Publications by authors named "Nikhil K Khankari"

24 Publications

  • Page 1 of 1

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

Cancer Epidemiol Biomarkers Prev 2020 Dec 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

Soy Intake and Colorectal Cancer Risk: Results from a Pooled Analysis of Prospective Cohort Studies Conducted in China and Japan.

J Nutr 2020 09;150(9):2442-2450

Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Background: Soy is commonly consumed in east Asian countries and is suggested to reduce colorectal cancer (CRC) risk. However, results from epidemiologic studies are inconsistent, despite the anti-inflammatory and antiproliferative properties of soy isoflavones and soy protein.

Objective: We evaluated the association between soy isoflavones and soy protein and CRC risk using 4 prospective cohort studies from China and Japan.

Methods: Data were pooled from the Shanghai Women's Health Study (SWHS), Shanghai Men's Health Study (SMHS), Japan Public Health Center-based Prospective Study Cohort 1 (JPHC1), and Cohort 2 (JPHC2). Cox proportional hazards models estimated HRs and corresponding 95% CIs for the association of soy protein and isoflavone intake with CRC risk. The study included 205,060 individuals, among whom 2971 were diagnosed with incident CRC over an average follow-up of 12.7 y.

Results: No statistically significant associations with CRC risk were observed for soy protein or isoflavone intake. No association was observed among ever smokers consuming higher isoflavones (HRisoflavones: 0.83; 95% CI: 0.68, 1.00) and soy protein (HRsoy protein: 0.81; 95% CI: 0.39, 1.10). However, risk reductions were observed among premenopausal women with a body mass index [BMI (kg/m2)] <23.0 at baseline for higher isoflavone (HRisoflavones: 0.58, 95% CI: 0.34, 0.98).

Conclusions: No evidence for an overall reduction in CRC risk by increasing soy food intake (i.e., protein or isoflavones) was observed. However, the association between soy and CRC risk may vary by BMI, smoking, and menopausal status among women. Future investigations are needed to further understand the biologic mechanisms observed.
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http://dx.doi.org/10.1093/jn/nxaa194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762761PMC
September 2020

Menopausal hormone therapy use and long-term all-cause and cause-specific mortality in the Long Island Breast Cancer Study Project.

Int J Cancer 2020 12 30;147(12):3404-3415. Epub 2020 Jul 30.

Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.

Previous studies have observed a reduced mortality risk associated with menopausal hormone therapy (MHT) use among breast cancer survivors. We sought to clarify whether such association could be explained by tumor heterogeneity, specific causes of death, confounding from comorbidities or health behaviors, and a comparison group of women without breast cancer. We interviewed 1508 women newly diagnosed with first primary breast cancer in 1996 to 1997 (~3 months after diagnosis), and 1556 age-matched women without breast cancer, about MHT use history. The National Death Index was used to ascertain vital status after a median of 17.6 years of follow-up (N = 597 deaths for breast cancer subjects). Multivariable-adjusted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs) for all-cause mortality, and cause-specific HR (cHR) for breast cancer and cardiovascular disease (CVD). The Fine-Gray model was used to account for competing causes of death. Among women with breast cancer, ever vs never MHT use was inversely associated with all-cause (HR = 0.77, 95%CI = 0.62-0.95), breast cancer-specific (cHR = 0.69, 95%CI = 0.48-0.98), and CVD-specific mortality (cHR = 0.57, 95%CI = 0.38-0.85). Difference of the association was observed in breast cancer-specific mortality according to hormone receptor status (negative tumors: cHR = 0.44, 95%CI = 0.19-1.01; positive tumors: cHR = 0.96, 95%CI = 0.60-1.53). Among the comparison group, we observed similar, but more modest inverse associations for all-cause and CVD-specific mortality. MHT use was inversely associated with mortality after breast cancer, even after accounting for competing causes of death and multiple confounders, and was evident among women without breast cancer. Potential heterogeneity by hormone receptor status requires more study.
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http://dx.doi.org/10.1002/ijc.33174DOI Listing
December 2020

Urinary Estrogen Metabolites and Long-Term Mortality Following Breast Cancer.

JNCI Cancer Spectr 2020 Jun 2;4(3):pkaa014. Epub 2020 Mar 2.

Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.

Background: Estrogen metabolite concentrations of 2-hydroxyestrone (2-OHE) and 16-hydroxyestrone (16-OHE) may be associated with breast carcinogenesis. However, no study has investigated their possible impact on mortality after breast cancer.

Methods: This population-based study was initiated in 1996-1997 with spot urine samples obtained shortly after diagnosis (mean = 96 days) from 683 women newly diagnosed with first primary breast cancer and 434 age-matched women without breast cancer. We measured urinary concentrations of 2-OHE and 16-OHE using an enzyme-linked immunoassay. Vital status was determined via the National Death Index (n = 244 deaths after a median of 17.7 years of follow-up). We used multivariable-adjusted Cox proportional hazards to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the estrogen metabolites-mortality association. We evaluated effect modification using likelihood ratio tests. All statistical tests were two-sided.

