Publications by authors named "Susan M Gapstur"

348 Publications

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Nat Commun 2021 02 17;12(1):1078. Epub 2021 Feb 17.

Copenhagen General Population Study, Herlev and Gentofte Hospital Copenhagen University Hospital, Herlev, Denmark.

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
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http://dx.doi.org/10.1038/s41467-020-20496-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890067PMC
February 2021

Breast Cancer Risk Factors and Survival by Tumor Subtype: Pooled Analyses from the Breast Cancer Association Consortium.

Cancer Epidemiol Biomarkers Prev 2021 Apr 26;30(4):623-642. Epub 2021 Jan 26.

Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype.

Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype.

Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype ( > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age ≥30 years versus <20 years at first pregnancy [0.79 (0.72-0.86)]; >0-<5 years versus ≥10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking.

Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype.

Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026532PMC
April 2021

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers.

Br J Cancer 2021 02 26;124(4):842-854. Epub 2021 Jan 26.

Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk.

Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry.

Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10).

Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
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http://dx.doi.org/10.1038/s41416-020-01185-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884683PMC
February 2021

Proportion of cancer cases and deaths attributable to alcohol consumption by US state, 2013-2016.

Cancer Epidemiol 2021 04 19;71(Pt A):101893. Epub 2021 Jan 19.

Data Science Research Program, American Cancer Society, Atlanta, GA, United States. Electronic address:

Background: Alcohol consumption is an established risk factor for several cancer types, but there are no contemporary published estimates of the state-level burden of cancer attributed to alcoholic beverage consumption. Such estimates are needed to inform public policy and cancer control efforts. We estimated the proportion and number of incident cancer cases and cancer deaths attributable to alcohol consumption by sex in adults aged ≥30 years in all 50 states and the District of Columbia in 2013-2016.

Methods: Age-, sex-, and state-specific cancer incidence and mortality data (2013-2016) were obtained from the US Cancer Statistics database. State-level, self-reported age and sex stratified alcohol consumption prevalence was estimated using the 2003-2006 Behavioral Risk Factor Surveillance System surveys and adjusted with state sales data.

Results: The proportion of alcohol-attributable incident cancer cases ranged from 2.9 % (95 % confidence interval: 2.7 %-3.1 %) in Utah to 6.7 % (6.4 %-7.0 %) in Delaware among men and women combined, from 2.7 % (2.5 %-3.0 %) in Utah to 6.3 % (5.9 %-6.7 %) in Hawaii among men, and from 2.7 % (2.4 %-3.0 %) in Utah to 7.7 % (7.2 %-8.3 %) in Delaware among women. The proportion of alcohol-attributable cancer deaths also varied considerably across states: from 1.9 % to 4.5 % among men and women combined, from 2.1% to 5.0% among men, and from 1.4 % to 4.4 % among women. Nationally, alcohol consumption accounted for 75,199 cancer cases and 18,947 cancer deaths annually.

Conclusion: Alcohol consumption accounts for a considerable proportion of cancer incidence and mortality in all states. Implementing state-level policies and cancer control efforts to reduce alcohol consumption could reduce this cancer burden.
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http://dx.doi.org/10.1016/j.canep.2021.101893DOI Listing
April 2021

A Population-Based Study of Genes Previously Implicated in Breast Cancer.

N Engl J Med 2021 02 20;384(5):440-451. Epub 2021 Jan 20.

