Publications by authors named "Olufunmilayo I Olopade"

357 Publications

Correction: Intrinsic adriamycin resistance in p53-mutated breast cancer is related to the miR-30c/FANCF/REV1-mediated DNA damage response.

Cell Death Dis 2022 Jan 25;13(1):82. Epub 2022 Jan 25.

Department of Pharmacology, School of Pharmacy, China Medical University, No. 77 Puhe Road, Shenyang North New Area, 110122, Shenyang City, Liaoning, China.

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http://dx.doi.org/10.1038/s41419-022-04543-zDOI Listing
January 2022

Polygenic risk modeling for prediction of epithelial ovarian cancer risk.

Eur J Hum Genet 2022 Jan 14. Epub 2022 Jan 14.

Maria Sklodowska-Curie National Research Institute of Oncology, Department of Pathology and Laboratory Diagnostics, Warsaw, Poland.

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
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http://dx.doi.org/10.1038/s41431-021-00987-7DOI Listing
January 2022

Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes.

Nat Commun 2021 11 26;12(1):6946. Epub 2021 Nov 26.

Center for Clinical Cancer Genetics and Global Health, Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA.

Black women across the African diaspora experience more aggressive breast cancer with higher mortality rates than white women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast cancers, with RNA-seq in a subset, from women in Nigeria in comparison with The Cancer Genome Atlas (n = 76) reveal a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations with a 10.5-year younger age at diagnosis. We also find non-coding mutations in bona fide drivers (ZNF217 and SYPL1) and a previously unreported INDEL signature strongly associated with African ancestry proportion, underscoring the need to expand inclusion of diverse populations in biomedical research. Finally, we demonstrate that characterizing tumors for homologous recombination deficiency has significant clinical relevance in stratifying patients for potentially life-saving therapies.
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http://dx.doi.org/10.1038/s41467-021-27079-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626467PMC
November 2021

Feasibility of genetic testing for cancer risk assessment programme in Nigeria.

Ecancermedicalscience 2021 7;15:1283. Epub 2021 Sep 7.

Center for Clinical Cancer Genetics, University of Chicago, Chicago, IL, 60637, USA.

Background: A high frequency of BRCA mutations has been established in Nigerian breast cancer (BC) patients. Recently, patients' and first-degree relatives' interest have been raised on cancer genetic risk assessment through our awareness activities in Nigeria. This led to the emergence of nurse-led cancer genetic counselling (CGC) and testing aimed at providing standard-of-care for individuals at increased risk of hereditary breast and ovarian cancers.

Methods: In June 2018, CGC and testing of patients with BC and ovarian cancer (OC) commenced in collaboration with Color Genomics Inc. for a 30-panel gene testing. Previously trained nurses in CGC at the University College Hospital, Ibadan offered genetic counselling (GC) to willing patients with BC and gynaecological cancer in four out-patient oncology clinics and departments for the pilot study. Consultation consisted of CGC, patient's history, pedigree and sample collection for genetic testing (GT).

Results: Forty-seven patients - 40 with BC, five with OC and two with endometrial cancer received GC, and all chose to undergo GT. The average age at testing was 48.2 ± 12.1 years. Eight women reported a known family cancer history and there were more perceived benefits than barriers to GT with the patients experiencing the desire for none of their relative to have cancer. Results revealed no mutations in 27 (57.4%), 16 (4.0%) variants of unknown significance and 4 (8.5%) pathogenic mutations.

Conclusion: Personalised cancer care utilises GC and testing for cancer risk assessment towards prevention and early detection in high risk women. The study indicates the necessity of expanded cancer genetic services for integration into patient care and cancer prevention.
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http://dx.doi.org/10.3332/ecancer.2021.1283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8580592PMC
September 2021

Associations between age of menarche and genetic variation in women of African descent: genome-wide association study and polygenic score analysis.

J Epidemiol Community Health 2021 Oct 27. Epub 2021 Oct 27.

Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA

Introduction: Many diseases of adulthood are associated with a woman's age at menarche. Genetic variation affects age at menarche, but it remains unclear whether in women of African ancestry the timing of menarche is regulated by genetic variants that were identified in predominantly European and East Asian populations.

Methods: We explored the genetic architecture of age at menarche in 3145 women of African ancestry who live in the USA, Barbados and Nigeria. We undertook a genome-wide association study, and evaluated the performance of previously identified variants.