Results: Urinary concentrations of the 2-OHE to 16-OHE ratio (>median of 1.8 vs ≤median) were inversely associated with all-cause mortality (HR = 0.74, 95% CI = 0.56 to 0.98) among women with breast cancer. Reduced hazard was also observed for breast cancer mortality (HR = 0.73, 95% CI = 0.45 to 1.17) and cardiovascular diseases mortality (HR = 0.76, 95% CI = 0.47 to 1.23), although the 95% confidence intervals included the null. Similar findings were also observed for women without breast cancer. The association with all-cause mortality was more pronounced among breast cancer participants who began chemotherapy before urine collection (n = 118, HR = 0.42, 95% CI = 0.22 to 0.81) than among those who had not (n = 559, HR = 0.98, 95% CI = 0.72 to 1.34; = .008).

Conclusions: The urinary 2-OHE to 16-OHE ratio may be inversely associated with long-term all-cause mortality, which may depend on cancer treatment status at the time of urine collection.
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http://dx.doi.org/10.1093/jncics/pkaa014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236781PMC
June 2020

Diabetes and cardiovascular disease mortality among a population-based cohort of women with and without breast cancer.

Cancer Causes Control 2020 May 7;31(5):517-524. Epub 2020 Mar 7.

Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.

Purpose: We investigated whether the relationship between diabetes and all-cause and CVD-related mortality differed between women with and without breast cancer among a cohort drawn from the same source population.

Methods: We interviewed 1,363 women newly diagnosed with breast cancer in 1996-1997, and 1,358 age-matched women without breast cancer, to assess history of physician-diagnosed diabetes. All-cause (n = 631) and CVD-specific mortality (n = 234) was determined by the National Death Index through 2009. We estimated multivariable-adjusted hazard ratios (HRs) for the rates of all-cause and CVD-specific mortality and, to account for competing causes of death, and subdistribution HRs (sHRs) for risk of CVD-related death.

Results: Among women with and without breast cancer, respectively, diabetes was associated with: all-cause mortality [HR (95% CI) 1.52 (1.13, 2.05) and 2.17 (1.46, 3.22)]; CVD-specific deaths [1.74 (1.06, 2.84) and 2.06 (1.11, 3.84)]; and risk of CVD-related death [sHR 1.36 (0.81, 2.27) and 1.79 (0.94, 3.40)]. Differences in effect estimates between women with and without breast cancer did not reach statistical significance (p-interaction > 0.10).

Conclusion: We found that the positive association between a history of physician-diagnosed diabetes and risk of all-cause and CVD-related mortality is of similar magnitude among a population-based cohort of women with or without breast cancer.
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http://dx.doi.org/10.1007/s10552-020-01292-2DOI Listing
May 2020

Mendelian Randomization of Circulating Polyunsaturated Fatty Acids and Colorectal Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2020 04 12;29(4):860-870. Epub 2020 Feb 12.

Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.

Background: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk.

Methods: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined.

Results: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [OR = 0.96; 95% confidence interval (CI) = 0.93-0.98; = 5.2 × 10] and α-linolenic acid (OR = 0.95; 95% CI = 0.92-0.97; = 5.4 × 10), whereas modest increased risks were observed for arachidonic (OR = 1.06; 95% CI = 1.03-1.08; = 3.3 × 10), eicosapentaenoic (OR = 1.04; 95% CI = 1.01-1.07; = 2.5 × 10), and docosapentaenoic acids (OR = 1.03; 95% CI = 1.01-1.06; = 1.2 × 10). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses.

Conclusions: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk.

Impact: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125012PMC
April 2020

A Mendelian randomization analysis of circulating lipid traits and breast cancer risk.

Int J Epidemiol 2020 08;49(4):1117-1131

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.

Background: Conventional epidemiologic studies have evaluated associations between circulating lipid levels and breast cancer risk, but results have been inconsistent. As Mendelian randomization analyses may provide evidence for causal inference, we sought to evaluate potentially unbiased associations between breast cancer risk and four genetically predicted lipid traits.

Methods: Previous genome-wide association studies (GWAS) have identified 164 discrete variants associated with high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides and total cholesterol. We used 162 of these unique variants to construct weighted genetic scores (wGSs) for a total of 101 424 breast cancer cases and 80 253 controls of European ancestry from the Breast Cancer Association Consortium (BCAC). Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between per standard deviation increase in genetically predicted lipid traits and breast cancer risk. Additional Mendelian randomization analysis approaches and sensitivity analyses were conducted to assess pleiotropy and instrument validity.

