Publications by authors named "Edward L Giovannucci"

639 Publications

Unrestrained eating behavior and risk of digestive system cancers: a prospective cohort study.

Am J Clin Nutr 2021 Jul 22. Epub 2021 Jul 22.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Background: Unrestrained eating behavior, as a potential proxy for diet frequency, timing, and caloric intake, has been questioned as a plausible risk factor for digestive system cancers, but epidemiological evidence remains sparse.

Objectives: We investigated prospectively the associations between unrestrained eating behavior and digestive system cancer risk.

Methods: Participants in the Nurses' Health Study who were free of cancer and reported dietary information in 1994 were followed for ≤18 y. Cox models were used to estimate HRs and 95% CIs for unrestrained eating (eating anything at any time, no concern with figure change, or both) and risk of digestive system cancers.

Results: During follow-up, 2064 digestive system cancer cases were documented among 70,450 eligible participants in analyses of eating anything at any time, In total, 2081 digestive system cancer cases were documented among 72,468 eligible participants in analyses of no concern with figure change. In fully adjusted analyses, women with the behavior of eating anything at any time had a higher risk of overall digestive system cancer (HR: 1.22; 95% CI: 1.10, 1.35), overall gastrointestinal tract cancer ((HR: 1.33; 95% CI: 1.18, 1.50), buccal cavity and pharynx cancer (HR: 1.50; 95% CI: 1.02, 2.21), esophageal cancer (HR: 1.62; 95% CI: 1.01, 2.62), small intestine cancer (HR: 1.92; 95% CI: 1.02,3. 59), and colorectal cancer (HR: 1.20; 95% CI: 1.04, 1.38), and a non-statistically significant increased risk of stomach cancer (HR: 1.54; 95% CI: 0.96,2.48), compared with women without this behavior. No statistically significant association was observed for pancreatic cancer and liver and gallbladder cancer. The combined effect of eating anything at any time and having no concern with figure change was associated with a significantly increased risk of overall digestive system cancer (HR: 1.27; 95% CI: 1.10, 1.46), overall gastrointestinal tract cancer (HR: 1.45; 95% CI: 1.23, 1.71), and colorectal cancer (HR: 1.34; 95% CI: 1.11, 1.63), compared with women exhibiting the opposite.

Conclusions: Unrestrained eating behavior was independently associated with increased risk of gastrointestinal tract cancers. The potential importance of unrestrained eating behavior modification in preventing gastrointestinal tract cancers should be noted.
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http://dx.doi.org/10.1093/ajcn/nqab235DOI Listing
July 2021

The sulfur microbial diet is associated with increased risk of early-onset colorectal cancer precursors.

Gastroenterology 2021 Jul 14. Epub 2021 Jul 14.

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address:

Background & Aims: Diet may contribute to the increasing incidence of colorectal cancer (CRC) before age 50 (early-onset CRC). Microbial metabolism of dietary sulfur produces hydrogen sulfide (HS), a gastrointestinal carcinogen that cannot be easily measured at scale. As a result, evidence supporting its role in early neoplasia is lacking.

Methods: We evaluated long-term adherence to the sulfur microbial diet, a dietary index defined a priori based on increased abundance of 43 bacterial species involved with sulfur metabolism, with risk of CRC precursors among 59,013 individuals who underwent lower endoscopy in the Nurses' Health Study II (NHSII, 1991-2015), a prospective cohort study with dietary assessment every four years through validated food frequency questionnaires and an assessment of dietary intake during adolescence in 1998. The sulfur microbial diet was characterized by intake high in processed meats and low in mixed vegetables and legumes, foods previously linked to CRC development. Multivariable logistic regression for clustered data was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

Results: We documented 2,911 cases of early-onset adenoma. After adjusting for established risk factors, higher sulfur microbial diet scores were associated with increased risk for early-onset adenomas (OR=1.31, 95% CI: 1.10 to 1.56, P=0.02), but not serrated lesions. Compared to the lowest, women in the highest quartile of sulfur microbial diet scores had significantly increased risk of early-onset adenomas with greater malignant potential (OR=1.65 for villous/tubulovillous histology, 95% CI: 1.12 to 2.43; P=0.04). Similar trends for early onset-adenoma were observed based on diet consumed during adolescence. In contrast, there was no clear association for adenomas identified after age 50.

Conclusion: Our findings in a cohort of young women support a role for dietary interactions with gut sulfur-metabolizing bacteria in early-onset colorectal carcinogenesis, possibly beginning in adolescence.
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http://dx.doi.org/10.1053/j.gastro.2021.07.008DOI Listing
July 2021

Adherence to the World Cancer Research Fund/American Institute for Cancer Research cancer prevention recommendations and colorectal cancer survival.

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

Department of Nutrition, Harvard T.H. Chan School of Public Health

Background: Cancer patients are recommended to follow cancer prevention guidelines due to inadequate evidence for specific recommendations for cancer survivors.

Methods: We examined whether diet and lifestyle scores measuring adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention guidelines were associated with colorectal cancer-specific and overall mortality among 1,491 colorectal cancer (CRC) patients in two prospective cohorts. Cox proportional hazards regression models were used to calculate the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: During a median follow-up of 7.92 years, there were 641 deaths (179 CRC-specific deaths). Patients in the highest quartile of the post-diagnostic lifestyle score including diet, body mass index (BMI), and physical activity had a 24% lower risk (HR=0.76, 95% CI: 0.49-1.18) of CRC-specific death and a 37% lower risk (HR=0.63, 95% CI: 0.50-0.78) of overall death compared with the lowest quartile. When BMI was not included in the lifestyle score due to potential disease-related weight loss, stronger inverse associations were observed for both CRC-specific and overall mortality for the same comparison (CRC-specific: HR=0.50, 95% CI: 0.32-0.79; overall: HR=0.59, 95% CI: 0.47-0.75). The post-diagnostic diet score was not statistically significantly associated with either CRC-specific or overall mortality.

Conclusions: Greater adherence to the WCRF/AICR cancer prevention recommendations was associated with improved survival in CRC patients.

Impact: The study provided support for CRC patients to follow cancer prevention recommendations after diagnosis. Future studies on cancer survivors will continue to contribute to evidence-based diet and lifestyle recommendations for cancer patients.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0120DOI Listing
July 2021

Prenatal and perinatal factors and risk of cancer in middle and older adulthood among men.