From Mayo Clinic, Rochester, MN (C. Hu, S.N.H., R.G., K.Y.L., J.N., J.L., S. Yadav, N.J.B., T.L., J.E.O., C.S., C.M.V., E.C.P., F.J.C.); Harvard University T.H. Chan School of Public Health (H.H., C.G., D.J.H., P.K.), Slone Epidemiology Center at Boston University (K.A.B., J.R.P., L.R.), and Brigham and Women's Hospital (H.E.) - all in Boston; Qiagen, Hilden, Germany (R.S., J.K.); Roswell Park Comprehensive Cancer Center, Buffalo (C.B.A., S. Yao), and Weill Cornell Medicine, New York (R.T.) - both in New York; the University of California, Irvine (H.A.-C., A.Z.), Beckman Research Institute of City of Hope, Duarte (L.B., H.M., S.N., J.N.W.), Keck School of Medicine, University of Southern California, Los Angeles (C. Haiman), and Stanford University School of Medicine, Stanford (E.M.J., A.W.K.) - all in California; the University of Wisconsin-Milwaukee Joseph J. Zilber School of Public Health, Milwaukee (P.A.), and the University of Wisconsin-Madison, Madison (E.S.B., I.M.O., A.T.-D.); the Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, State University of New Jersey, New Brunswick (E.V.B.); the Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta (B.D.C., S.M.G., M.G., J.M.H., E.J.J., A.V.P.); the University of Oxford, Oxford, United Kingdom (D.J.H.); the Fred Hutchinson Cancer Research Center (C.K., P.A.N.) and the Department of Epidemiology, University of Washington (S.L.) - both in Seattle; the Epidemiology Program, University of Hawaii Cancer Center, Honolulu (L.L.M.); the National Institute of Environmental Health Sciences, Durham, NC (K.M.O., D.P.S., J.A.T., C.W.); Vanderbilt University, Nashville (T.P., S.R.); the University of Utah, Salt Lake City (D.E.G.); and the Department of Medicine and the Basser Center for BRCA, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (S.M.D., K.L.N.).

Background: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants.

Methods: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed.

Results: Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in and were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in , , and were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in , , and were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657_661del5 founder pathogenic variant in , were not associated with an increased risk of breast cancer.

Conclusions: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.).
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http://dx.doi.org/10.1056/NEJMoa2005936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127622PMC
February 2021

Composition of time in movement behaviors and weight change in Latinx, Black and white participants.

PLoS One 2021 8;16(1):e0244566. Epub 2021 Jan 8.

American Cancer Society, Atlanta, Georgia, United States of America.

Background: The relationship between time-use behaviors and prospective weight change is poorly understood.

Methods: A subset of Cancer Prevention Study-3 participants (n = 549, 58% women, 66% non-Latinx white) self-reported weight in 2015 and 2018 and completed an accelerometer protocol for seven days. Sedentary time, sleep, light, moderate, and vigorous intensity physical activity (PA) were treated as a compositional variable and multiple linear regression was used to examine associations between activity composition and weight change stratified by sex and race/ethnicity. Compositional isotemporal substitution analysis was used to quantify change in weight associated with reallocating 30 min./day.

Results: Activity composition was associated with weight change among women (p = 0.007), but not men (p = 0.356), and among Latinx (p = 0.032) and white participants (p = 0.001), but not Black participants (p = 0.903). Replacement of 30 min./day sedentary time with moderate-vigorous PA was associated with 3.49 lbs. loss (-6.76, -0.22) in Latinx participants and replacement with sleep was associated with 1.52 (0.25, 2.79) and 1.31 (0.40, 2.21) lbs. gain in white women and men.

Conclusion: The distribution of time spent in daily behaviors was associated with three-year weight change in women, Latinx, and white participants. This was the first longitudinal compositional study of weight change; thus, more studies are needed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244566PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793306PMC
May 2021

Breast cancer risk factors by mode of detection among screened women in the Cancer Prevention Study-II.

Breast Cancer Res Treat 2021 Apr 4;186(3):791-805. Epub 2021 Jan 4.

Behavioral and Epidemiology Research Program, American Cancer Society, 250 Williams Street, Atlanta, GA, 30303, USA.

Background: Identifying risk factors for women at high risk of symptom-detected breast cancers that were missed by screening would enable targeting of enhanced screening regimens. To this end, we examined associations of breast cancer risk factors by mode of detection in screened women from the Cancer Prevention Study (CPS)-II Nutrition Cohort.

Methods: Among 77,206 women followed for a median of 14.8 years, 2711 screen-detected and 1281 symptom-detected breast cancer cases were diagnosed. Multivariable-adjusted associations were estimated using joint Cox proportional hazards regression models with person-time calculated contingent on screening.

Results: Factors associated with higher risks of symptom-detected and screen-detected breast cancer included current combined hormone therapy (HT) use (HR 2.07, 95% CI 1.72-2.48 and 1.45, 1.27-1.65, respectively) and history of benign breast disease (1.85, 1.64-2.08 and 1.43, 1.31-1.55, respectively). Current estrogen-only HT use was associated with symptom-detected (1.40, 1.15-1.71) but not screen-detected (0.95, 0.83-1.09) breast cancer. Higher risk of screen-detected but not symptom-detected breast cancer was observed for obese vs. normal body mass index (1.22, 1.01-1.48 and 0.76, 0.56-1.01, respectively), per 3 h/day sitting time (1.10, 1.04-1.16 and 0.97, 0.89-1.06, respectively), and ≥ 2 drinks per day vs. nondrinker (1.40, 1.16-1.69 and 1.27, 0.97-1.66, respectively).

