Publications by authors named "Kala Visvanathan"

212 Publications

Association between pre-diagnostic circulating adipokines and colorectal cancer and adenoma in the CLUE II cohort.

Cancer Causes Control 2021 May 17. Epub 2021 May 17.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Rm. E6133, Baltimore, MD, 21205, USA.

Objective: Obesity is a known risk factor for colorectal cancer (CRC) and adenoma. Obese individuals have higher circulating concentrations of certain endocrine and immune factors produced by adipocytes thought to partially underlie the association between obesity and colorectal neoplasia. Thus, we evaluated the association of plasma concentrations of adiponectin, leptin, and soluble tumor necrosis factor receptor-2 (sTNFR2) with CRC and adenoma.

Methods: We ascertained 193 CRC cases and 193 matched controls, and 131 colorectal adenoma cases and 131 matched controls who had had an endoscopy nested in the CLUE II cohort of Washington County, MD. Plasma markers were measured using ELISA. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from conditional logistic regression for quartiles of the plasma markers separately for CRC and adenoma.

Results: Adjusting for leptin and adiponectin, sTNFR2 was positively associated with CRC only in men (Q4 vs. Q1: OR = 3.14, 95% CI 1.11-8.86), which was unchanged adjusting for BMI (3.46, 95% CI 1.19-10.06). Leptin and adiponectin were not associated with CRC risk overall or in men or women. Adiponectin, leptin, and sTNFR2 were not associated with adenoma risk overall or in men or women.

Conclusion: In this study, leptin and adiponectin were not associated with colorectal carcinogenesis and thus do not appear to underlie the association between obesity and colorectal carcinogenesis. sTNFR2, which we measured as a correlate of TNF-α, was positively associated with CRC in men adjusting for BMI, suggesting that TNF-α may influence colorectal carcinogenesis independent of adipocyte production.
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http://dx.doi.org/10.1007/s10552-021-01441-1DOI Listing
May 2021

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

Am J Clin Nutr 2021 May 8. Epub 2021 May 8.

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

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

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

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

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

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

Antihypertensive Drug Use and the Risk of Ovarian Cancer Death among Finnish Ovarian Cancer Patients-A Nationwide Cohort Study.

Cancers (Basel) 2021 Apr 26;13(9). Epub 2021 Apr 26.

Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland.

Ovarian cancer (OC) has a poor prognosis. Hypertension may be a prognostic factor for OC, but it is unclear whether antihypertensive (anti-HT) drug use of modifies OC prognosis. We performed a population-based analysis assessing the effect of anti-HT drug use on OC mortality. A cohort of 12,122 women identified from the Finnish Cancer Registry with OC in 1995-2013 was combined with information on their anti-HT drug use during the same time period. Use of each anti-HT drug was analysed as a time-dependent variable. Analyses were run for five, ten and full follow-up (19-year) mortality with cardiovascular morbidity risk evaluated in competing risk analysis. No anti-HT drug group was associated with OC survival within five years after OC diagnosis. At ten years, a dose-dependent association was observed between pre-diagnostic ACE-inhibitor use and improved OC survival. With full follow-up, post-diagnostic high-intensity use associated with reduced OC death risk for multiple anti-HT drug groups. In competing risk analysis, only the post-diagnostic use of ACE-inhibitors associated with increased OC survival. Anti-HT drugs were not associated with survival benefits within five years after OC diagnosis. ACE-inhibitors may confer survival benefits in women with OC, but further confirmatory studies are needed.
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http://dx.doi.org/10.3390/cancers13092087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123393PMC
April 2021

Association of Oophorectomy and Fat and Lean Body Mass: Evidence from a Population-Based Sample of U.S. Women.

Cancer Epidemiol Biomarkers Prev 2021 Apr 20. Epub 2021 Apr 20.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Background: Bilateral oophorectomy during a nonmalignant hysterectomy is frequently performed for ovarian cancer prevention in premenopausal women. Oophorectomy before menopause leads to an abrupt decline in ovarian hormones that could adversely affect body composition. We examined the relationship between oophorectomy and whole-body composition.