Results: Corresponding to approximately 15 mg/dL, one standard deviation increase in genetically predicted HDL-C was associated with a 12% increased breast cancer risk (OR: 1.12, 95% CI: 1.08-1.16). Findings were consistent after adjustment for breast cancer risk factors and were robust in several sensitivity analyses. Associations with genetically predicted triglycerides and total cholesterol were inconsistent, and no association for genetically predicted LDL-C was observed.

Conclusions: This study provides strong evidence that circulating HDL-C may be associated with an increased risk of breast cancer, whereas LDL-C may not be related to breast cancer risk.
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http://dx.doi.org/10.1093/ije/dyz242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750975PMC
August 2020

Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis.

Int J Epidemiol 2019 06;48(3):795-806

Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.

Background: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear.

Methods: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium.

Results: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p  =  5.09  ×  10-4], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p  =  4.02  ×  10-4), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p  =  5.05  ×  10-19) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p  =  9.22  ×  10-6). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2-h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer.

Conclusions: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.
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http://dx.doi.org/10.1093/ije/dyy201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734940PMC
June 2019

Fish/shellfish intake and the risk of head and neck cancer.

Eur J Cancer Prev 2019 03;28(2):102-108

Departments of Epidemiology.

Fish intake and other dietary sources of omega-3 fatty acids have been shown to be associated with a reduced risk for some cancers. Although previous studies of head and neck cancer have reported associations with different dietary factors, including reduced risks for fruits and vegetables and putatively healthy dietary patterns, associations specific to fish intake are unclear. This study investigated the association between fish/shellfish intake and risk of squamous cell carcinoma of the head and neck (SCCHN) using data from the Carolina Head and Neck Cancer Epidemiology Study, a population-based case-control study conducted in 46 North Carolina counties with cases recruited from 2002 through 2006. Controls were frequency matched to the cases on age, sex, and race; the final sample size was 1039 cases and 1375 controls. Demographic, lifestyle, and dietary information were collected using an in-person interviewer-administered structured questionnaire. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with unconditional logistic regression. Patients whose fish/shellfish intake was among the highest tertile had a 20% lower odds of SCCHN compared with those in the lowest tertile (OR: 0.80; 95% CI: 0.60-1.07) after adjustment for the matching and other factors (income, energy intake, fruit intake, cigarette smoking, and alcohol intake). The inverse association was more pronounced for oral cavity and oropharyngeal tumors, for African Americans, and for females, but CIs were wide. To further investigate this potential risk reduction strategy for SCCHN, future studies should consider examining specific fish/shellfish, cooking practices, and other omega-3 fatty acid sources.
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http://dx.doi.org/10.1097/CEJ.0000000000000431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077110PMC
March 2019

Evaluation of genetic variants in association with colorectal cancer risk and survival in Asians.

Int J Cancer 2017 09 21;141(6):1130-1139. Epub 2017 Jun 21.

Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN.

Genome-wide association studies (GWAS) have identified over 40 genetic loci associated with colorectal cancer (CRC) risk. The association of single nucleotide polymorphisms (SNPs) at these loci with CRC risk and survival has not been adequately evaluated in East Asians. GWAS-identified CRC risk variants were used to construct weighted genetic risk scores (GRSs). We evaluated these GRSs in association with CRC risk in 3,303 CRC cases and 3,553 controls using logistic regression models. Associations with overall and CRC-specific survival were assessed in 731 CRC patients using Cox regression models. The association between the GRSs (overall and Asian-specific) and CRC risk was approximately twofold (highest vs. lowest quintile), and the shape of the dose-response was linear (p  = 1.24 × 10 and 3.02 × 10 for overall GRS and Asian-specific GRS, respectively). The association of the GRS with CRC risk was stronger among those with a family history of CRC (p  = 0.007). Asian-specific GRS using previously reported survival SNPs increased risk for mortality and the shape of the dose-response was linear for CRC-specific and all-cause mortality (p  = 0.01 and 0.006, respectively). Furthermore, the minor alleles of rs6983267 and rs1957636 were associated with worse CRC-specific and overall survival. We show that GRSs constructed using GWAS-identified common variants are strongly associated with CRC risk in Asians. We confirm previous findings for the possible association between some SNPs with survival, and provide evidence for two additional CRC risk variants that may be related to CRC survival.
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http://dx.doi.org/10.1002/ijc.30812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524202PMC
September 2017

Total and Free Circulating Vitamin D and Vitamin D-Binding Protein in Relation to Colorectal Cancer Risk in a Prospective Study of African Americans.

Cancer Epidemiol Biomarkers Prev 2017 08 8;26(8):1242-1247. Epub 2017 May 8.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.