Results: One variant was associated with age at menarche, a deletion at chromosome 2 (chr2:207216165) (p=1.14×10). 349 genotyped variants overlapped with these identified in populations of non-African ancestry; these replicated weakly, with 51.9% having concordant directions of effect. However, collectively, a polygenic score constructed of those previous variants was suggestively associated with age at menarche (beta=0.288 years; p=0.041). Further, this association was strong in women enrolled in the USA and Barbados (beta=0.445 years, p=0.008), but not in Nigerian women (beta=0.052 years; p=0.83).

Discussion: This study suggests that in women of African ancestry the genetic drivers of age at menarche may differ from those identified in populations of non-African ancestry, and that these differences are more pronounced in women living in Nigeria, although some associated trait loci may be shared across populations. This highlights the need for well-powered ancestry-specific genetic studies to fully characterise the genetic influences of age at menarche.
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http://dx.doi.org/10.1136/jech-2020-216000DOI Listing
October 2021

Weight Gain and the Risk of Ovarian Cancer in and Mutation Carriers.

Cancer Epidemiol Biomarkers Prev 2021 Nov 23;30(11):2038-2043. Epub 2021 Aug 23.

Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada.

Background: Weight gain and other anthropometric measures on the risk of ovarian cancer for women with mutations are not known. We conducted a prospective analysis of weight change since age 18, height, body mass index (BMI) at age 18, and current BMI and the risk of developing ovarian cancer among and mutation carriers.

Methods: In this prospective cohort study, height, weight, and weight at age 18 were collected at study enrollment. Weight was updated biennially. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for ovarian cancer.

Results: This study followed 4,340 women prospectively. There were 121 incident cases of ovarian cancer. Weight gain of more than 20 kg since age 18 was associated with a 2-fold increased risk of ovarian cancer, compared with women who maintained a stable weight (HR, 2.00; 95% CI, 1.13-3.54; = 0.02). Current BMI of 26.5 kg/m or greater was associated with an increased risk of ovarian cancer in mutation carriers, compared with those with a BMI less than 20.8 kg/m (Q4 vs. Q1 HR, 2.13; 95% CI, 1.04-4.36; = 0.04). There were no significant associations between height or BMI at age 18 and risk of ovarian cancer.

Conclusions: Adult weight gain is a risk factor for ovarian cancer in women with a or mutation.

Impact: These findings emphasize the importance of maintaining a healthy body weight throughout adulthood in women at high risk for ovarian cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0296DOI Listing
November 2021

Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores.

J Natl Cancer Inst 2022 Jan;114(1):109-122

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.

Background: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.

Methods: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk.

Results: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.

Conclusions: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.
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http://dx.doi.org/10.1093/jnci/djab147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8755508PMC
January 2022

The impact of coronavirus disease 2019 on the quality of life and treatment disruption of patients with breast cancer in a multiethnic cohort.

Cancer 2021 11 22;127(21):4072-4080. Epub 2021 Jul 22.

Department of Public Health Sciences, University of Chicago, Chicago, Illinois.

Background: As the coronavirus disease 2019 (COVID-19) pandemic continues to spread, it remains unclear how vulnerable populations with preexisting health conditions like cancer have been affected.

Methods: Between July and September of 2020, the authors conducted a cross-sectional study that surveyed 2661 patients with breast cancer who were registered in the Chicago Multiethnic Epidemiologic Breast Cancer Cohort and received 1300 responses (71.5% White patients and 22.4% Black patients). The survey measured the psychosocial well-being of participants before and during the COVID-19 pandemic and examined whether they experienced any type of financial challenges or treatment disruption.

Results: The results indicated that feelings of isolation increased significantly during the pandemic. Meanwhile, the overall median isolation/stress score was 1.2 on a scale from 0 (never) to 4 (always), which was not significantly different between White patients and Black patients. One-third of patients experienced some type of financial challenge during this time. Medicaid recipients, of whom almost 80% were Black, were more likely to experience financial challenges. In addition, approximately one-fourth of patients experienced difficulty getting treatment.

Conclusions: This study indicates that the quality of life of patients with breast cancer and their scheduled treatments have been adversely affected during the COVID-19 pandemic. These findings suggest that more support should be provided by hospital centers and the medical research community to patients with cancer during this challenging pandemic.