Conclusions: Differences in risk factors for symptom-detected vs. screen-detected breast cancer were observed and most notably, use of combined and estrogen-only HT and a history of benign breast disease were associated with increased risk of symptomatic detected breast cancer.

Impact: If confirmed, these data suggest that such women may benefit from more intensive screening to facilitate early detection.
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http://dx.doi.org/10.1007/s10549-020-06025-2DOI Listing
April 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

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

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
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http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
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

Response to letter to the editor: Caffeinated and decaffeinated coffee intake and colorectal cancer: A risk assessment.

Cancer Epidemiol 2020 12 22;69:101843. Epub 2020 Oct 22.

Department of Population Science, American Cancer Society, Atlanta, GA, United States.

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http://dx.doi.org/10.1016/j.canep.2020.101843DOI Listing
December 2020

Joint associations of physical activity and body mass index with the risk of established excess body fatness-related cancers among postmenopausal women.

Cancer Causes Control 2021 Feb 13;32(2):127-138. Epub 2020 Nov 13.

American Cancer Society, Behavioral and Epidemiology Research Group, 250 Williams St, Atlanta, GA, USA.

Purpose: Excess body fatness and physical activity independently influence the risk of several types of cancer. However, few studies have examined whether physical activity mitigates the excess risk associated with higher body mass index (BMI).

Methods: We examined the individual and joint associations between BMI (kg/m) and leisure-time moderate-to-vigorous physical activity (MVPA, MET-hours/week) with the risk of three established excess body fatness-related cancers (breast, colon, and endometrial) among 43,795 postmenopausal women in the Cancer Prevention Study II (CPS-II) Nutrition Cohort (1992/1993-2015). Further exclusions for women without an intact uterus resulted in 31,805 women for endometrial cancer analyses. Multivariable Cox proportional hazards regression was used to calculate hazard ratio (HR) and 95% confidence intervals (CIs) with interaction terms to assess multiplicative interaction. The relative excess risk due to interaction (RERI) was calculated to assess additive interaction.

Results: BMI and MVPA were individually associated with breast and endometrial cancer risk, but only BMI was associated with colon cancer risk. In joint analyses, increasing levels of MVPA did not lower the risk of these cancers among obese women. For example, compared to the common referent (BMI 18.5- < 25 kg/m, MVPA > 0- < 7.5 MET-hours/week), BMI ≥ 30 kg/m was associated with a higher risk of breast cancer among women with low MVPA (> 0-< 7.5 MET-hours/week: HR = 1.42, 95% CI: 1.22 - 1.67) and high MVPA (≥ 15 MET-hours/week: HR = 1.53, 95% CI: 1.25 - 1.87; RERI = 0.20, 95% CI: -0.14, 0.54, multiplicative P = 0.64).

Conclusion: Our results do not support the hypothesis that leisure-time physical activity mitigates the excess risk associated with higher BMI for risk of breast, endometrial, or colon cancer among postmenopausal women.
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http://dx.doi.org/10.1007/s10552-020-01365-2DOI Listing
February 2021

Self-reported physical activity, sitting time, and mental and physical health among older cancer survivors compared with adults without a history of cancer.

Cancer 2020 Jan 20;127(1):115-123. Epub 2020 Oct 20.

Department of Population Science, American Cancer Society, Atlanta, Georgia.

Background: To the authors' knowledge, few studies to date have examined associations between moderate to vigorous physical activity (MVPA) and sitting time with quality of life in cancer survivors compared with a cancer-free group. The current study examined differences in global mental health (GMH) and global physical health (GPH) across levels of MVPA and sitting among cancer survivors and cancer-free participants.