Previous studies rarely evaluated the associations between vitamin D-binding protein and free vitamin D with colorectal cancer risk. We assessed these biomarkers and total 25-hydroxyvitamin D in relation to colorectal cancer risk in a sample of African Americans. Cases comprised 224 African American participants of the Southern Community Cohort Study diagnosed with incident colorectal cancer. Controls ( = 440) were selected through incidence density sampling and matched to cases on age, sex, and race. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for associations between biomarker levels and colorectal cancer risk. Vitamin D was inversely associated with colorectal cancer risk where the OR per-SD increase in total and free 25-hydroxyvitamin D were 0.82 (95% CI, 0.66-1.02) and 0.82 (95% CI, 0.66-1.01), respectively. Associations were most apparent among cases diagnosed >3 years after blood draw: ORs for the highest tertile versus the lowest were 0.69 (95% CI, 0.21-0.93) for total 25-hydroxyvitamin D and 0.71 (95% CI, 0.53-0.97) for free 25-hydroxyvitamin D. Inverse associations were seen in strata defined by sex, BMI, and anatomic site, although not all findings were statistically significant. Vitamin D-binding protein was not associated with colorectal cancer risk. Our findings suggest that total and free 25-hydroxyvitamin D may be inversely associated with colorectal cancer risk among African Americans. These findings highlight a potential role for vitamin D in colorectal cancer prevention in African Americans. .
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http://dx.doi.org/10.1158/1055-9965.EPI-17-0133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540758PMC
August 2017

Modification of the association between recreational physical activity and survival after breast cancer by promoter methylation in breast cancer-related genes.

Breast Cancer Res 2017 02 21;19(1):19. Epub 2017 Feb 21.

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

Background: Mechanisms underlying the inverse association between physical activity and survival after breast cancer are unresolved, but DNA methylation may play a role. We hypothesized that promoter methylation of breast cancer-related genes, as well as global methylation, may modify the association between prediagnostic recreational physical activity (RPA) and breast cancer mortality.

Methods: Using a population-based sample of 1254 women diagnosed with first primary breast cancer, we examined modification of the RPA-mortality association by gene-specific promoter methylation and global methylation. Average lifetime RPA was assessed from menarche to diagnosis through structured in-home interviews. Promoter methylation of 13 breast cancer-related genes was evaluated in archived tumor by methylation-specific polymerase chain reaction and MethyLight assay. Global methylation in white blood cell DNA was determined at long interspersed nucleotide element 1 and by the luminometric methylation assay. After approximately 15 years of follow-up, 486 patients had died, and 186 of the deaths were breast cancer-related. We used Cox proportional hazards regression to estimate HRs and 95% CIs as well as likelihood ratio tests to assess multiplicative interactions.

Results: All-cause mortality was lower only among physically active women with methylated promoter of APC (HR 0.60, 95% CI 0.40-0.80), CCND2 (HR 0.56, 95% CI 0.32-0.99), HIN (HR 0.55, 95% CI 0.38-0.80), and TWIST1 (HR 0.28, 95% CI 0.14-0.56) in tumors, but not among those with unmethylated tumors (significant interaction p < 0.05). We found no interaction between RPA and global methylation.

Conclusions: The improved survival after breast cancer that is associated with RPA may be more pronounced in women with promoter tumor methylation in biologically plausible genes.
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http://dx.doi.org/10.1186/s13058-017-0811-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319077PMC
February 2017

Prediagnosis body mass index and waist-hip circumference ratio in association with colorectal cancer survival.

Int J Cancer 2017 Jan 24;140(2):292-301. Epub 2016 Oct 24.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN.

The association of obesity on survival among patients with colorectal cancer (CRC) has not been well characterized. We investigated the association of prediagnostic body mass index (BMI)/waist-hip ratio (WHR) and total/cause-specific mortality in CRC patients. Our study included 1,452 patients who participated in two large cohort studies and were diagnosed with CRC during follow-up period. Participants were measured for anthropometrics and interviewed to collect relevant information at baseline, prior to any cancer diagnosis. Data on site-specific cancer incidence and cause-specific mortality were obtained via in-person surveys and annual record linkage with cancer and vital statistics registries. Cox proportional hazard models were used to evaluate the associations of BMI and WHR with survival. A total of 547 participants died during the follow-up period, including 499 who died of CRC. Relative to normal BMI (18.5 to <25.0 kg/m ), obesity (BMI ≥ 30 kg/m ) was associated with increased mortality resulting from all causes [hazard ratio (HR) = 1.5, 95% confidence interval (CI): 1.1-2.1] and CRC (HR = 1.5, 95% CI: 1.1-2.1). Elevated risk of death was also found among underweight patients (BMI < 18.5 kg/m ), although not all risk estimates were statistically significant. Overweight BMI (25.0 to <30.0 kg/m ) was not associated with risk of death among CRC patients, nor was WHR. In conclusion, prediagnostic BMI was associated with survival among CRC patients following a U-shape pattern; obesity was associated with high mortality after CRC diagnosis. These findings provide support for maintaining healthy weight to improve the survival of CRC patients.
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http://dx.doi.org/10.1002/ijc.30459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531439PMC
January 2017

Association between Adult Height and Risk of Colorectal, Lung, and Prostate Cancer: Results from Meta-analyses of Prospective Studies and Mendelian Randomization Analyses.

