Publications by authors named "Sarah Nyante"

63 Publications

Impact of the COVID-19 Pandemic on Breast Cancer Mortality in the US: Estimates From Collaborative Simulation Modeling.

J Natl Cancer Inst 2021 11;113(11):1484-1494

Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.

Background: The coronavirus disease 2019 (COVID-19) pandemic has disrupted breast cancer control through short-term declines in screening and delays in diagnosis and treatments. We projected the impact of COVID-19 on future breast cancer mortality between 2020 and 2030.

Methods: Three established Cancer Intervention and Surveillance Modeling Network breast cancer models modeled reductions in mammography screening use, delays in symptomatic cancer diagnosis, and reduced use of chemotherapy for women with early-stage disease for the first 6 months of the pandemic with return to prepandemic patterns after that time. Sensitivity analyses were performed to determine the effect of key model parameters, including the duration of the pandemic impact.

Results: By 2030, the models project 950 (model range = 860-1297) cumulative excess breast cancer deaths related to reduced screening, 1314 (model range = 266-1325) associated with delayed diagnosis of symptomatic cases, and 151 (model range = 146-207) associated with reduced chemotherapy use in women with hormone positive, early-stage cancer. Jointly, 2487 (model range = 1713-2575) excess breast cancer deaths were estimated, representing a 0.52% (model range = 0.36%-0.56%) cumulative increase over breast cancer deaths expected by 2030 in the absence of the pandemic's disruptions. Sensitivity analyses indicated that the breast cancer mortality impact would be approximately double if the modeled pandemic effects on screening, symptomatic diagnosis, and chemotherapy extended for 12 months.

Conclusions: Initial pandemic-related disruptions in breast cancer care will have a small long-term cumulative impact on breast cancer mortality. Continued efforts to ensure prompt return to screening and minimize delays in evaluation of symptomatic women can largely mitigate the effects of the initial pandemic-associated disruptions.
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http://dx.doi.org/10.1093/jnci/djab097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344930PMC
November 2021

Cross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women.

Nat Commun 2021 07 7;12(1):4198. Epub 2021 Jul 7.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.

Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P < 0.05 from African ancestry GWAS meta-analysis (9241 cases and 10193 controls), then meta-analyze with European ancestry GWAS data (122977 cases and 105974 controls) from the Breast Cancer Association Consortium. The approach identifies four loci for overall breast cancer risk [1p13.3, 5q31.1, 15q24 (two independent signals), and 15q26.3] and two loci for estrogen receptor-negative disease (1q41 and 7q11.23) at genome-wide significance. Four of the index single nucleotide polymorphisms (SNPs) lie within introns of genes (KCNK2, C5orf56, SCAMP2, and SIN3A) and the other index SNPs are located close to GSTM4, AMPD2, CASTOR2, and RP11-168G16.2. Here we present risk loci with consistent direction of associations in African and European descendants. The study suggests that replication across multiple ancestry populations can help improve the understanding of breast cancer genetics and identify causal variants.
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http://dx.doi.org/10.1038/s41467-021-24327-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263739PMC
July 2021

Evaluating Polygenic Risk Scores for Breast Cancer in Women of African Ancestry.

J Natl Cancer Inst 2021 Sep;113(9):1168-1176

Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.

Background: Polygenic risk scores (PRSs) have been demonstrated to identify women of European, Asian, and Latino ancestry at elevated risk of developing breast cancer (BC). We evaluated the performance of existing PRSs trained in European ancestry populations among women of African ancestry.

Methods: We assembled genotype data for women of African ancestry, including 9241 case subjects and 10 193 control subjects. We evaluated associations of 179- and 313-variant PRSs with overall and subtype-specific BC risk. PRS discriminatory accuracy was assessed using area under the receiver operating characteristic curve. We also evaluated a recalibrated PRS, replacing the index variant with variants in each region that better captured risk in women of African ancestry and estimated lifetime absolute risk of BC in African Americans by PRS category.

Results: For overall BC, the odds ratio per SD of the 313-variant PRS (PRS313) was 1.27 (95% confidence interval [CI] = 1.23 to 1.31), with an area under the receiver operating characteristic curve of 0.571 (95% CI = 0.562 to 0.579). Compared with women with average risk (40th-60th PRS percentile), women in the top decile of PRS313 had a 1.54-fold increased risk (95% CI = 1.38-fold to 1.72-fold). By age 85 years, the absolute risk of overall BC was 19.6% for African American women in the top 1% of PRS313 and 6.7% for those in the lowest 1%. The recalibrated PRS did not improve BC risk prediction.

Conclusion: The PRSs stratify BC risk in women of African ancestry, with attenuated performance compared with that reported in European, Asian, and Latina populations. Future work is needed to improve BC risk stratification for women of African ancestry.
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http://dx.doi.org/10.1093/jnci/djab050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418423PMC
September 2021

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Am J Hum Genet 2021 04 12;108(4):564-582. Epub 2021 Mar 12.

The Charles R. Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059339PMC
April 2021

Population-level impact of coronavirus disease 2019 on breast cancer screening and diagnostic procedures.

Cancer 2021 06 26;127(12):2111-2121. Epub 2021 Feb 26.

Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Background: To understand how health care delays may affect breast cancer detection, the authors quantified changes in breast-related preventive and diagnostic care during the coronavirus disease 2019 (COVID-19) pandemic.