Methods: Our study population included cancer-free women 35 to 70 years old from the 1999-2006 National Health and Nutrition Examination Survey, a representative sample of the U.S.

Population: A total of 4,209 women with dual-energy x-ray absorptiometry scans were identified, including 445 with hysterectomy, 552 with hysterectomy and oophorectomy, and 3,212 with no surgery. Linear regression was used to estimate the difference in total and regional (trunk, arms, and legs) fat and lean body mass by surgery status.

Results: In multivariable models, hysterectomy with and without oophorectomy was associated with higher total fat mass [mean percent difference (β); β: 1.61%; 95% confidence interval (CI), 1.00-2.28; β: 0.88%; 95% CI, 0.12-1.58] and lower total lean mass [β: -1.48%; 95% CI, -2.67, -1.15; β: -0.87%; 95% CI, -1.50, -0.24) compared with no surgery. Results were stronger in women with a normal body mass index (BMI) and those <45 years at surgery. All body regions were significantly affected for women with oophorectomy, whereas only the trunk was affected for women with hysterectomy alone.

Conclusions: Hysterectomy with oophorectomy, particularly in young women, may be associated with systemic changes in fat and lean body mass irrespective of BMI.

Impact: Our results support prospective evaluation of body composition in women undergoing hysterectomy with oophorectomy at a young age.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1849DOI Listing
April 2021

Comorbidities and the risk of cardiovascular disease mortality among racially diverse patients with breast cancer.

Cancer 2021 Apr 1. Epub 2021 Apr 1.

Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Background: Women who have coexisting comorbidities at the time of breast cancer diagnosis have an increased risk of breast cancer and overall mortality. However, the associations between newly diagnosed comorbidities and the risk of cardiovascular disease (CVD) mortality among these patients have not been examined.

Methods: The authors compared the associations between coexisting and newly diagnosed CVD, type 2 diabetes, and hypertension and the risk of CVD mortality among patients with breast cancer identified in the Missouri Cancer Registry. In total, 33,099 women who had incident invasive breast cancer with inpatient and outpatient hospital discharge data within 2 years after breast cancer diagnosis were included: 9.3% were Black. Subdistribution hazard ratios (sdHRs) and 95% CIs were calculated for the risk of CVD-related mortality using adjusted Cox proportional hazards regression models, accounting for a competing risk of breast cancer deaths.

Results: Within the first 2 years after breast cancer, the most reported newly diagnosed comorbidity was hypertension (9%), followed by CVD (4%), and type 2 diabetes (2%). CVD mortality was increased in women who had newly diagnosed CVD (sdHR, 2.49; 95% CI, 2.09-2.99), diabetes (sdHR, 2.16; 95% CI, 1.68-2.77), or hypertension (sdHR, 2.06; 95% CI, 1.71-2.48) compared with women who did not have these conditions. Associations were similar by race. The strongest association was among women who received chemotherapy and then developed CVD (sdHR, 3.82; 95% CI, 2.69-5.43).

Conclusions: Monitoring for diabetes, hypertension, and CVD from the time of breast diagnosis may reduce CVD mortality.
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http://dx.doi.org/10.1002/cncr.33530DOI Listing
April 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 Antibody Responses to Proteins Are Not Associated with Risk of Colorectal Cancer in a Large U.S. Consortium.

Cancer Epidemiol Biomarkers Prev 2021 Jun 18;30(6):1279-1282. Epub 2021 Mar 18.

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

Background: The association between prediagnostic antibody responses to () and subsequent risk of colorectal cancer is not established.

Methods: We conducted a nested case-control study of 8,126 participants in a consortium of 10 prospective cohorts in the United States.

Results: Higher seroprevalence of any antibody was observed among non-White participants (51.1%) compared with White participants (31.2%). We did not find any statistically significant association between seropositivity to any of the eight proteins and colorectal cancer risk.

Conclusions: Prediagnostic antibody responses to proteins were not associated with the risk of colorectal cancer.

Impact: Future studies may consider a more specific detection of the immunoglobulin isotypes or focus on examining in stool or tissue samples.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172443PMC
June 2021

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

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

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

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

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

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

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

Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3.