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

Department of Epidemiology, Harvard T.H. Chan School of Public Health.

Background: Prenatal factors have been associated with risk of cancers later in life, although studies in men have largely been case-control and focused on birth size only.

Methods: We used data from 5,845 men in the Health Professionals Follow-up Study to prospectively examine associations between several prenatal and perinatal factors and incident adult cancer risk. In 1994, mothers of participants reported information on characteristics and behaviors related to their pregnancy with their sons. We used multivariable Cox proportional hazards models to calculate hazard ratios (HR) and 95% confidence intervals (CI) of associations between prenatal and perinatal risk factors and cancer risk.

Results: During 20 years of follow-up, 1228 incident cases of overall cancer were documented. Men with a birth weight of >=4 kg had a 21% increased risk of overall cancer (HR: 1.21; 95% CI: 1.02-1.43) compared with those with a birth weight of 2.5-3.9 kg. Greater weight gain during pregnancy (>13.6 kg vs 6.8-8.6 kg) was also associated with a higher risk of overall cancer (HR: 1.22; 95% CI: 1.02-1.46), and was stronger for men whose mothers had a pre-pregnancy BMI<21 kg/m2 (HR: 1.30, 95% CI: 1.00-1.67) compared with BMI>=21 kg/m2 (HR: 1.14, 95% CI: 0.85-1.51). There was no association between maternal age and overall cancer risk.

Conclusion: Higher birth weight and maternal weight gain are associated with increased cancer risk in adult men.

Impact: Our findings support the hypothesis that the in utero environment plays a role in the etiology of cancer in middle and older adulthood.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0316DOI Listing
July 2021

Sugar-sweetened beverage, artificially sweetened beverage and sugar intake and colorectal cancer survival.

Br J Cancer 2021 Jul 15. Epub 2021 Jul 15.

Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA, USA.

Background: The influence of a high sugar diet on colorectal cancer (CRC) survival is unclear.

Methods: Among 1463 stage I-III CRC patients from the Nurses' Health Study and Health Professionals Follow-up Study, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC-specific and all-cause mortality in relation to intake of post-diagnosis sugar-sweetened beverages (SSB), artificially sweetened beverages (ASB), fruit juice, fructose and other sugars.

Results: Over a median 8.0 years, 781 cases died (173 CRC-specific deaths). Multivariable-adjusted HRs for post-diagnosis intake and CRC-specific mortality were 1.21 (95% CI: 0.87-1.68) per 1 serving SSBs per day (serving/day) and 1.24 (95% CI: 0.95-1.63) per 20 grams fructose per day. Significant positive associations for CRC-specific mortality were primarily observed ≤5 years from diagnosis (HR per 1 serving/day of SSBs = 1.59, 95% CI: 1.06-2.38). Significant inverse associations were observed between ASBs and CRC-specific and all-cause mortality (HR for ≥5 versus <1 serving/week = 0.44, 95% CI: 0.26-0.75 and 0.70, 95% CI: 0.55-0.89, respectively).

Conclusions: Higher post-diagnosis intake of SSBs and sugars may be associated with higher CRC-specific mortality, but only up to 5 years from diagnosis, when more deaths were due to CRC. The inverse association between ASBs and CRC-specific mortality warrants further examination.
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http://dx.doi.org/10.1038/s41416-021-01487-7DOI Listing
July 2021

Adiposity, Adulthood Weight Change and Risk of Incident Hepatocellular Carcinoma.

Cancer Prev Res (Phila) 2021 Jul 15. Epub 2021 Jul 15.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital

Prospective data are limited regarding dynamic adulthood weight changes and hepatocellular carcinoma (HCC) risk. We included 77,238 women (1980-2012) and 48,026 men (1986-2012), who recalled young-adult weight (age 18 years [women]; 21 years [men]), and provided biennially-updated information regarding weight, body mass index (BMI) and comorbidities. Overall adulthood weight change was defined as the difference in weight (kilograms) between young-adulthood and present. Using Cox proportional hazards models, we calculated multivariable-adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). Over 3,676,549 person-years, we documented 158 incident HCC cases. Elevated HCC risk was observed with higher BMI in both young-adulthood and later-adulthood (continuous aHRs per each 1-unit=1.05, 95%CI=1.02-1.09 [Ptrend=0.019], and 1.08, 95%CI=1.06-1.10 [Ptrend=0.004], respectively). Moreover, overall adulthood weight gain was also significantly associated with increased HCC risk (aHR per each 1-kg increase=1.03, 95%CI=1.01-1.08; Ptrend=0.010), including after further adjusting for young-adult BMI (Ptrend=0.010) and later-adult BMI (Ptrend=0.008). Compared to adults with stable weight (+/-5kg), the multivariable-aHRs with weight gain of 5-<10kg, 10-<20kg and {greater than or equal to}20kg were, 1.40 (95%CI=0.67-2.16), 2.09 (95%CI=1.11-3.95) and 2.61 (95%CI=1.42-5.22), respectively. In two prospective, nationwide cohorts, adulthood weight gain was significantly associated with increased HCC risk.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0549DOI 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

Total vitamin D intake and risks of early-onset colorectal cancer and precursors.

Gastroenterology 2021 Jul 7. Epub 2021 Jul 7.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address:

Background & Aims: Vitamin D has been implicated in colorectal cancer (CRC) pathogenesis, but it remains unknown whether total vitamin D intake is associated with early-onset CRC and precursors diagnosed before age 50.

Methods: We prospectively examined the association between total vitamin D intake and risks of early-onset CRC and precursors among women enrolled in the Nurses' Health Study II. Multivariable-adjusted hazard ratio (HR) and 95% confidence interval (CI) for early-onset CRC were estimated with Cox proportional hazards model. Multivariable-adjusted odds ratio (OR) and 95% CI for early-onset conventional adenoma and serrated polyp were estimated with logistic regression model.