Methods: Cancer Prevention Study II participants (59.9% of whom were female with an age of 77.8 ± 5.8 years) were grouped as: 1) survivors who were 1 to 5 years after diagnosis (3718 participants); 2) survivors who were 6 to 10 years after diagnosis (4248 participants); and 3) cancer-free participants (ie, no history of cancer; 69,860 participants). In 2009, participants completed MVPA, sitting, and Patient-Reported Outcomes Measurement Information System GMH/GPH surveys. Mean differences in GMH and GPH T scores across MVPA (none, 0 to <7.5, 7.5 to <15, 15 to <22.5, and ≥22.5 metabolic equivalent [MET]-hours/week) and sitting (0 to <3, 3 to <6, and ≥6 hours/day) were assessed using multivariate generalized linear models.

Results: The mean GMH and GPH scores were statistically significantly higher in cancer-free participants compared with cancer survivor groups, although the differences were not clinically meaningful (mean difference of 0.52 for GMH and 0.88 for GPH). More MVPA was associated with higher GMH and GPH scores for all 3 groups (P for trend <.001), and differences between the least and most active participants were found to be clinically meaningful (mean differences of ≥4.34 for GMH and ≥6.39 for GPH). Similarly, a lower duration of sitting was associated with higher GMH and GPH scores for all groups (P for trend <.001), with clinically meaningful differences observed between the least and most sedentary participants (mean differences of ≥2.74 for GMH and ≥3.75 for GPH).

Conclusions: The findings of the current study provide evidence of the importance of increased MVPA and decreased sitting for improved health in older adults with or without a prior cancer diagnosis.
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http://dx.doi.org/10.1002/cncr.33257DOI Listing
January 2020

Research Participants' Perspectives on Using an Electronic Portal for Engagement and Data Collection: Focus Group Results From a Large Epidemiologic Cohort.

J Med Internet Res 2020 10 1;22(10):e18556. Epub 2020 Oct 1.

American Cancer Society, Atlanta, GA, United States.

Background: Epidemiologic cohort studies have begun to leverage electronic research participant portals to facilitate data collection, integrate wearable technologies, lower costs, and engage participants. However, little is known about the acceptability of portal use by research participants.

Objective: The aim of this study is to conduct focus groups among a sample of Cancer Prevention Study-3 (CPS-3) participants to better understand their preferences and concerns about research portals.

Methods: CPS-3 participants were stratified based on sex, race and ethnicity, age, and cancer status, and randomly invited to participate. Focus groups used an exploratory case design with semistructured guides to prompt discussion. Using a constant comparison technique, transcripts were assigned codes to identify themes.

Results: Participants (31/59, 52% women; 52/59, 88% White/non-Latinx) were favorably disposed toward using a research participant portal to take surveys, communicate with the study staff, and upload data. Most participants indicated that a portal would be beneficial and convenient but expressed concerns over data safety. Participants stressed the importance of an easy-to-use and trustworthy portal that is compatible with mobile devices.

Conclusions: In addition to being beneficial to researchers, portals may also benefit participants as long as the portals are secure and simple. Participants believe that portals can provide convenient ways to report data and remain connected to the study.
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http://dx.doi.org/10.2196/18556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563628PMC
October 2020

Outdoor air pollution and cancer: An overview of the current evidence and public health recommendations.

CA Cancer J Clin 2020 Aug 25. Epub 2020 Aug 25.

Health Effects Institute, Boston, Massachusetts.

Outdoor air pollution is a major contributor to the burden of disease worldwide. Most of the global population resides in places where air pollution levels, because of emissions from industry, power generation, transportation, and domestic burning, considerably exceed the World Health Organization's health-based air-quality guidelines. Outdoor air pollution poses an urgent worldwide public health challenge because it is ubiquitous and has numerous serious adverse human health effects, including cancer. Currently, there is substantial evidence from studies of humans and experimental animals as well as mechanistic evidence to support a causal link between outdoor (ambient) air pollution, and especially particulate matter (PM) in outdoor air, with lung cancer incidence and mortality. It is estimated that hundreds of thousands of lung cancer deaths annually worldwide are attributable to PM air pollution. Epidemiological evidence on outdoor air pollution and the risk of other types of cancer, such as bladder cancer or breast cancer, is more limited. Outdoor air pollution may also be associated with poorer cancer survival, although further research is needed. This report presents an overview of outdoor air pollutants, sources, and global levels, as well as a description of epidemiological evidence linking outdoor air pollution with cancer incidence and mortality. Biological mechanisms of air pollution-derived carcinogenesis are also described. This report concludes by summarizing public health/policy recommendations, including multilevel interventions aimed at individual, community, and regional scales. Specific roles for medical and health care communities with regard to prevention and advocacy and recommendations for further research are also described.
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http://dx.doi.org/10.3322/caac.21632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904962PMC
August 2020

A Large Cohort Study of Body Mass Index and Pancreatic Cancer by Smoking Status.