Lay Summary: The authors surveyed patients with breast cancer in Chicago using a questionnaire to examine how their lives have been affected during the coronavirus disease 2019 (COVID-19) pandemic. The results indicate that the lives of patients with breast cancer and their scheduled treatments have been adversely affected during the pandemic. In addition, patients who were covered by Medicaid, most of whom were Black, were more likely to experience financial challenges. The findings suggest that hospital centers and the medical research community should reach out and provide more information to support patients with cancer during this challenging pandemic.
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http://dx.doi.org/10.1002/cncr.33798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426957PMC
November 2021

The impact of site-specific digital histology signatures on deep learning model accuracy and bias.

Nat Commun 2021 07 20;12(1):4423. Epub 2021 Jul 20.

Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA.

The Cancer Genome Atlas (TCGA) is one of the largest biorepositories of digital histology. Deep learning (DL) models have been trained on TCGA to predict numerous features directly from histology, including survival, gene expression patterns, and driver mutations. However, we demonstrate that these features vary substantially across tissue submitting sites in TCGA for over 3,000 patients with six cancer subtypes. Additionally, we show that histologic image differences between submitting sites can easily be identified with DL. Site detection remains possible despite commonly used color normalization and augmentation methods, and we quantify the image characteristics constituting this site-specific digital histology signature. We demonstrate that these site-specific signatures lead to biased accuracy for prediction of features including survival, genomic mutations, and tumor stage. Furthermore, ethnicity can also be inferred from site-specific signatures, which must be accounted for to ensure equitable application of DL. These site-specific signatures can lead to overoptimistic estimates of model performance, and we propose a quadratic programming method that abrogates this bias by ensuring models are not trained and validated on samples from the same site.
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http://dx.doi.org/10.1038/s41467-021-24698-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292530PMC
July 2021

Addressing health disparities in cancer with genomics.

Nat Rev Genet 2021 10;22(10):621-622

Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, IL, USA.

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http://dx.doi.org/10.1038/s41576-021-00390-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267506PMC
October 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

Effects of Slide Storage on Detection of Molecular Markers by IHC and FISH in Endometrial Cancer Tissues From a Clinical Trial: An NRG Oncology/GOG Pilot Study.

Appl Immunohistochem Mol Morphol 2022 01;30(1):27-35

University of Arkansas for Medical Sciences, Little Rock, AR.

We performed a pilot study in anticipation of using long-aged precut formalin-fixed paraffin-embedded tissue sections stored in real-world conditions for translational biomarker studies of topoisomerase 2A (TOP2A), Ki67, and human epidermal growth factor receptor 2 (HER2) in endometrial cancer. Formalin-fixed paraffin-embedded tissue blocks or unstained slides or both from GOG-0177 were collected centrally (1999-2000) and stored at room temperature. During 2004 to 2011 specimens were stored at 4°C. Matched pairs of stored slides and freshly cut slides from stored blocks were analyzed for TOP2A (KiS1), Ki67 (MIB1), and HER2 (HercepTest) proteins. To assess DNA stability (HER2 PathVision), fluorescence in situ hybridization (FISH) was repeated on stored slides from 21 cases previously shown to be HER2 amplified. Immunohistochemistry (IHC) staining intensity and extent, mean FISH copies/cell, and copy number ratios were compared using the κ statistic for concordance or signed rank test for differences in old cut versus new cut slides. IHC results reflected some protein degradation in stored slides. The proportion of cells with TOP2A staining was lower on average by 12% in older sections (P=0.03). The proportion of Ki67-positive cells was lower in stored slides by an average of 10% (P<0.01). Too few cases in the IHC cohort were FISH positive for any conclusions. HER2 amplification by FISH was unaffected by slide storage. We conclude that use of aged stored slides for proliferation markers TOP2A and Ki67 is feasible but may modestly underestimate true values in endometrial cancer. Pilot studies for particular storage conditions/durations/antigens to be used in translational studies are warranted.
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http://dx.doi.org/10.1097/PAI.0000000000000949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8664981PMC
January 2022

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant.

Genet Med 2021 09 10;23(9):1726-1737. Epub 2021 Jun 10.

Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.

Purpose: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.

Methods: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS and CBC risk.

Results: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively.

Conclusion: The PRS can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.
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http://dx.doi.org/10.1038/s41436-021-01198-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460445PMC
September 2021

Precision oncology: Directing genomics and pharmacogenomics toward reducing cancer inequities.

Cancer Cell 2021 06 20;39(6):730-733. Epub 2021 May 20.

