positively associated with oesophageal adenocarcinoma (highest vs lowest category: HR = 2.33, 95%-CI:1.65-3.28; HR = 1.56, 95%-CI:1.15-2.13; HR = 2.30, 95%-CI:1.47-3.57; HR = 1.71, 95%-CI:1.01-2.90; HR = 2.87, 95%-CI:1.88-4.38; HR = 1.96, 95%-CI:1.30-2.96; HR = 2.34, 95%-CI:1.70-3.22, respectively). Although there were no statistically significant associations in combined sex analyses, BMI (HR = 1.83, 95%-CI:1.00-3.37), waist circumference (HR = 2.21, 95%-CI:1.27-3.84) and waist-to-hip ratio (HR = 1.92, 95%-CI:1.11-3.29) were associated with gastric cardia cancer in men; however, mutual adjustment attenuated the associations for BMI and waist-to-hip ratio. For oesophageal squamous cell carcinoma, statistically significant inverse associations were observed among women for BMI, hip circumference, waist circumference, waist-to-height ratio, total body fat and trunk fat, although they were based on small numbers. In addition, older age at first (HR = 0.44, 95%-CI:0.22-0.88) and last live birth (HR = 0.44, 95%-CI:0.22-0.87) were inversely associated with oesophageal squamous cell carcinoma and having a stillbirth/miscarriage/termination was positively associated (HR = 1.84, 95%-CI:1.10-3.07).

Conclusions: Obesity and abdominal obesity specifically may be a risk factor for oesophageal adenocarcinoma and gastric cardia cancer in men. Some reproductive factors may be associated with oesophageal squamous cell carcinoma in women.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240413PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575071PMC
December 2020

Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects.

Gastroenterology 2021 03 12;160(4):1164-1178.e6. Epub 2020 Oct 12.

Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Background And Aims: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes.

Methods: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted.

Results: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis.

Conclusions: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.
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http://dx.doi.org/10.1053/j.gastro.2020.08.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956223PMC
March 2021

Circulating adipokine concentrations and risk of five obesity-related cancers: A Mendelian randomization study.

Int J Cancer 2021 04 26;148(7):1625-1636. Epub 2020 Oct 26.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Obesity is considered a chronic inflammatory state characterized by continued secretion of adipokines and cytokines. Experimental and epidemiological evidence indicates that circulating adipokines may be associated with the development of obesity-related cancers, but it is unclear if these associations are causal or confounded. We examined potential causal associations of specific adipokines (adiponectin, leptin, soluble leptin receptor [sOB-R] and plasminogen activator inhibitor-1 [PAI-1]) with five obesity-related cancers (colorectal, pancreatic, renal cell carcinoma [RCC], ovarian and endometrial) using Mendelian randomization (MR) methods. We used summary-level data from large genetic consortia for 114 530 cancer cases and 245 284 controls. We constructed genetic instruments using 18 genetic variants for adiponectin, 2 for leptin and 4 for both sOB-R and PAI-1 (P value for inclusion<5 × 10 ). Causal estimates were obtained using two-sample MR methods. In the inverse-variance weighted models, we found an inverse association between adiponectin and risk of colorectal cancer (odds ratio per 1 μg/mL increment in adiponectin concentration: 0.90 [95% confidence interval = 0.84-0.97]; P = .01); but, evidence of horizontal pleiotropy was detected and the association was not present when this was taken into consideration. No association was found for adiponectin and risks of pancreatic cancer, RCC, ovarian cancer and endometrial cancer. Leptin, sOB-R and PAI-1 were also similarly unrelated to risk of obesity-related cancers. Despite the large sample size, our MR analyses do not support causal effects of circulating adiponectin, leptin, sOB-R and PAI-1 concentrations on the development of five obesity-related cancers.
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http://dx.doi.org/10.1002/ijc.33338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894468PMC
April 2021

Weight change in middle adulthood and risk of cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Int J Cancer 2021 04 9;148(7):1637-1651. Epub 2020 Nov 9.

Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Turin, Italy.

Obesity is a risk factor for several major cancers. Associations of weight change in middle adulthood with cancer risk, however, are less clear. We examined the association of change in weight and body mass index (BMI) category during middle adulthood with 42 cancers, using multivariable Cox proportional hazards models in the European Prospective Investigation into Cancer and Nutrition cohort. Of 241 323 participants (31% men), 20% lost and 32% gained weight (>0.4 to 5.0 kg/year) during 6.9 years (average). During 8.0 years of follow-up after the second weight assessment, 20 960 incident cancers were ascertained. Independent of baseline BMI, weight gain (per one kg/year increment) was positively associated with cancer of the corpus uteri (hazard ratio [HR] = 1.14; 95% confidence interval: 1.05-1.23). Compared to stable weight (±0.4 kg/year), weight gain (>0.4 to 5.0 kg/year) was positively associated with cancers of the gallbladder and bile ducts (HR = 1.41; 1.01-1.96), postmenopausal breast (HR = 1.08; 1.00-1.16) and thyroid (HR = 1.40; 1.04-1.90). Compared to maintaining normal weight, maintaining overweight or obese BMI (World Health Organisation categories) was positively associated with most obesity-related cancers. Compared to maintaining the baseline BMI category, weight gain to a higher BMI category was positively associated with cancers of the postmenopausal breast (HR = 1.19; 1.06-1.33), ovary (HR = 1.40; 1.04-1.91), corpus uteri (HR = 1.42; 1.06-1.91), kidney (HR = 1.80; 1.20-2.68) and pancreas in men (HR = 1.81; 1.11-2.95). Losing weight to a lower BMI category, however, was inversely associated with cancers of the corpus uteri (HR = 0.40; 0.23-0.69) and colon (HR = 0.69; 0.52-0.92). Our findings support avoiding weight gain and encouraging weight loss in middle adulthood.
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http://dx.doi.org/10.1002/ijc.33339DOI Listing
April 2021

A transient enhancement of Mercury's exosphere at extremely high altitudes inferred from pickup ions.

Nat Commun 2020 09 29;11(1):4350. Epub 2020 Sep 29.

NASA Jet Propulsion Laboratory, California Institute of Technology, Pasadena, CA, USA.

Mercury has a global dayside exosphere, with measured densities of 10 cm at ~1500 km. Here we report on the inferred enhancement of neutral densities (<10 cm) at high altitudes (~5300 km) by the MESSENGER spacecraft. Such high-altitude densities cannot be accounted for by the typical exosphere. This event was observed by the Fast-Imaging Plasma Spectrometer (FIPS), which detected heavy ions of planetary origin that were recently ionized, and "picked up" by the solar wind. We estimate that the neutral density required to produce the observed pickup ion fluxes is similar to typical exospheric densities found at ~700 km altitudes. We suggest that this event was most likely caused by a meteroid impact. Understanding meteoroid impacts is critical to understanding the source processes of the exosphere at Mercury, and the use of plasma spectrometers will be crucial for future observations with the Bepi-Colombo mission.
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http://dx.doi.org/10.1038/s41467-020-18220-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525509PMC
September 2020

Mendelian Randomization Analysis of n-6 Polyunsaturated Fatty Acid Levels and Pancreatic Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2020 12 23;29(12):2735-2739. Epub 2020 Sep 23.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome.

Methods: We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data.

Results: Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98-1.02; arachidonic acid OR = 1.00, 95% CI = 0.99-1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87-1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex.

Conclusions: Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk.

Impact: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710600PMC
December 2020

Association between nutritional profiles of foods underlying Nutri-Score front-of-pack labels and mortality: EPIC cohort study in 10 European countries.

BMJ 2020 09 16;370:m3173. Epub 2020 Sep 16.

AOU Federico II, Naples, Italy.