Cancer Epidemiol Biomarkers Prev 2020 12 22;29(12):2680-2685. Epub 2020 Sep 22.

Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia.

Background: Some evidence suggests the association between body mass index (BMI) and pancreatic cancer risk is weaker among current smokers than among never smokers.

Methods: We examined the association between BMI and pancreatic cancer mortality among adults who reported smoking status at enrollment into Cancer Prevention Study-II in 1982, including 420,543 never smokers, 282,244 former cigarette smokers, and 219,885 current cigarette smokers. After excluding the first 3 years of follow-up to reduce reverse causation, we calculated multivariable-adjusted hazard ratios (HR).

Results: During the full follow-up period from 1985 to 2014, 7,904 participants died of pancreatic cancer. The HR per 5 BMI units was lower among current smokers [HR = 1.14; 95% confidence interval (CI), 1.07-1.20] than never smokers (HR = 1.22; 95% CI, 1.17-1.27), although this difference was not statistically significant ( = 0.06). BMI was significantly less strongly associated with pancreatic cancer mortality among current smokers reporting ≥20 cigarettes/day (HR = 1.10; 95% CI, 1.03-1.18) than among never smokers. During follow-up within 10 years of enrollment, when current smokers at enrollment were the most likely to have still been smoking, BMI was not associated with pancreatic cancer mortality among current smokers (HR = 1.02; 95% CI, 0.90-1.16, = 0.03 for difference between current and never smokers). BMI HRs were similar among former and never smokers.

Conclusions: These results support a weaker association between BMI and pancreatic cancer among current smokers than among never smokers.

Impact: In populations with low smoking prevalence, the pancreatic cancer burden due to BMI is likely to be higher than that predicted by risk estimates from studies including substantial numbers of smokers.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0591DOI Listing
December 2020

Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer.

J Natl Cancer Inst 2021 May;113(5):616-625

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Background: There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive vs nonaggressive disease.

Methods: Participants were 5545 European-ancestry men, including 2775 nonaggressive and 2770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency < 0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are 2-sided.

Results: BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D BRCA2 alleles (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.94 to 5.25, P = 8.58 × 10-7) and 0.65% of aggressive and 0.11% of nonaggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79 × 10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P = .02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than nonaggressive cases (carrier frequencies = 14.2% vs 10.6%, respectively; P = 5.56 × 10-5). However, this difference was non-statistically significant (P = .18) on excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI = -1.65 to 0.48, P = 3.71 × 10-4).

Conclusions: Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.
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http://dx.doi.org/10.1093/jnci/djaa132DOI Listing
May 2021

Coffee Consumption and Invasive Breast Cancer Incidence among Postmenopausal Women in the Cancer Prevention Study-II Nutrition Cohort.

Cancer Epidemiol Biomarkers Prev 2020 11 14;29(11):2383-2386. Epub 2020 Aug 14.

Department of Population Science, American Cancer Society, Atlanta, Georgia.

Background: There is limited evidence of a potential inverse association between coffee, particularly caffeinated coffee, consumption and postmenopausal breast cancer risk, and few studies have examined this association by tumor hormone receptor status. To provide further evidence, we examined total, caffeinated, and decaffeinated coffee consumption in relation to postmenopausal invasive breast cancer incidence overall, and by tumor estrogen receptor (ER) and/or progesterone receptor (PR) subtype.

Methods: Among 57,075 postmenopausal women in the Cancer Prevention Study-II Nutrition Cohort who were cancer free and reported coffee intake in 1999, we identified 2,980 women diagnosed with invasive breast cancer during follow-up through June 2015. Multivariable-adjusted Cox proportional hazards regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI).

Results: Neither total, caffeinated, nor decaffeinated coffee consumption was associated with invasive breast cancer risk; HRs (95% CIs) comparing consumption of ≥2 cups per day with <1 cup per month were 0.99 (0.89-1.11), 0.96 (0.87-1.06), and 1.06 (0.95-1.19), respectively. Similarly, coffee consumption was not associated with risk of hormone receptor-positive (ER or PR) or hormone receptor-negative (ER and PR) breast tumors.