Section of Hematology/Oncology, Department of Medicine, University of Chicago Medical Center, Chicago, IL 60637, USA; Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, IL 60637, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ccell.2021.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323992PMC
June 2021

The global role, impact, and limitations of Community Health Workers (CHWs) in breast cancer screening: a scoping review and recommendations to promote health equity for all.

Glob Health Action 2021 01;14(1):1883336

Pritzker School of Medicine, University of Chicago, Chicago, IL, USA.

: Innovative interventions are needed to address the growing burden of breast cancer globally, especially among vulnerable patient populations. Given the success of Community Health Workers (CHWs) in addressing communicable diseases and non-communicable diseases, this scoping review will investigate the roles and impacts of CHWs in breast cancer screening programs. This paper also seeks to determine the effectiveness and feasibility of these programs, with particular attention paid to differences between CHW-led interventions in low- and middle-income countries (LMICs) and high-income countries (HICs).: A scoping review was performed using six databases with dates ranging from 1978 to 2019. Comprehensive definitions and search terms were established for 'Community Health Workers' and 'breast cancer screening', and studies were extracted using the World Bank definition of LMIC. Screening and data extraction were protocolized using multiple independent reviewers. Chi-square test of independence was used for statistical analysis of the incidence of themes in HICs and LMICs.: Of the 1,551 papers screened, 33 were included based on inclusion and exclusion criteria. Study locations included the United States (n=27), Bangladesh (n=1), Peru (n=1), Malawi (n=2), Rwanda (n=1), and South Africa (n=1). Three primary roles for CHWs in breast cancer screening were identified: education (n=30), direct assistance or performance of breast cancer screening (n=7), and navigational services (n=6). In these roles, CHWs improved rates of breast cancer screening (n=23) and overall community member knowledge (n=21). Two studies performed cost-analyses of CHW-led interventions.: This review extends our understanding of CHW effectiveness to breast cancer screening. It illustrates how CHW involvement in screening programs can have a significant impact in LMICs and HICs, and highlights the three CHW roles of education, direct performance of screening, and navigational services that emerge as useful pillars around which governments and NGOs can design effective programs in this area.
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http://dx.doi.org/10.1080/16549716.2021.1883336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079044PMC
January 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

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

Impact of post-diagnosis weight change on survival outcomes in Black and White breast cancer patients.

Breast Cancer Res 2021 02 4;23(1):18. Epub 2021 Feb 4.

Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA.

Purpose: To evaluate weight change patterns over time following the diagnosis of breast cancer and to examine the association of post-diagnosis weight change and survival outcomes in Black and White patients.

Methods: The study included 2888 women diagnosed with non-metastatic breast cancer in 2000-2017 in Chicago. Longitudinal repeated measures of weight and height were collected, along with a questionnaire survey including questions on body size. Multilevel mixed-effects models were used to examine changes in body mass index (BMI). Delayed entry Cox proportional hazards models were used to investigate the impacts of changing slope of BMI on survival outcomes.

Results: At diagnosis, most patients were overweight or obese with a mean BMI of 27.5 kg/m and 31.5 kg/m for Blacks and Whites, respectively. Notably, about 45% of the patients had cachexia before death and substantial weight loss started about 30 months before death. In multivariable-adjusted analyses, compared to stable weight, BMI loss (> 0.5 kg/m/year) showed greater than 2-fold increased risk in overall survival (hazard ratio [HR] = 2.60, 95% CI 1.88-3.59), breast cancer-specific survival (HR = 3.05, 95% CI 1.91-4.86), and disease-free survival (HR = 2.12, 95% CI 1.52-2.96). The associations were not modified by race, age at diagnosis, and pre-diagnostic weight. BMI gain (> 0.5 kg/m/year) was also related to worse survival, but the effect was weak (HR = 1.60, 95% CI 1.10-2.33 for overall survival).

Conclusion: BMI loss is a strong predictor of worse breast cancer outcomes. Growing prevalence of obesity may hide diagnosis of cancer cachexia, which can occur in a large proportion of breast cancer patients long before death.
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http://dx.doi.org/10.1186/s13058-021-01397-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863526PMC
February 2021

Reply to Q. Chu et al.

JCO Glob Oncol 2021 02;7:185-186

Jason T. Semprini, MPP and Olufunmilayo I. Olopade, MD, University of Chicago, Center for Clinical Cancer Genetics and Global Health, Chicago, IL.