Results: We documented 111 incident cases of early-onset CRC during 1,250,560 person-years of follow-up (1991 to 2015). Higher total vitamin D intake was significantly associated with a reduced risk of early-onset CRC (HR for ≥450 IU/day vs <300 IU/day, 0.49; 95% CI, 0.26-0.93; P for trend = 0.01). The HR per 400 IU/day increase was 0.46 (95% CI, 0.26-0.83). The inverse association was significant and appeared more evident for dietary sources of vitamin D (HR per 400 IU/day increase, 0.34; 95% CI, 0.15-0.79) than supplemental vitamin D (HR per 400 IU/day increase, 0.77; 95% CI, 0.37-1.62). For CRC precursors, the ORs per 400 IU/day increase were 0.76 (95% CI, 0.65-0.88) for conventional adenoma (n = 1,439) and 0.85 (95% CI, 0.75-0.97) for serrated polyp (n = 1,878).

Conclusions: In a cohort of younger women, higher total vitamin D intake was associated with decreased risks of early-onset CRC and precursors.
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http://dx.doi.org/10.1053/j.gastro.2021.07.002DOI Listing
July 2021

Discovery and features of an alkylating signature in colorectal cancer.

Cancer Discov 2021 Jun 17. Epub 2021 Jun 17.

Department of Medical Oncology, Dana-Farber Cancer Institute

Several risk factors have been established for colorectal carcinoma (CRC), yet their direct mutagenic effects in patients' tumours remain to be elucidated. Here, we leveraged whole-exome sequencing data from 900 CRC cases that had occurred in three US-wide prospective studies with extensive dietary and lifestyle information. We found an alkylating signature which was previously undescribed in CRC, and then showed the existence of a similar mutational process in normal colonic crypts. This alkylating signature is associated with high intakes of processed and unprocessed red meat prior to diagnosis. Additionally, this signature was more abundant in the distal colorectum, predicted to target cancer driver mutations KRAS p.G12D, KRAS p.G13D and PIK3CA p.E5454K, and associated with poor survival. Together, these results link for the first time a colorectal mutational signature to a component of diet, and further implicate the role of red meat in CRC initiation and progression.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1656DOI Listing
June 2021

Dietary fiber intake, the gut microbiome, and chronic systemic inflammation in a cohort of adult men.

Genome Med 2021 Jun 17;13(1):102. Epub 2021 Jun 17.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Background: A higher intake of dietary fiber is associated with a decreased risk of chronic inflammatory diseases such as cardiovascular disease and inflammatory bowel disease. This may function in part due to abrogation of chronic systemic inflammation induced by factors such as dysbiotic gut communities. Data regarding the detailed influences of long-term and recent intake of differing dietary fiber sources on the human gut microbiome are lacking.

Methods: In a cohort of 307 generally healthy men, we examined gut microbiomes, profiled by shotgun metagenomic and metatranscriptomic sequencing, and long-term and recent dietary fiber intake in relation to plasma levels of C-reactive protein (CRP), an established biomarker for chronic inflammation. Data were analyzed using multivariate linear mixed models.

Results: We found that inflammation-associated gut microbial configurations corresponded with higher CRP levels. A greater intake of dietary fiber was associated with shifts in gut microbiome composition, particularly Clostridiales, and their potential for carbohydrate utilization via polysaccharide degradation. This was particularly true for fruit fiber sources (i.e., pectin). Most striking, fiber intake was associated with significantly greater CRP reduction in individuals without substantial Prevotella copri carriage in the gut, whereas those with P. copri carriage maintained stable CRP levels regardless of fiber intake.

Conclusions: Our findings offer human evidence supporting a fiber-gut microbiota interaction, as well as a potential specific mechanism by which gut-mediated systemic inflammation may be mitigated.
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http://dx.doi.org/10.1186/s13073-021-00921-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212460PMC
June 2021

Analysis of Survival Among Adults With Early-Onset Colorectal Cancer in the National Cancer Database.

JAMA Netw Open 2021 Jun 1;4(6):e2112539. Epub 2021 Jun 1.

Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut.

Importance: While increased adherence to colorectal cancer (CRC) screening guidelines in the US has been associated with significant reductions in cancer incidence in US individuals aged 50 years and older, the incidence of CRC among those aged younger than 50 years has been steadily increasing. Understanding the survival among individuals with early-onset CRC compared with those aged 50 years and older is fundamental to informing treatment approaches and understanding the unique biological distinctiveness within early-onset CRC.

Objective: To characterize the overall survival for individuals with early-onset CRC.

Design, Setting, And Participants: This cohort study used data from the National Cancer Database. Included individuals were ages 0 to 90 years and diagnosed with primary CRC from January 1, 2004, through December 31, 2015. Individuals diagnosed at ages 51 through 55 years were selected as the reference group and defined as later-onset CRC for this study. Individuals diagnosed at age 50 years were excluded to minimize an apparent screening detection bias at that age in our population, given that these individuals disproportionately presented with earlier stage. All statistical analyses were conducted from January 4, 2020, through December 26, 2020.

Exposures: Early-onset CRC was defined as age younger than 50 years at diagnosis.

Main Outcomes And Measures: Overall survival was assessed by Kaplan-Meier analysis and Cox proportional hazards regression.

Results: Among 769 871 individuals with CRC (377 890 [49.1%] women; 636 791 White individuals [82.7%]), 353 989 individuals (46.0%) died (median [range] follow-up: 2.9 [0-14.0] years), 102 168 individuals (13.3%) had early-onset CRC, and 78 812 individuals (10.2%) had later-onset CRC. Individuals with early-onset CRC, compared with those diagnosed with CRC at ages 51 through 55 years, had a lower 10-year survival rate (53.6% [95% CI, 53.2%-54.0%] vs 54.3% [95% CI, 53.8%-54.8%]; P < .001) in unadjusted analysis. However, after adjustment for other factors associated with mortality, most notably stage, individuals with early-onset CRC had a lower risk of death compared with individuals diagnosed from ages 51 through 55 years (adjusted hazard ratio [HR], 0.95 [95% CI, 0.93-0.96]; P < .001). In the model adjusted for stage, the HR for individuals with early-onset CRC was 0.89 (95% CI, 0.88-0.90; P < .001). The survival advantage was greatest for individuals diagnosed at ages 35 through 39 years (adjusted HR, 0.88 [95% CI, 0.84-0.92]; P < .001) and stages I (adjusted HR, 0.87 [95% CI, 0.81-0.93]; P < .001) and II (adjusted HR, 0.86 [95% CI, 0.82-0.90]; P < .001) and was absent among those diagnosed at ages 25 years or younger and stages III through IV.