Conclusions: These findings do not support an association between coffee consumption and invasive breast cancer risk among postmenopausal women.

Impact: This large prospective study contributes to the limited evidence on coffee consumption and breast cancer risk, finding no association overall or by tumor receptor subtype.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1051DOI Listing
November 2020

Relationship Between Muscle-Strengthening Activity and Cause-Specific Mortality in a Large US Cohort.

Prev Chronic Dis 2020 08 6;17:E78. Epub 2020 Aug 6.

Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia.

Introduction: Muscle-strengthening activity (MSA) has beneficial effects on hypertension, glucose homeostasis, and other health conditions; however, its association with mortality is not as well understood.

Methods: We analyzed data from the Cancer Prevention Study-II Nutrition Cohort (data collection 1982-2014), a prospective US cohort that consisted of 72,462 men and women who were free of major chronic diseases; 18,034 of the cohort died during 13 years of follow-up (2001-2014). We used Cox proportional hazards modeling, controlling for various potential confounding factors, to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for MSA (none, >0 to <1 h/wk, 1 to <2 h/wk, and ≥2 h/wk) in relation to mortality risk, independent of and in combination with aerobic physical activity.

Results: The association between MSA and mortality appeared to be nonlinear (quadratic trend P value, <.001). After multivariable adjustment and comparison with no MSA, engaging in less than 2 hours per week of MSA was associated with lowered all-cause mortality (>0 to <1 h/wk: HR = 0.88, 95% CI, 0.82-0.94; 1 to <2 h/wk: HR = 0.90, 95% CI, 0.84-0.97), but engaging in 2 or more hours per week was not associated with reduced risk (HR = 1.01; 95% CI, 0.92-1.09). Associations were similar but not significant for cancer mortality. Engaging in >0 to <1 hr/wk of MSA was associated with a 19% lower risk (HR = 0.81; 95% CI, 0.71-0.92) of cardiovascular disease mortality, but more time spent in MSA was not associated with reduced risk (quadratic trend P value =.005). Associations did not vary by amount of moderate-to-vigorous aerobic physical activity.

Conclusion: Engaging in ≥2 hours per week of MSA was associated with lower all-cause mortality, independent of aerobic activity. Reasons for the lack of association with higher amounts of MSA are unclear. Our findings support recommending muscle-strengthening activities for overall health.
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http://dx.doi.org/10.5888/pcd17.190408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417019PMC
August 2020

Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk.

Sci Rep 2020 06 16;10(1):9688. Epub 2020 Jun 16.

Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany.

In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.
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http://dx.doi.org/10.1038/s41598-020-65665-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297796PMC
June 2020

Coffee consumption and risk of colorectal cancer in the Cancer Prevention Study-II Nutrition Cohort.

Cancer Epidemiol 2020 08 9;67:101730. Epub 2020 Jun 9.

Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, United States.

Background: The association between coffee consumption and colorectal cancer risk generally appears null, but recent evidence suggests that risk may vary by coffee type. We examined associations of caffeinated and decaffeinated coffee intake with colorectal cancer risk overall and with colon and rectum separately, among older U.S. men and women.

Methods: In 1999, 47,010 men and 60,051 women with no previous diagnosis of cancer, aged 47-96 years, in the Cancer Prevention Study-II Nutrition Cohort completed a food frequency questionnaire that assessed caffeinated and decaffeinated coffee intake; consumption was updated in 2003. A total of 1829 colorectal cancer cases were verified through June 2015. Cox proportional hazards regression was used to estimate multivariable-adjusted hazard rate ratios (HRs) and 95% confidence intervals (CIs), adjusting for smoking history, alcohol, caffeinated/decaffeinated coffee intake (depending on the model), and other colorectal cancer risk factors.

Results: Consumption of ≥2 cups/day of decaffeinated coffee, compared to no decaffeinated coffee, was associated with lower risk of overall colorectal cancer (HR = 0.82, 95% CI: 0.69-0.96, P-trend = 0.04), colon cancer (HR = 0.82, 95% CI: 0.69-0.99, P-trend = 0.05) and rectal cancer (HR = 0.63, 95% CI: 0.40-0.99, P-trend = 0.17). Consumption of ≥2 cups/day of caffeinated coffee was associated with higher risk of rectal cancer (HR = 1.37, 95% CI: 0.99-1.89, P-trend = 0.04), but not with colorectal or colon cancer.