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http://dx.doi.org/10.1200/GO.20.00531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081511PMC
February 2021

Prevalence of potential interactions of medications, including herbs and supplements, before, during, and after chemotherapy in patients with breast and prostate cancer.

Cancer 2021 06 1;127(11):1827-1835. Epub 2021 Feb 1.

Section of Hematology/Oncology, Department of Medicine, Northwestern University, Chicago, Illinois.

Background: The use of herbs and supplements (HS) is common among patients with cancer, yet limited information exists about potential medication interactions (PMIs) with HS use around chemotherapy.

Methods: Patients with breast or prostate cancer who had recently finished chemotherapy at 2 academic medical centers were surveyed by telephone. Interviewers inquired about all medications, including HS, before, during, and after chemotherapy. Micromedex, Lexicomp, and Natural Medicines Comprehensive Database interaction software programs were used to determine PMIs.

Results: A total of 67 subjects (age range, 39-77 years) were evaluated in this study. Participants were primarily White patients (73%) with breast cancer (87%). The median number of medications was 11 (range, 2-28) during the entire study and was highest during chemotherapy (7; range, 2-22). Approximately four-fifths (84%) used HS. A total of 1747 PMIs were identified, and they represented 635 unique PMIs across all 3 timeframes, with most occurring during chemotherapy. Prescription-related PMIs (70%) were the most common type, and they were followed by HS-related (56%) and anticancer treatment-related PMIs (22%). Approximately half of the PMIs (54%) were categorized as moderate interactions, and more than one-third (38%) were categorized as major interactions. Patient use of HS increased from 51% during chemotherapy to 66% after chemotherapy, and this correlated with an increased prevalence of HS PMIs (46% to 60%). HS users were more likely to be at risk for a major PMI than non-HS users (92% vs 70%; P = .038).

Conclusions: The use of HS remains prevalent among patients with cancer and may place them at risk for PMIs both during chemotherapy and after the completion of treatment.

Lay Summary: This study evaluates the risk of potential medication interactions for patients with breast or prostate cancer undergoing chemotherapy. The results show that patients often use herbs and supplements during treatment. Prescription medications are most often associated with medication interactions, which are followed by herb and supplement-related interactions. More than one-third of potential medication interactions are considered major. Patients should be educated about the risk of herb and supplement-related medication interactions during treatment.
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http://dx.doi.org/10.1002/cncr.33324DOI Listing
June 2021

Epidemiology of Triple-Negative Breast Cancer: A Review.

Cancer J 2021 Jan-Feb 01;27(1):8-16

From the Section of Hematology/Oncology.

Abstract: Triple-negative breast cancer accounted for 12% of breast cancers diagnosed in the United States from 2012 to 2016, with a 5-year survival 8% to 16% lower than hormone receptor-positive disease. However, preventive and screening strategies remain tailored to the demographics of less lethal luminal cancers. This review examines the ethnic, genetic, and modifiable risk factors associated with triple-negative breast cancer, which providers must recognize to address the societal disparities of this deadly disease. Most notable is that triple-negative cancers disproportionately affect African American women and carriers of germline BRCA and PALB2 mutations. Even controlling for treatment delays, stage, and socioeconomic factors, African Americans with triple-negative breast cancer remain nearly twice as likely to die of their disease. To level the playing field, we must integrate genomic predictors of disease and epidemiologic characteristics of molecular breast cancer subtypes to provide personalized risk assessment, screening, and treatment for each patient.
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http://dx.doi.org/10.1097/PPO.0000000000000500DOI Listing
September 2021

The Pseudogene Negatively Regulates Antitumor Responses through Inhibition of Innate Immune Defense Mechanisms.

Cancer Res 2021 03 20;81(6):1540-1551. Epub 2021 Jan 20.

Department of Medicine, Center for Clinical Cancer Genetics and Global Health, University of Chicago, Chicago, Illinois.