Conclusions And Relevance: These findings suggest that there is a survival benefit for individuals with early-onset CRC compared with those diagnosed with CRC at later ages. Further study is needed to understand the underlying heterogeneity of survival among individuals with early-onset CRC by age and stage.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.12539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209612PMC
June 2021

Muscle-strengthening activities and risk of cardiovascular disease, type 2 diabetes, cancer and mortality: A review of prospective cohort studies.

J Intern Med 2021 Jun 13. Epub 2021 Jun 13.

Departments of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

The benefits of aerobic moderate-to-vigorous physical activity (MVPA) on major non-communicable diseases (NCDs) are well established. However, much less is known whether muscle-strengthening activities (i.e., resistance/weight/strength training) confer similar benefits. Herein, we conducted a narrative literature review and summarized the existing evidence from large prospective cohort studies on muscle strengthening activities and risk of major chronic diseases and mortality in adults generally free of major NCDs at baseline. Current epidemiologic evidence suggests that engagement in muscle-strengthening activities over 1-2 sessions (or approximately 60-150 min) per week was associated with reduced risk of cardiovascular disease (seven studies; approximately 20%-25% reduction), type 2 diabetes (four studies; approximately 30% reduction), cancer mortality (four studies; approximately 15%-20% reduction) as well as all-cause mortality (six studies; approximately 20%-25% reduction). For diabetes, the risk appears to lower further with even higher levels of muscle-strengthening activities, but some studies for cardiovascular and all-cause mortality suggest a reversal whereby higher levels (≥2.5 h/week) have less benefit, or are even harmful, relative to lower levels of activity. The likely mechanisms contributing to a benefit include improvement in body composition, lipid profile, insulin resistance and inflammation. The evidence supports engaging in 1-2 sessions (up to 2.5 h) per week, preferably performed complementary to the recommended levels of aerobic MVPA. Although data are limited, caution is suggested for training exceeding 2.5 h per week. Further studies are required to better understand the influence of frequency, duration and intensity of muscle-strengthening activities on major NCDs and mortality in diverse populations.
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http://dx.doi.org/10.1111/joim.13344DOI Listing
June 2021

Can there be consensus on whether vasectomy is a prostate cancer risk factor?

Prostate Cancer Prostatic Dis 2021 Jun 9. Epub 2021 Jun 9.

Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

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http://dx.doi.org/10.1038/s41391-021-00400-wDOI Listing
June 2021

Association between weight cycling and risk of kidney cancer: a prospective cohort study and meta-analysis of observational studies.

Cancer Causes Control 2021 Sep 5;32(9):1029-1038. Epub 2021 Jun 5.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Purpose: Weight cycling is common in populations. However, it is unclear whether frequency and magnitude of weight cycling is associated with kidney cancer risk, independent of body mass index (BMI).

Methods: A prospective cohort study followed 85,562 participants from Health Professionals Follow-up Study and Nurses' Health Study (1992-2014). At baseline, participants reported frequency and magnitude of intentional weight loss in the past 4 years. Cox proportional hazard model was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). We also conducted a meta-analysis of all available observational studies including our two cohorts.

Results: During 22 years of follow-up, we identified 441 kidney cancer cases. Compared with non-weight cyclers (no attempt of intentional weight loss), severe cyclers (≥ 3 times of intentional weight loss of ≥ 4.5 kg) were at increased kidney cancer risk after adjusting for BMI before weight cycling (pooled multivariable-adjusted HR, 1.78; 95% CI, 1.19, 2.66). Additional adjustment for attained BMI after weight cycling had minimal influence. There was a positive trend between weight cycling by frequency and magnitude and kidney cancer risk (P-trend = 0.01). Moreover, the observed positive association did not differ by subtypes of cyclers (e.g., adiposity status, weight-loss methods). In the meta-analysis, we found a strong positive association between weight cycling and kidney cancer risk (summary relative risk for weight cyclers vs. non-cyclers, 1.51; 95% CI, 1.16, 1.96; I: 52.2%; 6 studies).

Conclusion: Frequent substantial weight cycling was associated with increased risk of kidney cancer, independent of BMI. Our study suggests that weight cycling may be an important risk factor for kidney cancer.
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http://dx.doi.org/10.1007/s10552-021-01455-9DOI Listing
September 2021

Muscle-strengthening activities and cancer incidence and mortality: a systematic review and meta-analysis of observational studies.

Int J Behav Nutr Phys Act 2021 05 29;18(1):69. Epub 2021 May 29.

Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Medicina Preventiva, São Paulo, SP, Brazil.

Background: Physical activity has been associated with reduced risk of seven types of cancer. It remains unclear, however, whether muscle-strengthening activities also reduce cancer incidence and mortality.

Methods: PubMed, Embase, Web of Science and Scopus were searched from inception to March 2020. Summary hazard ratio (HR) and 95% confidence intervals (CI) were estimated using random-effects models.

Results: Twelve studies (11 cohorts; 1 case-control), 6 to 25 years of follow-up, including 1,297,620 participants, 32,196 cases and 31,939 deaths, met inclusion criteria. Muscle-strengthening activities were associated with a 26% lower incidence of kidney cancer (HR for high vs low levels of muscle-strengthening activities: 0.74; 95% CI 0.56 to 0.98; I 0%; 2 studies), but not with incidence of other 12 types of cancer. Muscle-strengthening activities were associated with lower total cancer mortality: HRs for high vs low levels of muscle-strengthening activities was 0.87 (95% CI 0.73 to 1.02; I 58%; 6 studies); and HR for ≥2 times/week vs < 2 times/week of muscle-strengthening activities was 0.81 (95% CI 0.74 to 0.87; I 0%; 4 studies). Regarding the weekly duration of muscle-strengthening activities, HR for total cancer mortality were 0.91 (95% CI 0.82 to 1.01; I 0%; 2 studies) for 1-59 min/week and 0.98 (95% CI 0.89 to 1.07; I 0%) for ≥60 min/week vs none. Combined muscle-strengthening and aerobic activities (vs none) were associated with a 28% lower total cancer mortality (HR 0.72; 95% CI 0.53 to 0.98; I 85%; 3 studies).