Conclusion: In this prospective study, higher intake of decaffeinated coffee was associated with lower risk of colorectal, colon, and rectal cancers. Further study on associations of caffeinated and decaffeinated coffee with colorectal cancer risk by subsite is needed.
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http://dx.doi.org/10.1016/j.canep.2020.101730DOI Listing
August 2020

American Cancer Society guideline for diet and physical activity for cancer prevention.

CA Cancer J Clin 2020 07 9;70(4):245-271. Epub 2020 Jun 9.

Cancer Control, American Cancer Society, Atlanta, Georgia.

The American Cancer Society (ACS) publishes the Diet and Physical Activity Guideline to serve as a foundation for its communication, policy, and community strategies and, ultimately, to affect dietary and physical activity patterns among Americans. This guideline is developed by a national panel of experts in cancer research, prevention, epidemiology, public health, and policy, and reflects the most current scientific evidence related to dietary and activity patterns and cancer risk. The ACS guideline focuses on recommendations for individual choices regarding diet and physical activity patterns, but those choices occur within a community context that either facilitates or creates barriers to healthy behaviors. Therefore, this committee presents recommendations for community action to accompany the 4 recommendations for individual choices to reduce cancer risk. These recommendations for community action recognize that a supportive social and physical environment is indispensable if individuals at all levels of society are to have genuine opportunities to choose healthy behaviors. This 2020 ACS guideline is consistent with guidelines from the American Heart Association and the American Diabetes Association for the prevention of coronary heart disease and diabetes as well as for general health promotion, as defined by the 2015 to 2020 Dietary Guidelines for Americans and the 2018 Physical Activity Guidelines for Americans.
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http://dx.doi.org/10.3322/caac.21591DOI Listing
July 2020

Erythrocyte levels of cadmium and lead and risk of B-cell non-Hodgkin lymphoma and multiple myeloma.

Int J Cancer 2020 12 25;147(11):3110-3118. Epub 2020 Jun 25.

Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia, USA.

Cadmium and lead are persistent environmental toxins that are known or probable carcinogens, based on evidence for causality for nonhematologic cancers. Associations of these metals with risk of non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) are unknown but biologically plausible. To examine the associations of circulating levels of lead and cadmium exposure with risk of B-cell NHL (B-NHL) and multiple myeloma, we conducted a nested case-control study among 299 incident B-cell NHLs and 76 MM cases within the Cancer Prevention Study-II Nutrition Cohort (CPS-II NC). Each case was incidence-density matched to two eligible controls on age, race, sex and blood draw date. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) for lymphoid malignancies overall and stratified by subtype. We observed a significant positive association between high erythrocyte lead concentration and risk of lymphoid malignancies overall (RR = 1.16, 95% CI: 1.02-1.33 per 17.6 μg/L (1 standard deviation [SD])) and follicular lymphoma in particular (RR = 1.80, 95% CI: 1.15-2.80 per SD). In contrast, there was no association between erythrocyte cadmium and risk of B-NHL (RR = 0.89, 95% CI: 0.75-1.06 per 0.37 μg/L [1 SD]), or any B-NHL subtypes; but a strong inverse association with MM risk (RR = 0.59, 95% CI: 0.38-0.89, per SD). Results from our study suggest a positive association between erythrocyte lead level and risk of lymphoid malignancies and a possible inverse association between cadmium and myeloma. Additional research is needed to confirm and further explore these findings.
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http://dx.doi.org/10.1002/ijc.33136DOI Listing
December 2020

Associations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project.

J Hepatol 2020 10 11;73(4):863-872. Epub 2020 May 11.

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.

Background & Aims: Gallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear.

Methods: We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study.

Results: During 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25-2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06-1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04-1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09-1.31) and EHBDC (HR 1.11; 95% CI 1.01-1.22) in Asian women only.

Conclusion: We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography.

Lay Summary: Our findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.
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http://dx.doi.org/10.1016/j.jhep.2020.04.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901003PMC
October 2020

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Nat Genet 2020 06 18;52(6):572-581. Epub 2020 May 18.

Molecular Medicine Unit, Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
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http://dx.doi.org/10.1038/s41588-020-0609-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808397PMC
June 2020

A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry.