Methods: Eligible women (N = 39,444) were aged ≥18 years and received a screening mammogram, diagnostic mammogram, or breast biopsy between January 1, 2019 and September 30, 2020, at 7 academic and community breast imaging facilities in North Carolina. Changes in the number of mammography or breast biopsy examinations after March 3, 2020 (the first COVID-19 diagnosis in North Carolina) were evaluated and compared with the expected numbers based on trends between January 1, 2019 and March 2, 2020. Changes in the predicted mean monthly number of examinations were estimated using interrupted time series models. Differences in patient characteristics were tested using least squares means regression.

Results: Fewer examinations than expected were received after the pandemic's onset. Maximum reductions occurred in March 2020 for screening mammography (-85.1%; 95% CI, -100.0%, -70.0%) and diagnostic mammography (-48.9%; 95% CI, -71.7%, -26.2%) and in May 2020 for biopsies (-40.9%; 95% CI, -57.6%, -24.3%). The deficit decreased gradually, with no significant difference between observed and expected numbers by July 2020 (diagnostic mammography) and August 2020 (screening mammography and biopsy). Several months after the pandemic's onset, women who were receiving care had higher predicted breast cancer risk (screening mammography, P < .001) and more commonly lacked insurance (diagnostic mammography, P < .001; biopsy, P < .001) compared with the prepandemic population.

Conclusions: Pandemic-associated deficits in the number of breast examinations decreased over time. Utilization differed by breast cancer risk and insurance status, but not by age or race/ethnicity. Long-term studies are needed to clarify the contribution of these trends to breast cancer disparities.
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http://dx.doi.org/10.1002/cncr.33460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013451PMC
June 2021

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

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

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

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

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

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

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

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

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

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

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

A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry.

Blood Adv 2020 01;4(1):181-190

Division of Cancer Genetics and Epidemiology, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.

Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10-6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10-12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.
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http://dx.doi.org/10.1182/bloodadvances.2019000491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960456PMC
January 2020

Involution of Breast Lobules, Mammographic Breast Density and Prognosis Among Tamoxifen-Treated Estrogen Receptor-Positive Breast Cancer Patients.

J Clin Med 2019 Nov 4;8(11). Epub 2019 Nov 4.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.

Mammographic breast density (MD) reflects breast fibroglandular content. Its decline following adjuvant tamoxifen treated, estrogen receptor (ER)-positive breast cancer has been associated with improved outcomes. Breast cancers arise from structures termed lobules, and lower MD is associated with increased age-related lobule involution. We assessed whether pre-treatment involution influenced associations between MD decline and risk of breast cancer-specific death. ER-positive tamoxifen treated patients diagnosed at Kaiser Permanente Northwest (1990-2008) were defined as cases who died of breast cancer ( = 54) and matched controls (remained alive over similar follow-up; = 180). Lobule involution was assessed by examining terminal duct lobular units (TDLUs) in benign tissues surrounding cancers as TDLU count/mm, median span and acini count/TDLU. MD (%) was measured in the unaffected breast at baseline (median 6-months before) and follow-up (median 12-months after tamoxifen initiation). TDLU measures and baseline MD were positively associated among controls ( < 0.05). In multivariable regression models, MD decline (≥10%) was associated with reduced risk of breast cancer-specific death before (odds ratio (OR): 0.41, 95% CI: 0.18-0.92) and after (OR: 0.41, 95% CI: 0.18-0.94) adjustment for TDLU count/mm, TDLU span (OR: 0.34, 95% CI: 0.14-0.84), and acini count/TDLU (OR: 0.33, 95% CI: 0.13-0.81). MD decline following adjuvant tamoxifen is associated with reduced risk of breast cancer-specific death, irrespective of pre-treatment lobule involution.
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http://dx.doi.org/10.3390/jcm8111868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912285PMC
November 2019

Quantitative expression of MMPs 2, 9, 14, and collagen IV in LCIS and paired normal breast tissue.

Sci Rep 2019 09 17;9(1):13432. Epub 2019 Sep 17.

Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Certain matrix metalloproteinases (MMPs) have the ability to degrade collagen IV, a main component of the breast lobular basement membrane. In this cross-sectional study, we evaluated expression of MMPs 2, 9, and 14 and collagen IV in LCIS and adjacent normal breast tissue among LCIS patients without invasive breast cancer to determine whether expression differed between benign and preinvasive breast epithelial tissue. A total of 64 LCIS patients, diagnosed 2004-2014, were included; 44 had sufficient paired normal tissue for analysis. Marker epithelial expression was measured using immunofluorescence and quantified using the H score (MMPs) or pixel intensity (collagen IV). Associations were evaluated using the Spearman correlation or the Wilcoxon signed-rank test. In LCIS and normal tissue, there was a strong correlation between MMP2 and MMP14 expression (LCIS r = 0.69, normal r = 0.81, both P < 0.01). Other pairwise correlations were moderate to weak (range: LCIS r = 0.32-0.47, normal r = 0.19-0.32). For all markers, expression was lower in LCIS vs. normal tissue (all P ≤ 0.05). In sum, collagenase MMPs were expressed in normal breast and LCIS lesions of LCIS patients. However, expression was not higher in LCIS compared with normal tissue, suggesting collagenase MMP expression does not increase as breast tissue gains a more proliferative phenotype.
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http://dx.doi.org/10.1038/s41598-019-48602-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748975PMC
September 2019

Radiology Resident Journal Club: Enhancements Add Educational Value.

Acad Radiol 2020 04 5;27(4):591-595. Epub 2019 Jul 5.