PLoS Med 2016 Sep 6;13(9):e1002118. Epub 2016 Sep 6.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.

Background: Observational studies examining associations between adult height and risk of colorectal, prostate, and lung cancers have generated mixed results. We conducted meta-analyses using data from prospective cohort studies and further carried out Mendelian randomization analyses, using height-associated genetic variants identified in a genome-wide association study (GWAS), to evaluate the association of adult height with these cancers.

Methods And Findings: A systematic review of prospective studies was conducted using the PubMed, Embase, and Web of Science databases. Using meta-analyses, results obtained from 62 studies were summarized for the association of a 10-cm increase in height with cancer risk. Mendelian randomization analyses were conducted using summary statistics obtained for 423 genetic variants identified from a recent GWAS of adult height and from a cancer genetics consortium study of multiple cancers that included 47,800 cases and 81,353 controls. For a 10-cm increase in height, the summary relative risks derived from the meta-analyses of prospective studies were 1.12 (95% CI 1.10, 1.15), 1.07 (95% CI 1.05, 1.10), and 1.06 (95% CI 1.02, 1.11) for colorectal, prostate, and lung cancers, respectively. Mendelian randomization analyses showed increased risks of colorectal (odds ratio [OR] = 1.58, 95% CI 1.14, 2.18) and lung cancer (OR = 1.10, 95% CI 1.00, 1.22) associated with each 10-cm increase in genetically predicted height. No association was observed for prostate cancer (OR = 1.03, 95% CI 0.92, 1.15). Our meta-analysis was limited to published studies. The sample size for the Mendelian randomization analysis of colorectal cancer was relatively small, thus affecting the precision of the point estimate.

Conclusions: Our study provides evidence for a potential causal association of adult height with the risk of colorectal and lung cancers and suggests that certain genetic factors and biological pathways affecting adult height may also affect the risk of these cancers.
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http://dx.doi.org/10.1371/journal.pmed.1002118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012582PMC
September 2016

Polyunsaturated fatty acids and prostate cancer risk: a Mendelian randomisation analysis from the PRACTICAL consortium.

Br J Cancer 2016 08 4;115(5):624-31. Epub 2016 Aug 4.

Department of Medical Chemistry and Biochemistry, Molecular Medicine Center, Medical University-Sofia, 2 Zdrave Street, 1431 Sofia, Bulgaria.

Background: Prostate cancer is a common cancer worldwide with no established modifiable lifestyle factors to guide prevention. The associations between polyunsaturated fatty acids (PUFAs) and prostate cancer risk have been inconsistent. Using Mendelian randomisation, we evaluated associations between PUFAs and prostate cancer risk.

Methods: We used individual-level data from a consortium of 22 721 cases and 23 034 controls of European ancestry. Externally-weighted PUFA-specific polygenic risk scores (wPRSs), with explanatory variation ranging from 0.65 to 33.07%, were constructed and used to evaluate associations with prostate cancer risk per one standard deviation (s.d.) increase in genetically-predicted plasma PUFA levels using multivariable-adjusted unconditional logistic regression.

Results: No overall association was observed between the genetically-predicted PUFAs evaluated in this study and prostate cancer risk. However, risk reductions were observed for short-chain PUFAs, linoleic (ORLA=0.95, 95%CI=0.92, 0.98) and α-linolenic acids (ORALA=0.96, 95%CI=0.93, 0.98), among men <62 years; whereas increased risk was found among men ⩾62 years for LA (ORLA=1.04, 95%CI=1.01, 1.07). For long-chain PUFAs (i.e., arachidonic, eicosapentaenoic, and docosapentaenoic acids), increased risks were observed among men <62 years (ORAA=1.05, 95%CI=1.02, 1.08; OREPA=1.04, 95%CI=1.01, 1.06; ORDPA=1.05, 95%CI=1.02, 1.08).

Conclusion: Results from this study suggest that circulating ω-3 and ω-6 PUFAs may have a different role in the aetiology of early- and late-onset prostate cancer.
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http://dx.doi.org/10.1038/bjc.2016.228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997551PMC
August 2016

DNA methylation modifies the association between obesity and survival after breast cancer diagnosis.

Breast Cancer Res Treat 2016 Feb 5;156(1):183-94. Epub 2016 Mar 5.