Conclusions: Muscle-strengthening activities were associated with reduced incidence of kidney cancer and total cancer mortality. Combined muscle-strengthening and aerobic activities may provide a greater reduction in total cancer mortality.
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http://dx.doi.org/10.1186/s12966-021-01142-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164763PMC
May 2021

The Role of Mendelian Randomization Studies in Deciphering the Effect of Obesity on Cancer.

J Natl Cancer Inst 2021 May 21. Epub 2021 May 21.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Associations of obesity have been established for at least 11 cancer sites in observational studies, though some questions remain as to causality, strength of associations, and timing of associations throughout the life course. In recent years, Mendelian randomization (MR) has provided complementary information to traditional approaches, but the validity requires that the genetic instrumental variables be causally related to cancers only mediated by the exposure. We summarize and evaluate existing evidence from MR studies in comparison with conventional observational studies to provide insights into the complex relationship between obesity and multiple cancers. MR studies further establish the causality of adult obesity with esophageal adenocarcinoma, cancers of the colorectum, endometrium, ovary, kidney, and pancreas, as well as the inverse association of early life obesity with breast cancer. MR studies, which might account for lifelong adiposity, suggest that the associations in observational studies typically based on single measurement may underestimate the magnitude of the association. For lung cancer, MR studies find a positive association with obesity, supporting that the inverse association observed in some conventional observational studies likely reflects reverse causality (loss of lean body mass before diagnosis) and confounding by smoking. However, MR studies have not had sufficient power for gallbladder cancer, gastric cardia cancer, and multiple myeloma. In addition, more MR studies are needed to explore the effect of obesity at different time points on postmenopausal breast cancer and aggressive prostate cancer.
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http://dx.doi.org/10.1093/jnci/djab102DOI Listing
May 2021

Association of Screening Lower Endoscopy With Colorectal Cancer Incidence and Mortality in Adults Older Than 75 Years.

JAMA Oncol 2021 Jul;7(7):985-992

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard Medical School, Boston.

Importance: Evidence indicates that screening for colorectal cancer (CRC) beginning at 50 years of age can detect early-stage CRC and premalignant neoplasms (eg, adenomas) and thus prevent CRC-related mortality. At present, the US Preventive Services Task Force recommends continuing CRC screening until 75 years of age and individualized decision-making for adults older than 75 years, while accounting for a patient's overall health and screening history. However, scant data exist to support these recommendations.

Objective: To examine the association of lower gastrointestinal tract screening endoscopy with the risk of CRC incidence and CRC-related mortality in older US adults.

Design, Setting, And Participants: This prospective cohort study of health care professionals in the US included data from the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS) from January 1, 1988, through January 31, 2016, for the HPFS and June 30, 2016, for the NHS. Data were analyzed from May 8, 2019, to July 9, 2020.

Exposures: History of screening sigmoidoscopy or colonoscopy (routine/average risk or positive family history) to 75 years of age and after 75 years of age, assessed every 2 years.

Main Outcomes And Measures: Incidence of CRC and CRC-related mortality confirmed by National Death Index, medical records, and pathology reports.

Results: Among 56 374 participants who reached 75 years of age during follow-up (36.8% men and 63.2% women), 661 incident CRC cases and 323 CRC-related deaths were documented. Screening endoscopy after 75 years of age was associated with reduced risk of CRC incidence (multivariable hazard ratio [HR], 0.61; 95% CI, 0.51-0.74) and CRC-related mortality (HR, 0.60; 95% CI, 0.46-0.78), regardless of screening history. The HR comparing screening with nonscreening after 75 years of age was 0.67 (95% CI, 0.50-0.89) for CRC incidence and 0.58 (95% CI, 0.38-0.87) for CRC-related mortality among participants who underwent screening endoscopy before 75 years of age, and 0.51 (95% CI, 0.37-0.70) for CRC incidence and 0.63 (95% CI, 0.43-0.93) for CRC-related mortality among participants without a screening history. However, screening endoscopy after 75 years of age was not associated with risk reduction in CRC death among participants with cardiovascular disease (HR, 1.18; 95% CI, 0.59-2.35) or significant comorbidities (HR, 1.17; 95% CI, 0.57-2.43).

Conclusions And Relevance: In this cohort study, endoscopy among individuals older than 75 years was associated with lower risk of CRC incidence and CRC-related mortality. These data support continuation of screening after 75 years of age among individuals without significant comorbidities.
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http://dx.doi.org/10.1001/jamaoncol.2021.1364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138747PMC
July 2021

Risk prediction models for colorectal cancer: Evaluating the discrimination due to added biomarkers.

Int J Cancer 2021 Sep 17;149(5):1021-1030. Epub 2021 May 17.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Most risk prediction models for colorectal cancer (CRC) are based on questionnaires and show a modest discriminatory ability. Therefore, we aim to develop risk prediction models incorporating plasma biomarkers for CRC to improve discrimination. We assessed the predictivity of 11 biomarkers in 736 men in the Health Professionals Follow-up Study and 639 women in the Nurses' Health Study. We used stepwise logistic regression to examine whether a set of biomarkers improved the predictivity on the basis of predictors in the National Cancer Institute's (NCI) Colorectal Cancer Risk Assessment Tool. Model discrimination was assessed using C-statistics. Bootstrap with 500 randomly sampled replicates was used for internal validation. The models containing each biomarker generated a C-statistic ranging from 0.50 to 0.59 in men and 0.50 to 0.54 in women. The NCI model demonstrated a C-statistic (95% CI) of 0.67 (0.62-0.71) in men and 0.58 (0.54-0.63) in women. Through stepwise selection of biomarkers, the C-statistic increased to 0.70 (0.66-0.74) in men after adding growth/differentiation factor 15, total adiponectin, sex hormone binding globulin and tumor necrosis factor receptor superfamily member 1B (P for difference = 0.008); and increased to 0.62 (0.57-0.66) in women after further including insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 (P for difference = .06). The NCI + selected biomarkers model was internally validated with a C-statistic (95% CI) of 0.73 (0.70-0.77) in men and 0.66 (0.61-0.70) in women. Circulating plasma biomarkers may improve the performance of risk factor-based prediction model for CRC.
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http://dx.doi.org/10.1002/ijc.33621DOI Listing
September 2021

Tumor Long Interspersed Nucleotide Element-1 (LINE-1) Hypomethylation in Relation to Age of Colorectal Cancer Diagnosis and Prognosis.