Department of Radiology, University of North Carolina School of Medicine, 321 South Columbia Street, Chapel Hill, NC 27514. Electronic address:

Rationale And Objectives: Resident journal clubs are essential to develop skills to critically appraise existing literature. However, most reports of journal clubs focus on logistics of the activity and less on established roles of those involved. Our objective is to report on an innovative journal club from the perspective of key participants.

Materials And Methods: Journal club schedule, assignments, evaluations, and analysis are proffered from our institution. The journal club goals were formulated as: (1) improving resident understanding of research (biostatistical and epidemiologic) methods and statistical concepts, (2) teaching critical appraisal skills, and (3) promoting the use of evidence-based medicine. Each session's format is interactive, consisting of a 10 minute lecture with radiology examples of a research or statistical concept, followed by a journal club style discussion. Crucial to the success of this curriculum has been input and engagement of multiple parties: radiology residents, epidemiologist directors, and subspecialist clinician educator faculty members.

Conclusion: A well-thought out and well-run resident journal club offers numerous solutions to radiology residencies. To residency program leadership and to each individual resident annually, resident journal club offers cutting edge medical knowledge, interactive conferences in the formal didactic curriculum, resident training in critical thinking skills and research design, resident training in interpersonal and communication skills, opportunity for residents to be teachers, and expanded resident interprofessional education. It meets Accreditation Council for Graduate Medical Education common program, Residency Review Committee diagnostic radiology program, and American Board of Radiology Milestones requirements.
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http://dx.doi.org/10.1016/j.acra.2019.06.007DOI Listing
April 2020

Supplemental Breast Imaging Utilization After Breast Density Legislation in North Carolina.

J Am Coll Radiol 2020 Jan 1;17(1 Pt A):6-14. Epub 2019 Jul 1.

Department of Radiology and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Purpose: Breast density notification laws are increasingly common but little is known of how they affect supplemental screening use. The aim of this study was to investigate supplemental screening before and after density notification in North Carolina, where notification has been required since 2014.

Methods: Breast screening data from Carolina Mammography Registry participants aged 40 to 79 years with no personal histories of breast cancer or breast implants were evaluated. Supplemental screening was defined as a nondiagnostic digital breast tomosynthesis (DBT), whole-breast ultrasound, or breast MRI performed within 3 months of negative or benign results on screening mammography (2-D or DBT). Supplemental screening before (2012-2013) and after (2014-2016) the notification law was compared using logistic regression.

Results: During the study period, 78,967 women underwent 145,279 index screening mammographic examinations. Supplemental screening use was similar before and after the notification law, regardless of breast density (dense breasts: adjusted odds ratio [aOR], 1.01; 95% confidence interval [CI], 0.58-1.75; nondense breasts: aOR, 0.63; 95% CI, 0.38-1.04). Although there was no change in supplemental screening, new use of any screening DBT from 2014 to 2016 was greater for women with dense breasts (versus nondense breasts; aOR, 1.15; 95% CI, 1.08-1.23).

Conclusions: Data suggest that supplemental screening use in North Carolina did not change after enactment of a breast density notification law, though the increase in new use of any screening DBT was greater for women with dense breasts. The short-term lack of change in supplemental screening should be considered as additional notification laws are developed.
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http://dx.doi.org/10.1016/j.jacr.2019.05.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938553PMC
January 2020

Recruiting population controls for case-control studies in sub-Saharan Africa: The Ghana Breast Health Study.

PLoS One 2019 16;14(4):e0215347. Epub 2019 Apr 16.

National Cancer Institute, Rockville, MD, United States of America.

Background: In case-control studies, population controls can help ensure generalizability; however, the selection of population controls can be challenging in environments that lack population registries. We developed a population enumeration and sampling strategy to facilitate use of population controls in a breast cancer case-control study conducted in Ghana.

Methods: Household enumeration was conducted in 110 census-defined geographic areas within Ghana's Ashanti, Central, Eastern, and Greater Accra Regions. A pool of potential controls (women aged 18 to 74 years, never diagnosed with breast cancer) was selected from the enumeration using systematic random sampling and frequency-matched to the anticipated distributions of age and residence among cases. Multiple attempts were made to contact potential controls to assess eligibility and arrange for study participation. To increase participation, we implemented a refusal conversion protocol in which initial non-participants were re-approached after several months.

Results: 2,528 women were sampled from the enumeration listing, 2,261 (89%) were successfully contacted, and 2,106 were enrolled (overall recruitment of 83%). 170 women were enrolled through refusal conversion. Compared with women enrolled after being first approached, refusal conversion enrollees were younger and less likely to complete the study interview in the study hospital (13% vs. 23%). The most common reasons for non-participation were lack of interest and lack of time.

Conclusions: Using household enumeration and repeated contacts, we were able to recruit population controls with a high participation rate. Our approach may provide a blue-print for others undertaking epidemiologic studies in populations that lack accessible population registries.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215347PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467449PMC
January 2020

Image analysis with deep learning to predict breast cancer grade, ER status, histologic subtype, and intrinsic subtype.

NPJ Breast Cancer 2018 3;4:30. Epub 2018 Sep 3.

1Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA.