Innate immune defense mechanisms play a pivotal role in antitumor responses. Recent evidence suggests that antiviral innate immunity is regulated not only by exogenous non-self-RNA but also by host-derived pseudogene RNAs. A growing body of evidence also indicates a biological role for pseudogenes as gene expression regulators or immune modulators. Here, we report an important role for , the pseudogene of the tumor-suppressor gene, in regulating innate immune defense mechanisms in breast cancer cells. expresses a long-noncoding RNA (lncRNA) in breast cancer cells through divergent transcription. Expression of lncRNA- is increased in breast tumors compared with normal breast tissues. Depletion of induces an antiviral defense-like program, including the expression of antiviral genes in breast cancer cells. Furthermore, -deficient cancer cells mimic virus-infected cells by stimulating cytokines and inducing cell apoptosis. Accordingly, depletion of increases host innate immune responses and restricts virus replication. In converse, overexpression of reduces cytokine expression in breast cancer cells. Mechanistically, lncRNA- is localized in the nucleus, binds to the NF-κB subunit RelA, and negatively regulates antiviral gene expression. Finally, in a xenograft mouse model of breast cancer, depletion of stimulates cytokine expression and local immunity, and suppresses tumor growth. Our results suggest an important role for in innate immune defense mechanisms and antitumor responses. This mechanism of antiviral immunity regulated by a host-derived pseudogene RNA may guide the development of novel therapies targeting immune responses in breast cancer. SIGNIFICANCE: This study identifies a novel mechanism of innate immunity driven by a host pseudogene RNA that inhibits innate immune defense mechanisms and antitumor responses through regulation of antiviral gene expression.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969461PMC
March 2021

Comparison of DCE-MRI of murine model cancers with a low dose and high dose of contrast agent.

Phys Med 2021 Jan 26;81:31-39. Epub 2020 Dec 26.

Department of Radiology, The University of Chicago, Chicago, IL 60637, United States. Electronic address:

There are increasing concerns regarding intracellular accumulation of gadolinium (Gd) after multiple dynamic contrast enhanced (DCE) MRI scans. We investigated whether a low dose (LD) of Gd-based contrast agent is as effective as a high dose (HD) for quantitative analysis of DCE-MRI data, and evaluated the use of a split dose protocol to obtain new diagnostic parameters. Female C3H mice (n = 6) were injected with mammary carcinoma cells in the hind leg. MRI experiments were performed on 9.4 T scanner. DCE-MRI data were acquired with 1.5 s temporal resolution before and after a LD (0.04 mmol/kg), then again after 30 min followed by a HD (0.2 mmol/kg) bolus injection of Omniscan. The standard Tofts model was used to extract physiological parameters (K and v) with the arterial input function derived from muscle reference tissue. In addition, an empirical mathematical model was used to characterize maximum contrast agent uptake (A), contrast agent uptake rate (α) and washout rate (β and γ). There were moderate to strong correlations (r = 0.69-0.97, p < 0001) for parameters K, v, A, α and β from LD versus HD data. On average, tumor parameters obtained from LD data were significantly larger (p < 0.05) than those from HD data. The parameter ratios, K, v, A and α calculated from the LD data divided by the HD data, were all significantly larger than 1.0 (p < 0.003) for tumor. T* changes following contrast agent injection affected parameters calculated from HD data, but this was not the case for LD data. The results suggest that quantitative analysis of LD data may be at least as effective for cancer characterization as quantitative analysis of HD data. In addition, the combination of parameters from two different doses may provide useful diagnostic information.
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http://dx.doi.org/10.1016/j.ejmp.2020.11.023DOI Listing
January 2021

Racial disparities in survival outcomes among breast cancer patients by molecular subtypes.

Breast Cancer Res Treat 2021 Feb 27;185(3):841-849. Epub 2020 Oct 27.

Department of Public Health Sciences, University of Chicago, Chicago, IL, USA.

Purpose: Differences in tumor biology, genomic architecture, and health care delivery patterns contribute to the breast cancer mortality gap between White and Black patients in the US. Although this gap has been well documented in previous literature, it remains uncertain how large the actual effect size of race is for different survival outcomes and the four breast cancer subtypes.

Methods: We established a breast cancer patient cohort at the University of Chicago Comprehensive Cancer Center. We chose five major survival outcomes to study: overall survival, recurrence-free survival, breast-cancer-specific survival, time-to-recurrence and post-recurrence survival. Cox proportional hazards models were used to estimate the hazard ratios between Black and White patients, adjusting for selected patient, tumor, and treatment characteristics, and also stratified by the four breast cancer subtypes.