Cancer Res 2021 Jun 11;81(11):3134-3143. Epub 2021 Feb 11.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and < 5 × 10 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, = 3.08 × 10). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 ( = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178175PMC
June 2021

Fitness and prostate cancer screening, incidence, and mortality: Results from the Henry Ford Exercise Testing (FIT) Project.

Cancer 2021 Jun 9;127(11):1864-1870. Epub 2021 Feb 9.

Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background: The relation between cardiorespiratory fitness (CRF) and prostate cancer is not well established. The objective of this study was to determine whether CRF is associated with prostate cancer screening, incidence, or mortality.

Methods: The Henry Ford Exercise Testing Project is a retrospective cohort study of men aged 40 to 70 years without cancer who underwent physician-referred exercise stress testing from 1995 to 2009. CRF was quantified in metabolic equivalents of task (METs) (<6 [reference], 6-9, 10-11, and ≥12 METs), estimated from the peak workload achieved during a symptom-limited, maximal exercise stress test. Prostate-specific antigen (PSA) testing, incident prostate cancer, and all-cause mortality were analyzed with multivariable adjusted Poisson regression and Cox proportional hazard models.

Results: In total, 22,827 men were included, of whom 739 developed prostate cancer, with a median follow-up of 7.5 years. Men who had high fitness (≥12 METs) had an 28% higher risk of PSA screening (95% CI, 1.2-1.3) compared with those who had low fitness (<6 METs. After adjusting for PSA screening, fitness was associated with higher prostate cancer incidence (men aged <55 years, P = .02; men aged >55 years, P ≤ .01), but not with advanced prostate cancer. Among the men who were diagnosed with prostate cancer, high fitness was associated with a 60% lower risk of all-cause mortality (95% CI, 0.2-0.9).

Conclusions: Although men with high fitness are more likely to undergo PSA screening, this does not fully account for the increased incidence of prostate cancer seen among these individuals. However, men with high fitness have a lower risk of death after a prostate cancer diagnosis, suggesting that the cancers identified may be low-risk with little impact on long-term outcomes.
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http://dx.doi.org/10.1002/cncr.33426DOI Listing
June 2021

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.

Genome Med 2021 Feb 1;13(1):15. Epub 2021 Feb 1.

CIBERONC, Madrid, Spain.

Background: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance.

Methods: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants.

Results: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E-06 in 1D approach and a Local Moran's Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8-a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6.91E-05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1-a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support.

Conclusions: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.
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http://dx.doi.org/10.1186/s13073-020-00816-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849104PMC
February 2021

Secular Trends in Breast Cancer Risk Among Women With HIV Initiating ART in North America.

J Acquir Immune Defic Syndr 2021 May;87(1):663-670

Department of Epidemiology, Johns Hopkins University, Baltimore, MD.

Background: Studies suggest lower risk of breast cancer in women with HIV versus without HIV. These estimates may be biased by lower life expectancy and younger age distribution of women with HIV. Our analysis evaluated this bias and characterized secular trends in breast cancer among women with HIV initiating antiretroviral therapy. We hypothesized breast cancer risk would increase over time as mortality decreased.

Setting: Women with HIV prescribed antiretroviral therapy in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) from 1997 through 2016.

Methods: We estimated breast cancer hazard (cause-specific hazard ratios) and cumulative incidence accounting for competing risks (subdistribution hazard ratios) to assess changes in breast cancer risk over time. This was assessed overall (1997-2016) and within/across calendar periods. Analyses were adjusted for race/ethnicity and inverse probability weighted for cohort. Cumulative incidence was graphically assessed by calendar period and race/ethnicity.

Results: We observed 11,587 women during 1997-2016, contributing 63 incident breast cancer diagnoses and 1,353 deaths [73,445 person-years (median follow-up = 4.5 years)]. Breast cancer cumulative incidence was 3.2% for 1997-2016. We observed no secular trends in breast cancer hazard or cumulative incidence. There were annual declines in the hazard and cumulative incidence of death (cause-specific hazard ratios and subdistribution hazard ratios: 0.89, 95% confidence interval: 0.87 to 0.91) which remained within and across calendar periods.