RNA-based, multi-gene molecular assays are available and widely used for patients with ER-positive/HER2-negative breast cancers. However, RNA-based genomic tests can be costly and are not available in many countries. Methods for inferring molecular subtype from histologic images may identify patients most likely to benefit from further genomic testing. To identify patients who could benefit from molecular testing based on H&E stained histologic images, we developed an image analysis approach using deep learning. A training set of 571 breast tumors was used to create image-based classifiers for tumor grade, ER status, PAM50 intrinsic subtype, histologic subtype, and risk of recurrence score (ROR-PT). The resulting classifiers were applied to an independent test set ( = 288), and accuracy, sensitivity, and specificity of each was assessed on the test set. Histologic image analysis with deep learning distinguished low-intermediate vs. high tumor grade (82% accuracy), ER status (84% accuracy), Basal-like vs. non-Basal-like (77% accuracy), Ductal vs. Lobular (94% accuracy), and high vs. low-medium ROR-PT score (75% accuracy). Sampling considerations in the training set minimized bias in the test set. Incorrect classification of ER status was significantly more common for Luminal B tumors. These data provide proof of principle that molecular marker status, including a critical clinical biomarker (i.e., ER status), can be predicted with accuracy >75% based on H&E features. Image-based methods could be promising for identifying patients with a greater need for further genomic testing, or in place of classically scored variables typically accomplished using human-based scoring.
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http://dx.doi.org/10.1038/s41523-018-0079-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120869PMC
September 2018

PAM50 and Risk of Recurrence Scores for Interval Breast Cancers.

Cancer Prev Res (Phila) 2018 06 5;11(6):327-336. Epub 2018 Apr 5.

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

Breast cancers detected after a negative breast screening examination and prior to the next screening are referred to as interval cancers. These cancers generally have poor clinical characteristics compared with screen-detected cancers, but associations between interval cancer and genomic cancer characteristics are not well understood. Mammographically screened women diagnosed with primary invasive breast cancer from 1993 to 2013 ( = 370) were identified by linking the Carolina Breast Cancer Study and the Carolina Mammography Registry. Among women with a registry-identified screening mammogram 0 to 24 months before diagnosis, cancers were classified as screen-detected ( = 165) or interval-detected ( = 205). Using logistic regression, we examined the association of mode of detection with cancer characteristics (clinical, IHC, and genomic), overall, and in analyses stratified on mammographic density and race. Interval cancer was associated with large tumors [>2 cm; OR, 2.3; 95% confidence interval (CI), 1.5-3.7], positive nodal status (OR, 1.8; 95% CI, 1.1-2.8), and triple-negative subtype (OR, 2.5; 95% CI, 1.1-5.5). Interval cancers were more likely to have non-Luminal A subtype (OR, 2.9; 95% CI, 1.5-5.7), whereas screen-detected cancers tended to be more indolent (96% had low risk of recurrence genomic scores; 71% were PAM50 Luminal A). When stratifying by mammographic density and race, associations between interval detection and poor prognostic features were similar by race and density status. Strong associations between interval cancers and poor-prognosis genomic features (non-Luminal A subtype and high risk of recurrence score) suggest that aggressive tumor biology is an important contributor to interval cancer rates. .
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http://dx.doi.org/10.1158/1940-6207.CAPR-17-0368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984721PMC
June 2018

A functionally significant SNP in TP53 and breast cancer risk in African-American women.

NPJ Breast Cancer 2017 27;3. Epub 2017 Feb 27.

Department of Medicine, University of Chicago, Chicago, , IL 60637 USA.

A coding region polymorphism exists in the gene (Pro47Ser; rs1800371) in individuals of African descent, which reduces p53 tumor suppressor function in a mouse model. It has been unclear whether this functionally significant polymorphism alters cancer risk in humans. This analysis included 6907 women with breast cancer and 7644 controls from the AMBER, ROOT, and AABC consortia. We used multivariable logistic regression to estimate associations between the TP53 Pro47Ser allele and overall breast cancer risk. Because polymorphisms in tend to be associated with cancer risk in pre-menopausal women, we also limited our analyses to this population in the AMBER and ROOT consortia, where menopausal status was known, and conducted a fixed effects meta-analysis. In an analysis of all women in the AMBER, ROOT, and AABC consortia, we found no evidence for association of the Pro47Ser variant with breast cancer risk. However, when we restricted our analysis to only pre-menopausal women from the AMBER and ROOT consortia, there was a per allele odds ratio of 1.72 (95% confidence interval 1.08-2.76; -value = 0.023). Although the Pro47Ser variant was not associated with overall breast cancer risk, it may increase risk among pre-menopausal women of African ancestry. Following up on more studies in human populations may better elucidate the role of this variant in breast cancer etiology. However, because of the low frequency of the polymorphism in women of African ancestry, its impact at a population level may be minimal.
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http://dx.doi.org/10.1038/s41523-017-0007-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445618PMC
February 2017

Epidemiologic Risk Factors for In Situ and Invasive Breast Cancers Among Postmenopausal Women in the National Institutes of Health-AARP Diet and Health Study.

Am J Epidemiol 2017 Dec;186(12):1329-1340

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.