Results: The study included 2795 stage I-III breast cancer patients (54% White and 38% Black). After adjusting for selected patient, tumor and treatment characteristics, Black patients still did worse than White patients in all five survival outcomes. The racial difference was highest within the HR-/HER2+ subgroup, in both overall survival (hazard ratio = 4.00, 95% CI 1.47-10.86) and recurrence-free survival (hazard ratio = 3.00, 95% CI 1.36-6.60), adjusting for age at diagnosis, cancer stage, and comorbidities. There was also a significant racial disparity within the HR+/HER2- group in both overall survival and recurrence-free survival.

Conclusions: Our study confirmed that racial disparity existed between White and Black breast cancer patients in terms of both survival and recurrence, and found that this disparity was largest among HR-/HER2+ and HR+/HER2- patients.
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http://dx.doi.org/10.1007/s10549-020-05984-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925344PMC
February 2021

p50 mono-ubiquitination and interaction with BARD1 regulates cell cycle progression and maintains genome stability.

Nat Commun 2020 10 6;11(1):5007. Epub 2020 Oct 6.

Department of Surgery, Section of Neurosurgery, The University of Chicago, Chicago, IL, 60637, USA.

p50, the mature product of NFKB1, is constitutively produced from its precursor, p105. Here, we identify BARD1 as a p50-interacting factor. p50 directly associates with the BARD1 BRCT domains via a C-terminal phospho-serine motif. This interaction is induced by ATR and results in mono-ubiquitination of p50 by the BARD1/BRCA1 complex. During the cell cycle, p50 is mono-ubiquitinated in S phase and loss of this post-translational modification increases S phase progression and chromosomal breakage. Genome-wide studies reveal a substantial decrease in p50 chromatin enrichment in S phase and Cycln E is identified as a factor regulated by p50 during the G1 to S transition. Functionally, interaction with BARD1 promotes p50 protein stability and consistent with this, in human cancer specimens, low nuclear BARD1 protein strongly correlates with low nuclear p50. These data indicate that p50 mono-ubiquitination by BARD1/BRCA1 during the cell cycle regulates S phase progression to maintain genome integrity.
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http://dx.doi.org/10.1038/s41467-020-18838-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538584PMC
October 2020

Magnetic resonance angiography reveals increased arterial blood supply and tumorigenesis following high fat feeding in a mouse model of triple-negative breast cancer.

NMR Biomed 2020 10 5;33(10):e4363. Epub 2020 Aug 5.

Department of Radiology, The University of Chicago, Chicago, Illinois, US.

Breast cancer is the second most commonly diagnosed malignancy among women globally. Past MRI studies have linked a high animal fat diet (HAFD) to increased mammary cancer risk in the SV40Tag mouse model of triple-negative breast cancer. Here, serial MRI examines tumor progression and measures the arterial blood volume feeding mammary glands in low fat diet (LFD) or HAFD fed mice. Virgin female C3(1)SV40Tag mice (n = 8), weaned at 3 weeks old, were assigned to an LFD (n = 4, 3.7 kcal/g, 17.2% kcal from vegetable oil) or an HAFD (n = 4, 5.3 kcal/g, 60% kcal from lard) group. From ages 8 to 12 weeks, weekly fast spin echo MR images and time-of-flight (TOF) MR angiography of inguinal mammary glands were acquired at 9.4 T. Following in vivo MRI, mice were sacrificed. Inguinal mammary glands were excised and fixed for ex vivo MRI and histology. Tumor, blood, and mammary gland volumes for each time point were measured from manually traced regions of interest; tumors were classified as invasive by histopathology-blinded observers. Our analysis confirmed a strong correlation between total tumor volume and blood volume in the mammary gland. Tumor growth rates from weeks 8-12 were twice as high in HAFD-fed mice (0.42 ± 0.14/week) as in LFD-fed mice (0.21 ± 0.03/week), p < 0.004. Mammary gland blood volume growth rate was 2.2 times higher in HAFD mice (0.29 ± 0.11/week) compared with LFD mice (0.13 ± 0.06/week), p < 0.02. The mammary gland growth rate of HAFD-fed mice (0.071 ± 0.011/week) was 2.7 times larger than that of LFD-fed mice (0.026 ± 0.009/week), p < 0.01. This is the first non-invasive, in vivo MRI study to demonstrate a strong correlation between an HAFD and increased cancer burden and blood volume in mammary cancer without using contrast agents, strengthening the evidence supporting the adverse effects of an HAFD on mammary cancer. These results support the potential future use of TOF angiography to evaluate vasculature of suspicious lesions.
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http://dx.doi.org/10.1002/nbm.4363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034829PMC
October 2020
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