Conclusions: These findings contradict the hypothesis of increasing breast cancer risk with declining mortality over time among women with HIV, suggesting limited impact of changing mortality on breast cancer risk. Additional inquiry is merited as survival improves among women with HIV.
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http://dx.doi.org/10.1097/QAI.0000000000002627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026587PMC
May 2021

Screening and Preventative Strategies for Patients at High Risk for Breast Cancer.

JCO Oncol Pract 2021 Apr 11;17(4):e575-e581. Epub 2021 Jan 11.

Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

Purpose: Current US guidelines recommend more intensive breast cancer screening and preventive strategies for patients at more than 20% lifetime risk for breast and ovarian cancer (high risk for breast and ovarian cancer [HRBOC]). Guidelines recommend that yearly mammograms alternating with magnetic resonance imaging (MRI) screening should be considered as early as 30 years old. Furthermore, mutation carriers should consider bilateral mastectomy and bilateral oophorectomy after age 35. It was unclear what the uptake of screening and risk-reducing strategies were for patients who were cancer-free and cancer survivors seen by Kaiser Permanente Mid-Atlantic States (KPMAS) Genetics.

Methods: We retrospectively studied female patients (members of KPMAS between 2005 and 2016) diagnosed as HRBOC and/or tested for breast cancer-related mutations by KPMAS Genetics during 2013-2016. We identified cancer diagnoses, mammogram and breast MRI screening, mastectomies, and oophorectomies that occurred before and after the Genetics visit during the study period.

Results: Our cohort included 813 women with a HRBOC diagnosis, with a median 51 years of age at diagnosis, 45% White, 38% Black, and 15% other ethnicity. Most cancers occurred prior to the Genetics visit: 513/527 breast cancer diagnoses and 55/57 ovarian cancer diagnoses. Fewer than five prophylactic mastectomies and 89 prophylactic oophorectomies were identified. Among 228 patients who were 30-75 years old, breast cancer-free at the time of HRBOC diagnosis, and members for over 6 months, 190 (83%) had at least one screening test (mammogram or MRI) after the consultation with Genetic, but 79% never had an MRI before or after the consultation.

Conclusion: Our findings suggest that earlier detection of patients with HRBOC and closer monitoring is needed.
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http://dx.doi.org/10.1200/OP.20.00262DOI Listing
April 2021

Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2021 01 6;19(1):77-102. Epub 2021 Jan 6.

The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.
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http://dx.doi.org/10.6004/jnccn.2021.0001DOI Listing
January 2021

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

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

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

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

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

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

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

Relationship of circulating immune cells with lifestyle factors and cancer recurrence in early-stage breast cancer.

Breast Cancer Res Treat 2021 Apr 13;186(2):561-568. Epub 2020 Nov 13.

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 201 North Broadway, Rm 10262, Baltimore, MD, 21287, USA.

Purpose: To evaluate the relationship of circulating immune cells with recurrence and metabolic/lifestyle factors in patients with early-stage breast cancer.

Methods: Patients with early-stage breast cancer were identified from the electronic record and institutional registry. Lymphocyte and monocyte counts were obtained from blood samples at time of diagnosis prior to any chemotherapy. Correlations between lymphocyte and monocyte and recurrence were assessed in the entire cohort and among obese patients, those reporting alcohol consumption and smoking. Competing risk regression was used to analyze time to recurrence.

Results: A total of 950 patients with ≥ 5 years of follow-up were identified; 433 had complete data and were eligible for analysis. 293 (68%) had hormone receptor-positive breast cancer, 82 (19%) HER2 positive, and 53 (13%) triple negative. Patients in the highest quintile of lymphocytes compared to the lowest quintile had lower risk of recurrence (subhazard ratio (SHR) = 0.17, 95% CI [0.03-0.93], p = 0.041) while patients in the highest quintile of monocytes had lower risk for recurrence (SHR = 0.19, 95% CI [0.04, 0.92], p = 0.039). Higher monocytes were more strongly associated with lower recurrence among those reporting alcohol consumption (HR = 0.10, 95% CI [0.01, 0.91], p = 0.04). In obese patients, higher lymphocytes were associated with lower risk of recurrence (p = 0.046); in non-obese patients, higher monocytes were associated with lower risk of recurrence (p = 0.02). There were no correlations among patients who reported tobacco use.