Comparing risk factor associations between invasive breast cancers and possible precursors may further our understanding of factors related to initiation versus progression. Accordingly, among 190,325 postmenopausal participants in the National Institutes of Health-AARP Diet and Health Study (1995-2011), we compared the association between risk factors and incident ductal carcinoma in situ (DCIS; n = 1,453) with that of risk factors and invasive ductal carcinomas (n = 7,525); in addition, we compared the association between risk factors and lobular carcinoma in situ (LCIS; n = 186) with that of risk factors and invasive lobular carcinomas (n = 1,191). Hazard ratios and 95% confidence intervals were estimated from multivariable Cox proportional hazards regression models. We used case-only multivariable logistic regression to test for heterogeneity in associations. Younger age at menopause was associated with a higher risk of DCIS but lower risks of LCIS and invasive ductal carcinomas (P for heterogeneity < 0.01). Prior breast biopsy was more strongly associated with the risk of LCIS than the risk of DCIS (P for heterogeneity = 0.04). Increased risks associated with use of menopausal hormone therapy were stronger for LCIS than DCIS (P for heterogeneity = 0.03) and invasive lobular carcinomas (P for heterogeneity < 0.01). Associations were similar for race, age at menarche, age at first birth, family history, alcohol consumption, and smoking status, which suggests that most risk factor associations are similar for in situ and invasive cancers and may influence early stages of tumorigenesis. The differential associations observed for various factors may provide important clues for understanding the etiology of certain breast cancers.
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http://dx.doi.org/10.1093/aje/kwx206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860557PMC
December 2017

Characterizing Genetic Susceptibility to Breast Cancer in Women of African Ancestry.

Cancer Epidemiol Biomarkers Prev 2017 07 4;26(7):1016-1026. Epub 2017 Apr 4.

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

Genome-wide association studies have identified approximately 100 common genetic variants associated with breast cancer risk, the majority of which were discovered in women of European ancestry. Because of different patterns of linkage disequilibrium, many of these genetic markers may not represent signals in populations of African ancestry. We tested 74 breast cancer risk variants and conducted fine-mapping of these susceptibility regions in 6,522 breast cancer cases and 7,643 controls of African ancestry from three genetic consortia (AABC, AMBER, and ROOT). Fifty-four of the 74 variants (73%) were found to have ORs that were directionally consistent with those previously reported, of which 12 were nominally statistically significant ( < 0.05). Through fine-mapping, in six regions (), we observed seven markers that better represent the underlying risk variant for overall breast cancer or breast cancer subtypes, whereas in another two regions (), we identified suggestive evidence of signals that are independent of the reported index variant. Overlapping chromatin features and regulatory elements suggest that many of the risk alleles lie in regions with biological functionality. Through fine-mapping of known susceptibility regions, we have revealed alleles that better characterize breast cancer risk in women of African ancestry. The risk alleles identified represent genetic markers for modeling and stratifying breast cancer risk in women of African ancestry. .
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http://dx.doi.org/10.1158/1055-9965.EPI-16-0567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500414PMC
July 2017

Design considerations for identifying breast cancer risk factors in a population-based study in Africa.

Int J Cancer 2017 06 28;140(12):2667-2677. Epub 2017 Mar 28.

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

Although breast cancer is becoming more prevalent in Africa, few epidemiologic studies have been undertaken and appropriate methodologic approaches remain uncertain. We therefore conducted a population-based case-control study in Accra and Kumasi, Ghana, enrolling 2,202 women with lesions suspicious for breast cancer and 2,161 population controls. Biopsy tissue for cases prior to neoadjuvant therapy (if given), blood, saliva and fecal samples were sought for study subjects. Response rates, risk factor prevalences and odds ratios for established breast cancer risk factors were calculated. A total of 54.5% of the recruited cases were diagnosed with malignancies, 36.0% with benign conditions and 9.5% with indeterminate diagnoses. Response rates to interviews were 99.2% in cases and 91.9% in controls, with the vast majority of interviewed subjects providing saliva (97.9% in cases vs. 98.8% in controls) and blood (91.8% vs. 82.5%) samples; lower proportions (58.1% vs. 46.1%) provided fecal samples. While risk factor prevalences were unique as compared to women in other countries (e.g., less education, higher parity), cancer risk factors resembled patterns identified elsewhere (elevated risks associated with higher levels of education, familial histories of breast cancer, low parity and larger body sizes). Subjects with benign conditions were younger and exhibited higher socioeconomic profiles (e.g., higher education and lower parity) than those with malignancies, suggesting selective referral influences. While further defining breast cancer risk factors in Africa, this study showed that successful population-based interdisciplinary studies of cancer in Africa are possible but require close attention to diagnostic referral biases and standardized and documented approaches for high-quality data collection, including biospecimens.
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http://dx.doi.org/10.1002/ijc.30688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5926189PMC
June 2017

Genome-wide association studies in women of African ancestry identified 3q26.21 as a novel susceptibility locus for oestrogen receptor negative breast cancer.

Hum Mol Genet 2016 11;25(21):4835-4846

Department of Epidemiology, Gillings School of Global Public Health, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.

Multiple breast cancer loci have been identified in previous genome-wide association studies, but they were mainly conducted in populations of European ancestry. Women of African ancestry are more likely to have young-onset and oestrogen receptor (ER) negative breast cancer for reasons that are unknown and understudied. To identify genetic risk factors for breast cancer in women of African descent, we conducted a meta-analysis of two genome-wide association studies of breast cancer; one study consists of 1,657 cases and 2,029 controls genotyped with Illumina’s HumanOmni2.5 BeadChip and the other study included 3,016 cases and 2,745 controls genotyped using Illumina Human1M-Duo BeadChip. The top 18,376 single nucleotide polymorphisms (SNP) from the meta-analysis were replicated in the third study that consists of 1,984 African Americans cases and 2,939 controls. We found that SNP rs13074711, 26.5 Kb upstream of TNFSF10 at 3q26.21, was significantly associated with risk of oestrogen receptor (ER)-negative breast cancer (odds ratio [OR]=1.29, 95% CI: 1.18-1.40; P = 1.8 × 10 − 8). Functional annotations suggest that the TNFSF10 gene may be involved in breast cancer aetiology, but further functional experiments are needed. In addition, we confirmed SNP rs10069690 was the best indicator for ER-negative breast cancer at 5p15.33 (OR = 1.30; P = 2.4 × 10 − 10) and identified rs12998806 as the best indicator for ER-positive breast cancer at 2q35 (OR = 1.34; P = 2.2 × 10 − 8) for women of African ancestry. These findings demonstrated additional susceptibility alleles for breast cancer can be revealed in diverse populations and have important public health implications in building race/ethnicity-specific risk prediction model for breast cancer.
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http://dx.doi.org/10.1093/hmg/ddw305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975608PMC
November 2016