Eur Urol 2020 09 12;78(3):316-320. Epub 2020 May 12.

Department of Surgery, Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.
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http://dx.doi.org/10.1016/j.eururo.2020.04.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805560PMC
September 2020

Exogenous hormone use, reproductive factors and risk of intrahepatic cholangiocarcinoma among women: results from cohort studies in the Liver Cancer Pooling Project and the UK Biobank.

Br J Cancer 2020 07 7;123(2):316-324. Epub 2020 May 7.

Division of Medical Oncology, National Cancer Centre, Singapore, Singapore.

Background: Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. Cholangiocytes express both oestrogen receptor-α and -β, and oestrogens positively modulate cholangiocyte proliferation. Studies in women and men have reported higher circulating oestradiol is associated with increased ICC risk, further supporting a hormonal aetiology. However, no observational studies have examined the associations between exogenous hormone use and reproductive factors, as proxies of endogenous hormone levels, and risk of ICC.

Methods: We harmonised data from 1,107,498 women who enroled in 12 North American-based cohort studies (in the Liver Cancer Pooling Project, LCPP) and the UK Biobank between 1980-1998 and 2006-2010, respectively. Cox proportional hazards regression models were used to generate hazard ratios (HR) and 95% confidence internals (CI). Then, meta-analytic techniques were used to combine the estimates from the LCPP (n = 180 cases) and the UK Biobank (n = 57 cases).

Results: Hysterectomy was associated with a doubling of ICC risk (HR = 1.98, 95% CI: 1.27-3.09), compared to women aged 50-54 at natural menopause. Long-term oral contraceptive use (9+ years) was associated with a 62% increased ICC risk (HR = 1.62, 95% CI: 1.03-2.55). There was no association between ICC risk and other exogenous hormone use or reproductive factors.

Conclusions: This study suggests that hysterectomy and long-term oral contraceptive use may be associated with an increased ICC risk.
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http://dx.doi.org/10.1038/s41416-020-0835-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374167PMC
July 2020

Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk.

J Natl Cancer Inst 2021 Mar;113(3):329-337

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

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
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http://dx.doi.org/10.1093/jnci/djaa056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936056PMC
March 2021

Association of Body Mass Index With Colorectal Cancer Risk by Genome-Wide Variants.

J Natl Cancer Inst 2021 01;113(1):38-47

Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.

Background: Body mass index (BMI) is a complex phenotype that may interact with genetic variants to influence colorectal cancer risk.

Methods: We tested multiplicative statistical interactions between BMI (per 5 kg/m2) and approximately 2.7 million single nucleotide polymorphisms with colorectal cancer risk among 14 059 colorectal cancer case (53.2% women) and 14 416 control (53.8% women) participants. All analyses were stratified by sex a priori. Statistical methods included 2-step (ie, Cocktail method) and single-step (ie, case-control logistic regression and a joint 2-degree of freedom test) procedures. All statistical tests were two-sided.

Results: Each 5 kg/m2 increase in BMI was associated with higher risks of colorectal cancer, less so for women (odds ratio [OR] = 1.14, 95% confidence intervals [CI] = 1.11 to 1.18; P = 9.75 × 10-17) than for men (OR = 1.26, 95% CI = 1.20 to 1.32; P = 2.13 × 10-24). The 2-step Cocktail method identified an interaction for women, but not men, between BMI and a SMAD7 intronic variant at 18q21.1 (rs4939827; Pobserved = .0009; Pthreshold = .005). A joint 2-degree of freedom test was consistent with this finding for women (joint P = 2.43 × 10-10). Each 5 kg/m2 increase in BMI was more strongly associated with colorectal cancer risk for women with the rs4939827-CC genotype (OR = 1.24, 95% CI = 1.16 to 1.32; P = 2.60 × 10-10) than for women with the CT (OR = 1.14, 95% CI = 1.09 to 1.19; P = 1.04 × 10-8) or TT (OR = 1.07, 95% CI = 1.01 to 1.14; P = .02) genotypes.

Conclusion: These results provide novel insights on a potential mechanism through which a SMAD7 variant, previously identified as a susceptibility locus for colorectal cancer, and BMI may influence colorectal cancer risk for women.
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http://dx.doi.org/10.1093/jnci/djaa058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781451PMC
January 2021