Conclusions: High lymphocyte and monocyte counts are associated with lower recurrence rate in early-stage breast cancer, particularly in obese patients and those reporting alcohol consumption.
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http://dx.doi.org/10.1007/s10549-020-06016-3DOI Listing
April 2021

Association of Combined Sero-Positivity to and with Risk of Colorectal Cancer.

Microorganisms 2020 Oct 30;8(11). Epub 2020 Oct 30.

Infections and Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

Previously, we found that risk of colorectal cancer (CRC) is increased in individuals with serum antibody response to both (HP) Vacuolating Cytotoxin (VacA) toxin or (SGG) pilus protein Gallo2178. In the present analysis, we tested the hypothesis that combined seropositivity to both antigens is a better indicator of CRC risk than seropositivity to single antigens. We used multiplex serologic assays to analyze pre-diagnostic serum for antibody responses from 4063 incident CRC cases and 4063 matched controls from 10 US cohorts. To examine whether combined SGG Gallo2178 and HP VacA sero-status was associated with CRC risk, we used conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Compared to dual sero-negative individuals, there was no increased risk for individuals sero-positive to SGG Gallo2178 only (OR: 0.93; 95% CI: 0.66-1.31) or to HP VacA only (OR: 1.08; 95% CI: 0.98-1.19). However, dual sero-positive individuals had a >50% increased odds of developing CRC (OR: 1.54; 95% CI: 1.16-2.04), suggesting an interaction between antibody responses to these two pathogens and CRC risk (p = 0.06). In conclusion, this study suggests that dual sero-positivity to HP VacA and SGG Gallo2178 is an indicator of increased risk of CRC.
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http://dx.doi.org/10.3390/microorganisms8111698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693002PMC
October 2020

Economic Burden Among Gay, Bisexual, and Other Men Who Have Sex With Men Living With HIV or Living Without HIV in the Multicenter AIDS Cohort Study.

J Acquir Immune Defic Syndr 2020 12;85(4):436-443

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

Background: With HIV now considered a chronic disease, economic burden for people living with HIV (LWH) may threaten long-term disease outcomes. We studied associations between economic burden (employment, income, insurance, and financial difficulty) and HIV status for gay, bisexual, and other men who have sex with men (GBMSM) and how economic burden relates to disease progression.

Setting: We analyzed data collected every 6 months through 2015 from GBMSM LWH and GBMSM living without HIV from 2 waves (2001-2003 cohort and 2010+ new recruit cohort) of the Multicenter AIDS Cohort Study.

Methods: Using generalized estimating equations, we first assessed the association between HIV status (exposure) and economic burden indicators since the last study visit (outcomes) of employment (working/student/retired versus not currently working), personal annual income of ≥$10,000, insurance (public/private versus none), and financial difficulty meeting basic expenses. Then among people LWH, we assessed the relationships between economic burden indicators (exposures), risk of progressive immune suppression (CD4 ≤500 cells/uL), and progression to AIDS (CD4 ≤200; outcomes).

Results: Of 1721 participants, 59.5% were LWH (n = 1024). GBMSM LWH were 12% less likely to be employed, 16% more likely to have health insurance, and 9% more likely to experience financial difficulty than GBMSM living without HIV. Among GBMSM LWH, employment was associated with a 6% and 32% lower likelihood of immune suppression or progression to AIDS, respectively, and the income was associated with a 15% lower likelihood of progression to AIDS.

Conclusions: Interventions that stabilize employment, income, and offer insurance support may enrich GBMSM LWH's ability to prevent disease progression.
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http://dx.doi.org/10.1097/QAI.0000000000002478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592888PMC
December 2020

Body size and weight change over adulthood and risk of breast cancer by menopausal and hormone receptor status: a pooled analysis of 20 prospective cohort studies.

Eur J Epidemiol 2021 Jan 30;36(1):37-55. Epub 2020 Oct 30.

Epidemiology and Prevention Group, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan.