Cancers (Basel) 2021 Apr 22;13(9). Epub 2021 Apr 22.

Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Evidence indicates the pathogenic role of epigenetic alterations in early-onset colorectal cancers diagnosed before age 50. However, features of colorectal cancers diagnosed at age 50-54 (hereafter referred to as "intermediate-onset") remain less known. We hypothesized that tumor long interspersed nucleotide element-1 (LINE-1) hypomethylation might be increasingly more common with decreasing age of colorectal cancer diagnosis. In 1356 colorectal cancers, including 28 early-onset and 66 intermediate-onset cases, the tumor LINE-1 methylation level measured by bisulfite-PCR-pyrosequencing (scaled 0 to 100) showed a mean of 63.6 (standard deviation (SD) 10.1). The mean tumor LINE-1 methylation level decreased with decreasing age (mean 64.7 (SD 10.4) in age ≥70, 62.8 (SD 9.4) in age 55-69, 61.0 (SD 10.2) in age 50-54, and 58.9 (SD 12.0) in age <50; < 0.0001). In linear regression analysis, the multivariable-adjusted β coefficient (95% confidence interval (CI)) (vs. age ≥70) was -1.38 (-2.47 to -0.30) for age 55-69, -2.82 (-5.29 to -0.34) for age 50-54, and -4.54 (-8.24 to -0.85) for age <50 ( = 0.0003). Multivariable-adjusted hazard ratios (95% CI) for LINE-1 methylation levels of ≤45, 45-55, and 55-65 (vs. >65) were 2.33 (1.49-3.64), 1.39 (1.05-1.85), and 1.29 (1.02-1.63), respectively ( = 0.0005). In conclusion, tumor LINE-1 hypomethylation is increasingly more common with decreasing age of colorectal cancer diagnosis, suggesting a role of global DNA hypomethylation in colorectal cancer arising in younger adults.
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http://dx.doi.org/10.3390/cancers13092016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122644PMC
April 2021

The utility of predicted values in place of directly measured body composition.

Am J Clin Nutr 2021 Apr 20. Epub 2021 Apr 20.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

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http://dx.doi.org/10.1093/ajcn/nqab127DOI Listing
April 2021

Quality of plant-based diets and risk of hypertension: a Korean genome and examination study.

Eur J Nutr 2021 Apr 17. Epub 2021 Apr 17.

Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health and Harvard Medical School, Boston, MA, USA.

Background And Aims: Plant-based diets have been suggested to have beneficial effects on various health outcomes. However, the evidence on the association of plant-based diet quality with health outcomes is very limited in Asian populations, who may have a different dietary pattern than western populations. This study explored the prospective association between different types of plant-based diets and risk of hypertension using recently established indices in South Koreans.

Methods: Analyses were based on a community-based cohort of 5636 men and women (40-69 years of age at baseline, mean ± SD 50.6 ± 8.5 years) living in Ansan and Ansung, South Korea (2001-2016) without hypertension and related chronic diseases at baseline. Registration card and telephone registration number were used for the sampling. Dietary intakes were assessed using a validated food frequency questionnaire. Based on the questionnaire, scores of three plant-based diet indices [overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI)] were calculated.

Results: Over a follow-up of 14 years, 2244 participants developed hypertension. Individuals in the highest vs. lowest quintile of hPDI had 35% lower incidence of hypertension [hazard ratio (HR) 0.65, 95% CI 0.57, 0.75] and uPDI had 44% higher incidence of hypertension (HR 1.44, 95% CI 1.24, 1.67), adjusting for demographic characteristics, and lifestyle factors (P trend ≤ 0.0001 for both indices). A similar inverse association of hPDI was observed with risk of hypertension by age, sex, residence area, and obesity. The PDI was not associated with hypertension.

Conclusions: Our results highlight the importance of considering the quality of plant foods (relatively higher healthy plant foods and relatively lower less healthy plant foods consumption) for the prevention of hypertension in a population with a long-term adherence to predominantly plant-based diets.
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http://dx.doi.org/10.1007/s00394-021-02559-3DOI Listing
April 2021

Gallstone disease, diabetes, calcium, triglycerides, smoking and alcohol consumption and pancreatitis risk: Mendelian randomization study.

NPJ Genom Med 2021 Mar 29;6(1):27. Epub 2021 Mar 29.

Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

We conducted a Mendelian randomization study to determine the potential causal associations of gallstone disease, diabetes, serum calcium, triglyceride levels, smoking and alcohol consumption with acute and chronic pancreatitis. Genetic variants associated with the exposures at p < 5 × 10 were selected from corresponding genome-wide association studies. Summary-level data for pancreatitis were obtained from the FinnGen consortium and UK Biobank. Univariable and multivariable Mendelian randomization analyses were performed and results from FinnGen and UK Biobank were combined using the fixed-effects meta-analysis method. Genetic predisposition to gallstone disease, type 2 diabetes and smoking initiation was associated with an increased risk of acute pancreatitis. The combined odds ratios (ORs) were 1.74 (95% confidence interval (CI), 1.57, 1.93) for gallstone disease, 1.14 (95% CI, 1.06, 1.21) for type 2 diabetes and 1.56 (95% CI, 1.32, 1.83) for smoking initiation. The association for type 2 diabetes attenuated after adjustment for gallstone disease. Genetic predisposition to gallstone disease and smoking initiation as well as higher genetically predicted serum calcium and triglyceride levels were associated with an increased risk of chronic pancreatitis. The combined ORs of chronic pancreatitis were 1.27 (95% CI, 1.08, 1.50) for gallstone disease, 1.86 (95% CI, 1.43, 2.43) for smoking initiation, 2.20 (95% CI, 1.30, 3.72) for calcium and 1.47 (95% CI, 1.23, 1.76) for triglycerides. This study provides evidence in support that gallstone disease, type 2 diabetes, smoking and elevated calcium and triglyceride levels are causally associated with the risk of acute or chronic pancreatitis.
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http://dx.doi.org/10.1038/s41525-021-00189-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007637PMC
March 2021

History of Diverticulitis and Risk of Incident Cardiovascular Disease in Men: A Cohort Study.