Relationship between crown-like structures and sex-steroid hormones in breast adipose tissue and serum among postmenopausal breast cancer patients.

Breast Cancer Res 2017 01 19;19(1). Epub 2017 Jan 19.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, 20892, USA.

Background: Postmenopausal obesity is associated with increased circulating levels of androgens and estrogens and elevated breast cancer risk. Crown-like structures (CLS; microscopic foci of dying adipocytes surrounded by macrophages) are proposed to represent sites of increased aromatization of androgens to estrogens. Accordingly, we examined relationships between CLS and sex-steroid hormones in breast adipose tissue and serum from postmenopausal breast cancer patients.

Methods: Formalin-fixed paraffin embedded benign breast tissues collected for research from postmenopausal women (n = 83) diagnosed with invasive breast cancer in the Polish Breast Cancer Study (PBCS) were evaluated. Tissues were immunohistochemically stained for CD68 to determine the presence of CLS per unit area of adipose tissue. Relationships were assessed between CD68 density and CLS and previously reported sex-steroid hormones quantified using radioimmunoassays in serum taken at the time of diagnosis and in fresh frozen adipose tissue taken at the time of surgery. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the relationships between hormones (in tertiles) and CLS.

Results: CLS were observed in 36% of benign breast tissues, with a higher frequency among obese versus lean women (54% versus 17%, p = 0.03). Detection of CLS was not related to individual hormone levels or breast tumor pathology characteristics. However, detection of CLS was associated with hormone ratios. Compared with women in the highest tertile of estrone:androstenedione ratio in fat, those in the lowest tertile were less likely to have CLS (OR 0.12, 95% CI 0.03-0.59). A similar pattern was observed with estradiol:testosterone ratio in serum and CLS (lowest versus highest tertile, OR 0.18, 95% CI 0.04-0.72).

Conclusions: CLS were more frequently identified in the breast fat of obese women and were associated with increased ratios of select estrogens:androgens in the blood and tissues, but not with individual hormones. Additional studies on CLS, tissue and blood hormone levels, and breast cancer risk are needed to understand and confirm these findings.
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http://dx.doi.org/10.1186/s13058-016-0791-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244534PMC
January 2017

Pooled analysis of active cigarette smoking and invasive breast cancer risk in 14 cohort studies.

Int J Epidemiol 2017 06;46(3):881-893

Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.

Background: The 2014 US Surgeon General's report noted research gaps necessary to determine a causal relationship between active cigarette smoking and invasive breast cancer risk, including the role of alcohol consumption, timing of exposure, modification by menopausal status and heterogeneity by oestrogen receptor (ER) status.

Methods: To address these issues, we pooled data from 14 cohort studies contributing 934 681 participants (36 060 invasive breast cancer cases). Cox proportional hazard regression models were used to calculate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: Smoking duration before first birth was positively associated with risk ( P -value for trend = 2 × 10 -7 ) with the highest HR for initiation >10 years before first birth (HR = 1.18, CI 1.12-1.24). Effect modification by current alcohol consumption was evident for the association with smoking duration before first birth ( P -value=2×10 -4 ); compared with never-smoking non-drinkers, initiation >10 years before first birth was associated with risk in every category of alcohol intake, including non-drinkers (HR = 1.15, CI 1.04-1.28) and those who consumed at least three drinks per day (1.85, 1.55-2.21). Associations with smoking before first birth were limited to risk of ER+ breast cancer ( P -value for homogeneity=3×10 -3 ). Other smoking timing and duration characteristics were associated with risk even after controlling for alcohol, but were not associated with risk in non-drinkers. Effect modification by menopause was not evident.

Conclusions: Smoking, particularly if initiated before first birth, was modestly associated with ER+ breast cancer risk that was not confounded by amount of adult alcohol intake. Possible links with breast cancer provide additional motivation for young women to not initiate smoking.
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http://dx.doi.org/10.1093/ije/dyw288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837778PMC
June 2017

Association of Adjuvant Tamoxifen and Aromatase Inhibitor Therapy With Contralateral Breast Cancer Risk Among US Women With Breast Cancer in a General Community Setting.

JAMA Oncol 2017 02 6;3(2):186-193. Epub 2016 Oct 6.

Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Importance: Within 10 years after breast cancer diagnosis, roughly 5% of patients develop contralateral breast cancer (CBC). Randomized trials have found that therapy including tamoxifen citrate and aromatase inhibitors (AIs) reduces CBC risk. But little is known about the magnitude and duration of protective associations within the context of real-world clinical management settings, where varying durations of and gaps in treatment are common.

Objective: To determine the association between adjuvant tamoxifen and AI therapy and CBC risk within a general community setting.