Associations between anthropometric factors and breast cancer (BC) risk have varied inconsistently by estrogen and/or progesterone receptor (ER/PR) status. Associations between prediagnostic anthropometric factors and risk of premenopausal and postmenopausal BC overall and ER/PR status subtypes were investigated in a pooled analysis of 20 prospective cohorts, including 36,297 BC cases among 1,061,915 women, using multivariable Cox regression analyses, controlling for reproductive factors, diet and other risk factors. We estimated dose-response relationships and tested for nonlinear associations using restricted cubic splines. Height showed positive, linear associations for premenopausal and postmenopausal BC risk (6-7% RR increase per 5 cm increment), with stronger associations for receptor-positive subtypes. Body mass index (BMI) at cohort baseline was strongly inversely associated with premenopausal BC risk, and strongly positively-and nonlinearly-associated with postmenopausal BC (especially among women who never used hormone replacement therapy). This was primarily observed for receptor-positive subtypes. Early adult BMI (at 18-20 years) showed inverse, linear associations for premenopausal and postmenopausal BC risk (21% and 11% RR decrease per 5 kg/m, respectively) with stronger associations for receptor-negative subtypes. Adult weight gain since 18-20 years was positively associated with postmenopausal BC risk, stronger for receptor-positive subtypes, and among women who were leaner in early adulthood. Women heavier in early adulthood generally had reduced premenopausal BC risk, independent of later weight gain. Positive associations between height, baseline (adult) BMI, adult weight gain and postmenopausal BC risk were substantially stronger for hormone receptor-positive versus negative subtypes. Premenopausal BC risk was positively associated with height, but inversely with baseline BMI and weight gain (mostly in receptor-positive subtypes). Inverse associations with early adult BMI seemed stronger in receptor-negative subtypes of premenopausal and postmenopausal BC.
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http://dx.doi.org/10.1007/s10654-020-00688-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847460PMC
January 2021

Ethnic and biological differences in the association between physical activity and survival after breast cancer.

NPJ Breast Cancer 2020 9;6:51. Epub 2020 Oct 9.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA.

Physical activity is recommended for most cancer patients as a nonpharmacological therapy to improve prognosis. Few studies have investigated the association between physical activity and breast cancer prognosis by ethnicity, biological, and modifiable risk factors for mortality. We investigated the association between physical activity and long-term survival among breast cancer survivors. A total of 397 survivors (96 Hispanic and 301 non-Hispanic White (NHW)) from the New Mexico HEAL study contributed baseline and biological data approximately 6 months after diagnosis. Study outcomes included all-cause, breast cancer-specific, and non-breast cancer mortality. The exposure was self-reported physical activity within the past month. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox Proportional Hazards regression. A total of 133 deaths (53 breast cancer-specific deaths) were observed after a median follow-up time of 13 years. Engaging in >6.9 metabolic equivalent hours/week (MET-h/week) of moderate to vigorous physical activity (active) was inversely associated with all-cause mortality among all women (HR 0.66, 95% CI 0.43-0.99) and NHWs (HR 0.58, 95% CI 0.36-0.94). Active NHW women also had a reduced risk of non-breast cancer mortality (HR 0.56, 95% CI 0.31-0.99), compared to inactive women (0 MET-h/week). In subgroups, we observed the inverse associations with all-cause mortality among women >58 years old (-interaction= 0.03) and with localized stage (-interaction = 0.046). Our results confirm the protective association between physical activity and mortality after breast cancer diagnosis, and demonstrate that this association significantly differs by age and cancer stage. Larger studies are warranted to substantiate our findings.
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http://dx.doi.org/10.1038/s41523-020-00194-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547070PMC
October 2020

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

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

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

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

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

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

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

Auto-antibodies to p53 and the Subsequent Development of Colorectal Cancer in a U.S. Prospective Cohort Consortium.

Cancer Epidemiol Biomarkers Prev 2020 12 24;29(12):2729-2734. Epub 2020 Sep 24.

Cancer Control and Population Sciences Program, Duke Cancer Institute, and Department of Population Health Sciences, Duke University, Durham, North Carolina.

Background: Auto-antibodies to tumor suppressor p53 are found in a subset of patients with colorectal cancer. A recent prospective study in the United States has reported a significant 1.8-fold increased odds for colorectal cancer development with prediagnostic seropositivity to p53. In this study, we sought to examine this association in a U.S. colorectal cancer cohort consortium to evaluate the potential utility of p53 auto-antibodies as an early biomarker for colorectal cancer.