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

Mechanisms underlying the poor breast cancer prognosis among obese women are unresolved. DNA methylation levels are linked to obesity and to breast cancer survival. We hypothesized that obesity may work in conjunction with the epigenome to alter prognosis. Using a population-based sample of women diagnosed with first primary breast cancer, we examined modification of the obesity-mortality association by DNA methylation. In-person interviews were conducted approximately 3 months after diagnosis. Weight and height were assessed [to estimate body mass index (BMI)], and blood samples collected. Promoter methylation of 13 breast cancer-related genes was assessed in archived tumor by methylation-specific PCR and Methyl Light. Global methylation in white blood cell DNA was assessed by analysis of long interspersed elements-1 (LINE-1) and with the luminometric methylation assay (LUMA). Vital status among 1308 patients (with any methylation biomarker and complete BMI assessment) was determined after approximately 15 years of follow-up (N = 194/441 deaths due to breast cancer-specific/all-cause mortality). We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) using two-sided p values of 0.05. Breast cancer-specific mortality was higher among obese (BMI ≥ 30) patients with promoter methylation in APC (HR = 2.47; 95 % CI = 1.43-4.27) and TWIST1 (HR = 4.25; 95 % CI = 1.43-12.70) in breast cancer tissue. Estimates were similar, but less pronounced, for all-cause mortality. Increased all-cause (HR = 1.81; 95 % CI = 1.19-2.74) and breast cancer-specific (HR = 2.61; 95 % CI = 1.45-4.69) mortality was observed among obese patients with the lowest LUMA levels. The poor breast cancer prognosis associated with obesity may depend on methylation profiles, which warrants further investigation.
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http://dx.doi.org/10.1007/s10549-016-3724-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4890602PMC
February 2016

Polychlorinated biphenyls and their association with survival following breast cancer.

Eur J Cancer 2016 Mar 19;56:21-30. Epub 2016 Jan 19.

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Background: Polychlorinated biphenyls (PCBs) are hypothesised to influence breast carcinogenesis due to their persistence and potential to induce oestrogenic and anti-oestrogenic effects. Whether PCBs influence survival following breast cancer is unknown.

Methods: A population-based cohort of women diagnosed with first primary invasive or in situ breast cancer in 1996-1997 and with blood-measured PCBs (n=627) collected shortly after diagnosis was followed for vital status through 2011. After 5 and 15 years, we identified 54 and 187 deaths, respectively, of which 36 and 74 were breast cancer related. Using Cox regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality for baseline PCB concentrations, individually and as oestrogenic (ΣGroup 1B: PCB101, PCB174, PCB177, PCB187, and PCB199), anti-oestrogenic (ΣGroup 2A: PCB66, PCB74, PCB105, and PCB118; ΣGroup 2B: PCB138 and PCB170), and cytochrome P450 enzyme-inducing (ΣGroup 3: PCB99, PCB153, PCB180, PCB183, and PCB203) groups.

Results: The highest PCB174 tertile was associated with an increase in all-cause (HR=2.22, 95% CI: 1.14-4.30) and breast cancer-specific (HR=3.15, 95% CI: 1.23-8.09) mortalities within 5 years of diagnosis and remained associated with breast cancer-specific mortality (HR=1.88, 95% CI: 1.05-3.36) at 15 years. At 5 years, the highest tertile of PCB177 was positively associated with all-cause mortality (HR=2.12, 95% CI: 1.05-4.30). At 15 years, the highest tertiles of ΣGroup 2A congeners and PCB118 were inversely associated with all-cause mortality (HR=0.60, 95% CI: 0.39-0.83; HR=0.63, 95% CI: 0.43-0.92, respectively).

Conclusions: In this first US study of PCBs and breast cancer survival, PCBs were associated with mortality in biologically plausible directions. The investigation of other, structurally similar, chemicals may be warranted.
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http://dx.doi.org/10.1016/j.ejca.2015.11.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769903PMC
March 2016

Interaction between polyunsaturated fatty acids and genetic variants in relation to breast cancer incidence.

J Cancer Epidemiol Prev (iMedPub) 2016 30;1(1). Epub 2016 Dec 30.

Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27599, USA.