Design, Setting, And Participants: A retrospective cohort study of CBC risk among 7541 patients diagnosed with a first primary unilateral invasive breast cancer at Kaiser Permanente Institute for Health Research (Colorado) or Kaiser Permanente Northwest Center for Health Research (Oregon) between January 1, 1990, and December 31, 2008. Data were analyzed from 1 year after diagnosis of the first breast cancer through the earliest of the following events: CBC diagnosis, other second cancer diagnosis, death, last tumor registry follow-up, exit from the Kaiser Permanente health care plan, or end of study follow-up (December 31, 2010, for Oregon and December 31, 2011, for Colorado).

Exposures: Adjuvant tamoxifen use and AI therapy were treated as time-dependent exposures, assessed using electronic prescription records.

Main Outcomes And Measures: Incident CBC based on long-term systematic follow-up.

Results: Among 7541 women with invasive breast cancer, median age at initial breast cancer diagnosis was 60.6 years (age range, 24.9-84.9 years). Women were predominantly (92.9% [7009 of 7541]) of white race. During a median of 6.3 years (range, 1-20.9 years) of follow-up, 248 women developed CBC (45 in situ and 203 invasive). Contralateral breast cancer risk decreased significantly with increasing tamoxifen therapy duration. In current users, the relative risk (RR) per year of tamoxifen use was 0.76 (95% CI, 0.64-0.89), with an estimated 66% (RR, 0.34; 95% CI, 0.29-0.40) RR reduction for 4 years of use compared with nonusers. Risk reductions were slightly smaller for past users but were still significant at least 5 years after stopping tamoxifen therapy (RR per year of use, 0.85; 95% CI, 0.71-0.995). In addition, AI use without tamoxifen therapy was associated with reduced CBC risk (RR for AI users compared with nonusers, 0.48; 95% CI, 0.22-0.97). Risk reductions were most apparent among women whose primary and CBCs were estrogen receptor positive.

Conclusions And Relevance: Tamoxifen therapy was associated with reduced CBC risk during treatment and after its cessation, with risk progressively decreasing as tamoxifen therapy duration increased. Among those surviving at least 5 years, tamoxifen use for at least 4 years was estimated to prevent 3 CBCs per 100 women by 10 years after an estrogen receptor-positive first breast cancer, an absolute risk reduction that is consistent with findings from clinical trials. If adjuvant endocrine therapy is indicated for breast cancer treatment, these findings in concert with trial data suggest that women should be encouraged to complete the full course.
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http://dx.doi.org/10.1001/jamaoncol.2016.3340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757540PMC
February 2017

The association between mammographic calcifications and breast cancer prognostic factors in a population-based registry cohort.

Cancer 2017 01 28;123(2):219-227. Epub 2016 Sep 28.

Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Background: Mammographic calcifications can be a marker of malignancy, but their association with prognosis is less well established. In the current study, the authors examined the relationship between calcifications and breast cancer prognostic factors in the population-based Carolina Mammography Registry.

Methods: The current study included 8472 invasive breast cancers diagnosed in the Carolina Mammography Registry between 1996 and 2011 for which information regarding calcifications occurring within 2 years of diagnosis was reported. Calcification-specific Breast Imaging Reporting and Data System (BI-RADS) assessments were reported prospectively by a radiologist. Tumor characteristic data were obtained from the North Carolina Central Cancer Registry and/or pathology reports. Multivariable-adjusted associations between the presence of calcifications in the breast affected by cancer and tumor characteristics were estimated using logistic regression. Statistical tests were 2-sided.

Results: The presence of calcifications was found to be positively associated with tumors that were high grade (vs low grade: odds ratio [OR], 1.43; 95% confidence interval [95% CI], 1.10-1.88) or had an in situ component (vs without: OR, 2.15; 95% CI, 1.81-2.55). Calcifications were found to be inversely associated with hormone receptor-negative status (vs positive status: OR, 0.73; 95% CI, 0.57-0.93), size >35 mm (vs ≤8 mm: OR, 0.47; 95% CI, 0.37-0.61), and lobular tumors (vs ductal: OR, 0.39; 95% CI, 0.22-0.69). The association between the presence of calcifications and an in situ component was limited to BI-RADS category 4 and 5 calcifications and was absent for BI-RADS category 2 or 3 calcifications (P for heterogeneity <.01). The association with tumor size was found to be strongest for BI-RADS categories 3 and 4 (P for heterogeneity <.01).

Conclusions: Calcifications were found to be associated with both unfavorable (high grade) and favorable (small size, hormone receptor positivity) prognostic factors. Detailed analysis of the biological features of calcifications is necessary to understand the mechanisms driving these associations. Cancer 2017;123:219-227. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5287030PMC
January 2017

A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci.

Cancer Epidemiol Biomarkers Prev 2016 12 1;25(12):1609-1618. Epub 2016 Sep 1.

Keck School of Medicine of USC and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.

Background: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma.

Methods: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality.

Results: We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4 Correlated variants in 7p15.3 clustered around an enhancer at the 3' end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7 CONCLUSIONS: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles.

Impact: A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. ©2016 AACR.
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http://dx.doi.org/10.1158/1055-9965.EPI-15-1193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524541PMC
December 2016

Genetic variants in microRNA and microRNA biogenesis pathway genes and breast cancer risk among women of African ancestry.

Hum Genet 2016 10 5;135(10):1145-59. Epub 2016 Jul 5.