Dig Dis Sci 2021 Mar 26. Epub 2021 Mar 26.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.

Background: Diverticulitis and cardiovascular disease (CVD) are two highly prevalent disorders sharing common risk factors which are hypothesized to have an inflammatory basis.

Aims: To examine the association between history of diverticulitis and risk of incident CVD.

Methods: We conducted a prospective cohort study of 43,904 men aged 40 to 75 years without a history of CVD (fatal or nonfatal myocardial infarction and stroke) at enrollment who were followed up from 1986 to 2012 in the Health Professionals Follow-Up Study. Lifestyle factors, dietary intake, and disease information were self-reported biennially or quadrennially. Incident diverticulitis and CVD were confirmed by review of medical records. We used Cox proportional hazard models to calculate age- and multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) of incident CVD. We conducted a stratified analysis according to the presence or absence of CVD risk factors (smoking, hypertension, hyperlipidemia, and diabetes).

Results: We identified 3848 incident cases of CVD during 856,319 person-years of follow-up. Men with diverticulitis had higher incidence of CVD (727 cases per 100,000 person-years) compared to men without diverticulitis [446 cases per 100,000 person-years, multivariate HR of 1.35 (95% CI 1.07-1.70)]. The association of diverticulitis and subsequent CVD appeared more evident among men without known CVD risk factors (HR 4.06, 95% CI 2.04-8.08) compared to those with one or more CVD risk factors (HR 1.27, 95% CI 0.98-1.63).

Conclusions: Diverticulitis may be an independent risk factor of incident CVD, suggesting possible common etiopathogenic mechanisms. Diagnosis of diverticulitis underscores the importance of preventive measures to reduce future CVD.
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http://dx.doi.org/10.1007/s10620-021-06949-9DOI Listing
March 2021

Association of folate intake and colorectal cancer risk in the postfortification era in US women.

Am J Clin Nutr 2021 Jul;114(1):49-58

Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA.

Background: Folate may play a preventive role in the early stages of colorectal carcinogenesis, but long latencies may be needed to observe a reduction in colorectal cancer (CRC) incidence. In addition, concerns have been raised about the potential for cancer promotion with excessive folate intake, especially after the mandatory folic acid fortification in the United States in 1998.

Objective: We aimed to examine the association between folate intake in different chemical forms and CRC risk, especially in the postfortification era in the United States.

Design: We prospectively followed 86,320 women from the Nurses' Health Study (1980-2016). Folate intake was collected by validated food frequency questionnaires. CRC was self reported and confirmed by review of medical records. The association between the folate intake and CRC risk was assessed using Cox proportional hazards regression.

Results: We documented 1988 incident CRC cases during follow-up. Analyzing folate intake as a continuous variable, greater total folate intake 12-24 y before diagnosis was associated with lower risk of CRC (per increment of 400 dietary folate equivalents (DFE)/d, HR: 0.93, 95% CI: 0.85, 1.01 for 12-16 y; HR: 0.83, 95% CI: 0.75, 0.92 for 16-20 y; and HR: 0.87, 95% CI: 0.77, 0.99 for 20-24 y); and greater synthetic folic acid intake 16-24 y before diagnosis was also associated with a lower CRC risk (per increment of 400 DFE/d, HR: 0.91, 95% CI: 0.84, 0.99 for 16-20 y and HR: 0.91, 95% CI: 0.83-1.01 for 20-24 y). In the postfortification period (1998-2016), intake of total or specific forms of folate was not associated with CRC risk, even among multivitamin users.

Conclusions: Folate intake, both total and from synthetic forms, was associated with a lower risk of overall CRC after long latency periods. There was no evidence that high folate intake in the postfortification period was related to increased CRC risk in this US female population.
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http://dx.doi.org/10.1093/ajcn/nqab035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246607PMC
July 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

Prediagnostic Inflammation and Pancreatic Cancer Survival.

J Natl Cancer Inst 2021 Mar 19. Epub 2021 Mar 19.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.

Background: Chronic inflammation may promote initiation and progression of pancreatic cancer, but no studies have examined the association between inflammation in the period before diagnosis and pancreatic cancer survival.

Methods: We prospectively examined the association of prediagnostic plasma levels of C-reactive protein, interleukin-6, and tumor necrosis factor-α receptor 2 with survival among 492 participants from 5 large US prospective cohort studies who developed pancreatic cancer. Using an empirical dietary inflammatory pattern (EDIP) score, we evaluated whether long-term proinflammatory diets were associated with survival among 1153 patients from 2 of the 5 cohorts. Cox proportional hazards regression was used to estimate hazard ratios for death with adjustment for potential confounders.

Results: Higher prediagnostic levels of C-reactive protein, interleukin-6, and tumor necrosis factor-α receptor 2 were individually associated with reduced survival (Ptrend = .03, .01, and .04, respectively). Compared to patients with a combined inflammatory biomarker score of 0 (all 3 markers levels below medians), those with a score of 3 (all 3 markers levels above medians) had a hazard ratio for death of 1.57 (95% confidence interval = 1.16 to 2.12; Ptrend = .003), corresponding to median overall survival times of 8 versus 5 months. Patients consuming the most proinflammatory diets (EDIP quartile 4) in the prediagnostic period had a hazard ratio for death of 1.34 (95% confidence interval = 1.13 to 1.59; Ptrend = .01), compared to those consuming the least proinflammatory diets (EDIP quartile 1).

Conclusion: Prediagnostic levels of inflammatory biomarkers and long-term proinflammatory diets were inversely associated with pancreatic cancer survival.
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http://dx.doi.org/10.1093/jnci/djab040DOI Listing
March 2021

Long-Term Colorectal Cancer Incidence and Mortality After Colonoscopy Screening According to Individuals' Risk Profiles.

J Natl Cancer Inst 2021 Mar 18. Epub 2021 Mar 18.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: It remains unknown whether the benefit of colonoscopy screening against colorectal cancer (CRC) and the optimal age to start screening differ by CRC risk-profile.

Methods: Among 75,873 women and 42,875 men, we defined a CRC risk score (0-8) based on family history, aspirin, height, body mass index, smoking, physical-activity, alcohol, and diet. We calculated colonoscopy screening-associated hazard ratios (HRs) and absolute risk reductions (ARRs) for CRC incidence and mortality and age-specific CRC cumulative incidence according to risk score. All statistical tests were 2-sided.