Higher intake of ω-3 relative to ω-6 polyunsaturated fatty acids (PUFAs) may reduce breast carcinogenesis via different metabolic pathways. The PUFA-breast cancer association remains inconclusive, thus, we hypothesized that interactions between the ratio of dietary ω-3:ω-6 intake and polymorphisms from PUFA-related metabolic pathways would help elucidate an association. Utilizing resources from the Long Island Breast Cancer Study Project, a population-based case-control study (n=1035 cases/1075 controls), we examined interactions between ω-3:ω-6 ratio and 18 polymorphisms of 15 genes. Compared to the putative lowest risk group (high ω-3:ω-6,low-risk rs763110 CT/TT genotype), the odds ratio (OR) for breast cancer from unconditional logistic regression models was weakly increased for other exposure-genotype combinations (high ω-3:ω-6,high-risk CC genotype, OR=1.18,95% confidence interval(CI)=0.90,1.53; low ω-3:ω-6,CT/TT genotype, OR=1.35,95%CI=1.09,1.66); but was approximately null for the putative highest risk group (low ω-3:ω-6,CC genotype; OR=1.06,95%CI=0.81,1.38). We observed an interaction between the ω-3:ω-6 ratio and rs763110 on the additive scale [Relative Excess Risk Due to Interaction(RERI)=-0.47, 95%CI=-0.92,-0.02]. Interactions with other polymorphisms considered were not evident. Our findings suggest that the PUFA-breast cancer association may be modified by . However, additional research is needed given this interaction may be due to chance and is inconsistent with our biologic hypothesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621474PMC
December 2016

Polyunsaturated fatty acid interactions and breast cancer incidence: a population-based case-control study on Long Island, New York.

Ann Epidemiol 2015 Dec 14;25(12):929-35. Epub 2015 Sep 14.

Department of Epidemiology, University of North Carolina, Chapel Hill.

Purpose: Experimental studies demonstrate that ω-3 polyunsaturated fatty acids (PUFAs) inhibit inflammatory eicosanoids generated by ω-6 PUFAs. Epidemiologic studies on dietary ω-3 PUFA intake show consistent inverse associations with breast cancer incidence among Asian populations, where ω-3, relative to ω-6, intake is high. In contrast, associations are inconsistent among Western populations, where intake of ω-3, relative to ω-6, is low. We hypothesized that examining interactions between ω-3 and ω-6 would help elucidate the PUFA-breast cancer association in the United States.

Methods: In a Long Island, New York, population-based study of 1463 breast cancer cases and 1500 controls, we estimated multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression to examine interactions between ω-3 and ω-6 intake.

Results: We observed a super-additive interaction (relative excess risk due to interaction = 0.41; 95% confidence interval = 0.06-0.76) between ω-3 and ω-6 intake in association with breast cancer incidence, although the CIs for the joint exposure of low ω-3/high ω-6 compared to high ω-3/low ω-6 intake were wide (odds ratio = 1.20; 95% confidence interval = 0.85-1.69).

Conclusions: Breast cancer risk reduction may be possible for U.S. women with dietary consumption of higher ω-3, which has anti-inflammatory properties, in concert with lower ω-6, which induces inflammation. Replication from future U.S.-based investigations is needed.
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http://dx.doi.org/10.1016/j.annepidem.2015.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688221PMC
December 2015

Organochlorine insecticides DDT and chlordane in relation to survival following breast cancer.

Int J Cancer 2016 Feb 27;138(3):565-75. Epub 2015 Aug 27.

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Organochlorine insecticides have been studied extensively in relation to breast cancer incidence, and results from two meta-analyses have been null for late-life residues, possibly due to measurement error. Whether these compounds influence survival remains to be fully explored. We examined associations between organochlorine insecticides [p,p'-DDT (dichlorodiphenyltrichloroethane), its primary metabolite, p,p'-DDE, and chlordane] assessed shortly after diagnosis and survival among women with breast cancer. A population-based sample of women diagnosed with a first primary invasive or in situ breast cancer in 1996-1997 and with available organochlorine blood measures (n = 633) were followed for vital status through 2011. After follow-up of 5 and 15 years, we identified 55 and 189 deaths, of which 36 and 74, respectively, were breast cancer-related. Using Cox regression models, we estimated the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for lipid-adjusted organochlorine concentrations with all-cause and breast cancer-specific mortality. At 5 years after diagnosis, the highest tertile of DDT concentration was associated with all-cause (HR = 2.19; 95% CI: 1.02, 4.67) and breast cancer-specific (HR = 2.72; 95% CI: 1.04, 7.13) mortality. At 15 years, middle tertile concentrations of DDT (HR = 1.42; 95% CI 0.99, 2.06) and chlordane (HR = 1.42; 95% CI: 0.94, 2.12) were modestly associated with all-cause and breast cancer-specific mortality. Third tertile DDE concentrations were inversely associated with 15-year all-cause mortality (HR = 0.66; 95% CI: 0.44, 0.99). This is the first population-based study in the United States to show that DDT may adversely impact survival following breast cancer diagnosis. Further studies are warranted given the high breast cancer burden and the ubiquity of these chemicals.
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http://dx.doi.org/10.1002/ijc.29806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715584PMC
February 2016

Dietary intake of fish, polyunsaturated fatty acids, and survival after breast cancer: A population-based follow-up study on Long Island, New York.

Cancer 2015 Jul 24;121(13):2244-52. Epub 2015 Mar 24.

Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina.