Department of Public Health Sciences, University of Chicago, 5841 S. Maryland Ave., MC 2007, Chicago, IL, 60637, USA.

MicroRNAs (miRNA) regulate breast biology by binding to specific RNA sequences, leading to RNA degradation and inhibition of translation of their target genes. While germline genetic variations may disrupt some of these interactions between miRNAs and their targets, studies assessing the relationship between genetic variations in the miRNA network and breast cancer risk are still limited, particularly among women of African ancestry. We systematically put together a list of 822 and 10,468 genetic variants among primary miRNA sequences and 38 genes in the miRNA biogenesis pathway, respectively; and examined their association with breast cancer risk in the ROOT consortium which includes women of African ancestry. Findings were replicated in an independent consortium. Logistic regression was used to estimate the odds ratio (OR) and 95 % confidence intervals (CI). For overall breast cancer risk, three single-nucleotide polymorphisms (SNPs) in miRNA biogenesis genes DROSHA rs78393591 (OR = 0.69, 95 % CI: 0.55-0.88, P = 0.003), ESR1 rs523736 (OR = 0.88, 95 % CI: 0.82-0.95, P = 3.99 × 10(-4)), and ZCCHC11 rs114101502 (OR = 1.33, 95 % CI: 1.11-1.59, P = 0.002), and one SNP in primary miRNA sequence (rs116159732 in miR-6826, OR = 0.74, 95 % CI: 0.63-0.89, P = 0.001) were found to have significant associations in both discovery and validation phases. In a subgroup analysis, two SNPs were associated with risk of estrogen receptor (ER)-negative breast cancer, and three SNPs were associated with risk of ER-positive breast cancer. Several variants in miRNA and miRNA biogenesis pathway genes were associated with breast cancer risk. Risk associations varied by ER status, suggesting potential new mechanisms in etiology.
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http://dx.doi.org/10.1007/s00439-016-1707-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021583PMC
October 2016

Longitudinal Change in Mammographic Density among ER-Positive Breast Cancer Patients Using Tamoxifen.

Cancer Epidemiol Biomarkers Prev 2016 Jan 6;25(1):212-6. Epub 2015 Nov 6.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Tamoxifen-associated mammographic density (MD) reductions are linked to improved breast cancer survival. We evaluated MD at six time points to determine the timing of greatest reduction following tamoxifen initiation. We sampled 40 Kaiser Permanente Northwest estrogen receptor (ER)-positive breast cancer patients from a prior study of MD change, according to tamoxifen use duration and age at diagnosis: <4 years tamoxifen and ≤50 years (N = 6) or >50 years (N = 10) old; ≥4 years tamoxifen and ≤50 years (N = 13) or >50 years (N = 11) old. A single reader evaluated percent MD in the contralateral breast on baseline (pre-diagnosis) and five approximately yearly post-diagnostic (T1 to T5) mammograms. Mean MD change was calculated. Interactions with age (≤50 and >50 years), tamoxifen duration (<4 and ≥4 years), and baseline MD (tertiles) were tested in linear regression models. Overall, the largest MD decline occurred by T1 (mean 4.5%) with little additional decline by T5. Declines differed by tertile of baseline MD (Pinteraction < 0.01). In the highest tertile, the largest reduction occurred by T1 (mean 14.9%), with an additional reduction of 3.6% by T5. Changes were smaller in the middle and lowest baseline MD tertiles, with cumulative reductions of 3.0% and 0.4% from baseline to T5, respectively. There were no differences by age (Pinteraction = 0.36) or tamoxifen duration (Pinteraction = 0.42). Among ER-positive patients treated with tamoxifen and surviving ≥5 years, most of the MD reduction occurred within approximately 12 months of tamoxifen initiation, suggesting that MD measurement at a single time point following tamoxifen initiation can identify patients with substantial density declines.
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http://dx.doi.org/10.1158/1055-9965.EPI-15-0412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713329PMC
January 2016

Performance of digital screening mammography in a population-based cohort of black and white women.

Cancer Causes Control 2015 Oct 17;26(10):1495-9. Epub 2015 Jul 17.

Department of Radiology, The University of North Carolina, Chapel Hill, NC, USA.

Purpose: There is scarce information on whether digital screening mammography performance differs between black and white women.

Methods: We examined 256,470 digital screening mammograms performed from 2005 to 2010 among 31,654 black and 133,152 white Carolina Mammography Registry participants aged ≥40 years. We compared recall rate, sensitivity, specificity, and positive predictive value (PPV1) between black and white women, adjusting for potential confounders using random effects logistic regression.

Results: Breast cancer was diagnosed in 276 black and 1,095 white women. Recall rates were similar for blacks and whites (8.6 vs. 8.5 %), as were sensitivity (83.7 vs. 82.4 %), specificity (91.8 vs. 91.9 %), and PPV1 (4.8 vs. 5.3 %) (all p values >0.05). Stratified and adjusted models showed similar results. Despite comparable mammography performance, tumors diagnosed in black women were more commonly poorly differentiated and hormone receptor negative.

Conclusion: Equivalent performance of digital screening mammography by race suggests that efforts to understand tumor disparities should focus on etiologic factors that influence tumor biology.
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http://dx.doi.org/10.1007/s10552-015-0631-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567941PMC
October 2015

Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults.

PLoS One 2015 30;10(6):e0131106. Epub 2015 Jun 30.

Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States of America.

Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0131106PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488332PMC
April 2016
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