Methods: Auto-antibodies to p53 were measured in prediagnostic blood samples of 3,702 incident colorectal cancer cases and 3,702 controls, matched by age, race, and sex, from 9 U.S. prospective cohorts. The association of seropositivity to p53 with colorectal cancer risk, overall and by time between blood draw and diagnosis, was determined by conditional logistic regression.

Results: Overall, 5% of controls and 7% of cases were seropositive to p53, resulting in a statistically significant 33% increased colorectal cancer risk [odds ratio (OR), 1.33; 95% confidence interval (CI), 1.09-1.61]. By follow-up time, the association was only significant with colorectal cancer diagnoses within 4 years after blood draw (OR, 2.27; 95% CI, 1.62-3.19), but not thereafter (OR, 0.97; 95% CI, 0.76-1.24).

Conclusions: In this large consortium of prospective cohorts, we found that prediagnostic seropositivity to tumor suppressor p53 was significantly associated with an over 2-fold increased odds of developing colorectal cancer within 4 years after blood draw.

Impact: Our finding suggests that p53 seropositivity may not be a useful predictor of long-term colorectal cancer risk; however, it might be considered as a marker to aid in the early diagnosis of colorectal cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710535PMC
December 2020

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

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

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

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

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

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

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

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

Angiotensin Receptor Blockers Associated with Improved Breast Cancer Survival-A Nationwide Cohort Study from Finland.

Cancer Epidemiol Biomarkers Prev 2020 11 11;29(11):2376-2382. Epub 2020 Sep 11.

Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Background: Breast cancer incidence has been associated with hypertension, which might worsen disease prognosis, but few nationwide studies have investigated the association between antihypertensive drug use and breast cancer prognosis.

Methods: A cohort of 73,170 women diagnosed with breast cancer during 1995-2013 identified from the Finnish Cancer Registry was combined with information on antihypertensive drug use during the same time period from a national prescription database. Antihypertensive drugs were analyzed in groups categorized by mechanism of action. Usage of antihypertensive drugs, statins, antidiabetic, and anticoagulative drugs was analyzed as time-dependent exposure to model for simultaneous use of multiple drug groups. Influence of protopathic bias was evaluated in lag-time analyses.

Results: In prediagnostic use, only angiotensin receptor (ATR)-blockers were associated with decreased risk of breast cancer death as compared with nonusers (HR: 0.76, 95% confidence interval, CI: 0.69-0.82), and there was an inverse association with cumulative dose of use. Postdiagnostic use of ATR-blockers, angiotensin-converting enzyme (ACE)-inhibitors, beta-blockers, and calcium-channel blockers was dose dependently associated with better breast cancer survival compared with nonusers. The risk decrease was strongest for ATR-blockers (HR: 0.69, 95% CI: 0.63-0.75) and remained for exposures occurring up to 3 years earlier.

Conclusions: Only ATR-blockers were associated with improved breast cancer survival in both prediagnostic and postdiagnostic use. The association was dose dependent and supported by a biological rationale as a causal explanation. In postdiagnostic use, similar reduction was found also for other antihypertensives, supporting a prognostic role of hypertension control.

Impact: Inhibition of angiotensin receptor subtype 1 (AT) could be a promising novel way to affect breast cancer progression.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0711DOI Listing
November 2020

Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.

Am J Hum Genet 2020 09 5;107(3):432-444. Epub 2020 Aug 5.

School of Public Health, Imperial College London, London SW7 2AZ, UK.

Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.
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http://dx.doi.org/10.1016/j.ajhg.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477007PMC
September 2020

Ovarian Cancer Risk Factor Associations by Primary Anatomic Site: The Ovarian Cancer Cohort Consortium.

Cancer Epidemiol Biomarkers Prev 2020 10 30;29(10):2010-2018. Epub 2020 Jul 30.

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Background: Epithelial ovarian, fallopian tube, and primary peritoneal cancers have shared developmental pathways. Few studies have prospectively examined heterogeneity in risk factor associations across these three anatomic sites.