Objective: To determine if the Food Standards Agency nutrient profiling system (FSAm-NPS), which grades the nutritional quality of food products and is used to derive the Nutri-Score front-of-packet label to guide consumers towards healthier food choices, is associated with mortality.

Design: Population based cohort study.

Setting: European Prospective Investigation into Cancer and Nutrition (EPIC) cohort from 23 centres in 10 European countries.

Participants: 521 324 adults; at recruitment, country specific and validated dietary questionnaires were used to assess their usual dietary intakes. A FSAm-NPS score was calculated for each food item per 100 g content of energy, sugars, saturated fatty acids, sodium, fibre, and protein, and of fruit, vegetables, legumes, and nuts. The FSAm-NPS dietary index was calculated for each participant as an energy weighted mean of the FSAm-NPS score of all foods consumed. The higher the score the lower the overall nutritional quality of the diet.

Main Outcome Measure: Associations between the FSAm-NPS dietary index score and mortality, assessed using multivariable adjusted Cox proportional hazards regression models.

Results: After exclusions, 501 594 adults (median follow-up 17.2 years, 8 162 730 person years) were included in the analyses. Those with a higher FSAm-NPS dietary index score (highest versus lowest fifth) showed an increased risk of all cause mortality (n=53 112 events from non-external causes; hazard ratio 1.07, 95% confidence interval 1.03 to 1.10, P<0.001 for trend) and mortality from cancer (1.08, 1.03 to 1.13, P<0.001 for trend) and diseases of the circulatory (1.04, 0.98 to 1.11, P=0.06 for trend), respiratory (1.39, 1.22 to 1.59, P<0.001), and digestive (1.22, 1.02 to 1.45, P=0.03 for trend) systems. The age standardised absolute rates for all cause mortality per 10 000 persons over 10 years were 760 (men=1237; women=563) for those in the highest fifth of the FSAm-NPS dietary index score and 661 (men=1008; women=518) for those in the lowest fifth.

Conclusions: In this large multinational European cohort, consuming foods with a higher FSAm-NPS score (lower nutritional quality) was associated with a higher mortality for all causes and for cancer and diseases of the circulatory, respiratory, and digestive systems, supporting the relevance of FSAm-NPS to characterise healthier food choices in the context of public health policies (eg, the Nutri-Score) for European populations. This is important considering ongoing discussions about the potential implementation of a unique nutrition labelling system at the European Union level.
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http://dx.doi.org/10.1136/bmj.m3173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491938PMC
September 2020

A 50-Year Commitment to American Indian and Alaska Native Women.

Obstet Gynecol 2020 10;136(4):739-744

University of New Mexico, Albuquerque, New Mexico; the Uniformed Services University of the Health Sciences, Bethesda, Maryland; the Northern Navajo Medical Center, Shiprock, New Mexico; the Mid-Columbia Medical Center, The Dalles, Oregon; the University of Texas Rio Grande Valley, Edinburg, Texas; the Alaska Native Medical Center, Anchorage, Alaska; the University of Mississippi Medical Center, Jackson, Mississippi; the Oregon Health and Science University, Portland, Oregon; and the American College of Obstetricians and Gynecologists, Washington, DC.

Since 1970, the American College of Obstetricians and Gynecologists' Committee on American Indian and Alaska Native Women's Health has partnered with the Indian Health Service and health care facilities serving Native American women to improve quality of care in both rural and urban settings. Needs assessments have included formal surveys, expert panels, consensus conferences, and onsite program reviews. Improved care has been achieved through continuing professional education, recruitment of volunteer obstetrician-gynecologists, advocacy, and close collaboration at the local and national levels. The inclusive and multifaceted approach of this program should provide an effective model for collaborations between specialty societies and health care professionals providing primary care services that can reduce health disparities in underserved populations.
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http://dx.doi.org/10.1097/AOG.0000000000004040DOI Listing
October 2020
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