Background: In laboratory experiments, ω-3 polyunsaturated fatty acids (PUFAs) have been found to reduce inflammatory eicosanoids resulting from ω-6 PUFA metabolism via competitive inhibition, and the ω-3-induced cytotoxic environment increases apoptosis and reduces cell growth in breast cancer cells. To the authors' knowledge, epidemiologic investigations regarding whether dietary ω-3 PUFA intake benefits survival after breast cancer are limited and inconsistent.

Methods: The authors used resources from a population-based follow-up study conducted on Long Island, New York, among 1463 women newly diagnosed with first primary breast cancer who were interviewed an average of approximately 3 months after diagnosis to assess risk and prognostic factors, including dietary intake (using a food frequency questionnaire). Vital status was determined through 2011, yielding a median follow-up of 14.7 years and 485 deaths. Adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards regression.

Results: All-cause mortality was reduced among women with breast cancer reporting the highest quartile of intake (compared with never) for tuna (HR, 0.71; 95% CI, 0.55-0.92), other baked/broiled fish (HR, 0.75; 95% CI, 0.58-0.97), and the dietary long-chain ω-3 PUFAs docosahexaenoic acid (HR, 0.71; 95% CI, 0.55-0.92) and eicosapentaenoic acid (HR, 0.75; 95% CI, 0.58-0.97).

Conclusions: All-cause mortality was reduced by 16% to 34% among women with breast cancer who reported a high intake of fish and long-chain ω-3 PUFAs. Long-chain ω-3 PUFA intake from fish and other dietary sources may provide a potential strategy to improve survival after breast cancer.
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http://dx.doi.org/10.1002/cncr.29329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581907PMC
July 2015

Genetic variation in multiple biologic pathways, flavonoid intake, and breast cancer.

Cancer Causes Control 2014 Feb 27;25(2):215-26. Epub 2013 Nov 27.

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA,

Purpose: We previously reported an inverse association between flavonoid intake and breast cancer incidence, which has been confirmed by others, but no studies have considered simultaneously potential interactions of flavonoids with multiple genetic polymorphisms involved in biologically relevant pathways (oxidative stress, carcinogen metabolism, DNA repair, and one-carbon metabolism).

Methods: To estimate interaction effects between flavonoids and 13 polymorphisms in these four pathways on breast cancer risk, we used population-based data (n = 875 cases and 903 controls) and several statistical approaches, including conventional logistic regression and semi-Bayesian hierarchical modeling (incorporating prior information on the possible biologic functions of genes), which also provides biologic pathway-specific effect estimates.

Results: Compared to the standard multivariate model, the results from the hierarchical model indicate that gene-by-flavonoid interaction estimates are attenuated, but more precise. In the hierarchical model, the average effect of the deleterious versus beneficial gene, controlling for average flavonoid intake in the DNA repair pathway, and adjusted for the three other biologically relevant pathways (oxidative stress, carcinogen metabolism, and one-carbon metabolism), resulted in a 27 % increase risk for breast cancer [odds ratio = 1.27; 95 % confidence interval (CI) = 0.70, 2.29]. However, the CI was wide.

Conclusions: Based on results from the semi-Bayesian model, breast cancer risk may be influenced jointly by flavonoid intake and genes involved in DNA repair, but our findings require confirmation.
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http://dx.doi.org/10.1007/s10552-013-0324-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932534PMC
February 2014

Nutrient pathways and breast cancer risk: the Long Island Breast Cancer Study Project.

Nutr Cancer 2013 ;65(3):345-54

Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

The relative importance of biochemical pathways has not been previously examined when considering the influence of diet on breast cancer risk. To address this issue, we used interview data from a population-based sample of 1463 breast cancer cases and 1500 controls. Dietary intake was assessed shortly after diagnosis using a 101-item food frequency questionnaire. Age- and energy-adjusted odds ratios (ORs) for individual micro- and macronutrients were estimated with logistic regression. Hierarchical modeling was used to account for biologically plausible nutrient pathways (1-carbon metabolism, oxidative stress, glycemic control, and phytoestrogens). Effect estimates from hierarchical modeling were more precise and plausible compared to those from multivariable models. The strongest relationship observed was for the glycemic control pathway, but confidence intervals (CI) were wide [OR (95% CI): 0.86 (0.62, 1.21)]. Little or no effect was observed for the 1-carbon metabolism, oxidative stress, and phytoestrogen pathways. Associations were similar when stratified by supplement use. Our approach that emphasizes biochemical pathways, rather than individual nutrients, revealed that breast cancer risk may be more strongly associated with glycemic control factors than those from other pathways considered. Our study emphasizes the importance of accounting for multiple nutrient pathways when examining associations between dietary intake and breast cancer.
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http://dx.doi.org/10.1080/01635581.2013.767364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875325PMC
September 2013