Methods: We identified 3,738 ovarian, 337 peritoneal, and 176 fallopian tube incident cancer cases in 891,731 women from 15 prospective cohorts in the Ovarian Cancer Cohort Consortium. Associations between 18 putative risk factors and risk of ovarian, peritoneal, and fallopian tube cancer, overall and for serous and high-grade serous tumors, were evaluated using competing risks Cox proportional hazards regression. Heterogeneity was assessed by likelihood ratio tests.

Results: Most associations did not vary by tumor site ( ≥ 0.05). Associations between first pregnancy ( = 0.04), tubal ligation ( = 0.01), and early-adult (age 18-21 years) body mass index (BMI; = 0.02) and risk differed between ovarian and peritoneal cancers. The association between early-adult BMI and risk further differed between peritoneal and fallopian tube cancer ( = 0.03). First pregnancy and tubal ligation were inversely associated with ovarian, but not peritoneal, cancer. Higher early-adult BMI was associated with higher risk of peritoneal, but not ovarian or fallopian tube, cancer. Patterns were generally similar when restricted to serous and high-grade serous cases.

Conclusions: Ovarian, fallopian tube, and primary peritoneal cancers appear to have both shared and distinct etiologic pathways, although most risk factors appear to have similar associations by anatomic site.

Impact: Further studies on the mechanisms underlying the differences in risk profiles may provide insights regarding the developmental origins of tumors arising in the peritoneal cavity and inform prevention efforts.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541500PMC
October 2020

Genome-Wide Association Study Data Reveal Genetic Susceptibility to Chronic Inflammatory Intestinal Diseases and Pancreatic Ductal Adenocarcinoma Risk.

Cancer Res 2020 09 8;80(18):4004-4013. Epub 2020 Jul 8.

Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.

Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (±500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10, respectively). After excluding the 20 PDAC susceptibility regions (±500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC ( = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease ( = 0.22) and primary sclerosing cholangitis ( = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC. SIGNIFICANCE: The joint effects of common variants in genomic regions containing susceptibility loci for inflammatory bowel disease and chronic pancreatitis are associated with PDAC and may provide insights to understanding pancreatic cancer etiology.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861352PMC
September 2020

All-Cause and Cardiovascular Disease Mortality Among Breast Cancer Survivors in CLUE II, a Long-Standing Community-Based Cohort.

J Natl Cancer Inst 2021 02;113(2):137-145

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Background: There is growing evidence that breast cancer survivors have higher cardiovascular disease (CVD) mortality relative to the general population. Information on temporal patterns for all-cause and CVD mortality among breast cancer survivors relative to cancer-free women is limited.

Methods: All-cause and CVD-related mortality were compared in 628 women with breast cancer and 3140 age-matched cancer-free women within CLUE II, a prospective cohort. We calculated adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression for all-cause mortality, and Fine and Gray models for CVD-related mortality to account for competing risks.

Results: Over 25 years of follow-up, 916 deaths occurred (249 CVD related). Breast cancer survivors had an overall higher risk of dying compared with cancer-free women (HR = 1.79, 95% CI = 1.53 to 2.09) irrespective of time since diagnosis, tumor stage, estrogen receptor status, and older age at diagnosis (≥70 years). Risk of death was greatest among older survivors at more than 15 years after diagnosis (HR = 2.69, 95% CI = 1.59 to 4.55). CVD (69.1% ischemic heart disease) was the leading cause of death among cancer-free women and the second among survivors. Survivors had an increase in CVD-related deaths compared with cancer-free women beginning at 8 years after diagnosis (HR = 1.65, 95% CI = 1.00 to 2.73), with the highest risk among older survivors (HR = 2.24, 95% CI = 1.29 to 3.88) and after estrogen receptor-positive disease (HR = 1.85, 95% CI = 1.06 to 3.20).

Conclusions: Breast cancer survivors continue to have an elevated mortality compared with the general population for many years after diagnosis. Preventing cardiac deaths, particularly among older breast cancer patients, could lead to reductions in mortality.
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http://dx.doi.org/10.1093/jnci/djaa096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850550PMC
February 2021