Results: During a median of 26 years' follow-up, we documented 2,407 CRC cases and 874 CRC deaths. While the screening-associated hazard ratio did not vary by risk score, the absolute risk reductions in multivariable-adjusted 10-year CRC incidence more than doubled for individuals with score 6-8 (ARR = 0.34%, 95% CI = 0.26% to 0.42%) compared to 0-2 (ARR = 0.15%, 95% CI = 0.12% to 0.18%; Ptrend<0.001). Similar results were found for CRC mortality (ARR = 0.22% [95% CI = 0.21% to 0.24%] vs. 0.08% [95% CI = 0.07% to 0.08%]; Ptrend<0.001). The absolute risk reduction in mortality of distal-colon and rectal cancers was four-fold higher for score 6-8 than 0-2 (distal-colon cancer: ARR = 0.08% [95% CI = 0.07% to 0.08%] vs. 0.02% [95% CI = 0.02% to 0.02%], Ptrend <0.001; rectal cancer: ARR = 0.08% [95% CI = 0.08% to 0.09%] vs. 0.02% [95% CI = 0.02% to 0.03%], Ptrend <0.001). When using age 45 years as the benchmark to start screening, individuals with risk score of 0-2, 3, 4, 5, and 6-8 attained the threshold CRC risk level (10-year cumulative risk of 0.47%) at age 51, 48, 45, 42, and 38 years, respectively.

Conclusions: The absolute benefit of colonoscopy screening is more than twice higher for individuals with the highest than lowest CRC risk profile. Individuals with a high and low risk profile may start screening up to 6-7 years earlier and later, respectively, than the recommended age 45 years.
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http://dx.doi.org/10.1093/jnci/djab041DOI Listing
March 2021

Fruit and Vegetable Intake and Mortality: Results From 2 Prospective Cohort Studies of US Men and Women and a Meta-Analysis of 26 Cohort Studies.

Circulation 2021 Apr 1;143(17):1642-1654. Epub 2021 Mar 1.

Channing Division for Network Medicine (D.D.W., S.N.B., B.A.R., Q.S., E.L.G., E.B.R., J.E.M., W.C.W., M.J.S., F.B.H.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Background: The optimal intake levels of fruit and vegetables for maintaining long-term health are uncertain.

Methods: We followed 66 719 women from the Nurses' Health Study (1984-2014) and 42 016 men from the Health Professionals Follow-up Study (1986-2014) who were free from cardiovascular disease (CVD), cancer, and diabetes at baseline. Diet was assessed using a validated semiquantitative food frequency questionnaire at baseline and updated every 2 to 4 years. We also conducted a dose-response meta-analysis, including results from our 2 cohorts and 24 other prospective cohort studies.

Results: We documented 33 898 deaths during the follow-up. After adjustment for known and suspected confounding variables and risk factors, we observed nonlinear inverse associations of fruit and vegetable intake with total mortality and cause-specific mortality attributable to cancer, CVD, and respiratory disease (all <0.001). Intake of ≈5 servings per day of fruit and vegetables, or 2 servings of fruit and 3 servings of vegetables, was associated with the lowest mortality, and above that level, higher intake was not associated with additional risk reduction. In comparison with the reference level (2 servings/d), daily intake of 5 servings of fruit and vegetables was associated with hazard ratios (95% CI) of 0.87 (0.85-0.90) for total mortality, 0.88 (0.83-0.94) for CVD mortality, 0.90 (0.86-0.95) for cancer mortality, and 0.65 (0.59-0.72) for respiratory disease mortality. The dose-response meta-analysis that included 145 015 deaths accrued in 1 892 885 participants yielded similar results (summary risk ratio of mortality for 5 servings/d=0.87 [95% CI, 0.85-0.88]; <0.001). Higher intakes of most subgroups of fruits and vegetables were associated with lower mortality, with the exception of starchy vegetables such as peas and corn. Intakes of fruit juices and potatoes were not associated with total and cause-specific mortality.

Conclusions: Higher intakes of fruit and vegetables were associated with lower mortality; the risk reduction plateaued at ≈5 servings of fruit and vegetables per day. These findings support current dietary recommendations to increase intake of fruits and vegetables, but not fruit juices and potatoes.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.048996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084888PMC
April 2021

Association of with Specific T-cell Subsets in the Colorectal Carcinoma Microenvironment.

Clin Cancer Res 2021 May 25;27(10):2816-2826. Epub 2021 Feb 25.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Purpose: While evidence indicates that () may promote colorectal carcinogenesis through its suppressive effect on T-cell-mediated antitumor immunity, the specific T-cell subsets involved remain uncertain.

Experimental Design: We measured DNA within tumor tissue by quantitative PCR on 933 cases (including 128 -positive cases) among 4,465 incident colorectal carcinoma cases in two prospective cohorts. Multiplex immunofluorescence combined with digital image analysis and machine learning algorithms for CD3, CD4, CD8, CD45RO (PTPRC isoform), and FOXP3 measured various T-cell subsets. We leveraged data on , microsatellite instability (MSI), tumor whole-exome sequencing, and M1/M2-type tumor-associated macrophages [TAM; by CD68, CD86, IRF5, MAF, and MRC1 (CD206) multimarker assay]. Using the 4,465 cancer cases and inverse probability weighting method to control for selection bias due to tissue availability, multivariable-adjusted logistic regression analysis assessed the association between and T-cell subsets.

Results: The amount of was inversely associated with tumor stromal CD3 lymphocytes [multivariable OR, 0.47; 95% confidence interval (CI), 0.28-0.79, for -high vs. -negative category; = 0.0004] and specifically stromal CD3CD4CD45RO cells (corresponding multivariable OR, 0.52; 95% CI, 0.32-0.85; = 0.003). These relationships did not substantially differ by MSI status, neoantigen load, or exome-wide tumor mutational burden. was not significantly associated with tumor intraepithelial T cells or with M1 or M2 TAMs.

Conclusions: The amount of tissue is associated with lower density of stromal memory helper T cells. Our findings provide evidence for the interactive pathogenic roles of microbiota and specific immune cells.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127352PMC
May 2021