Genetic Breast Cancer Research Articles

Shared genetics between breast cancer and predisposing diseases identifies novel breast cancer treatment candidates

BackgroundCurrent effective breast cancer treatment options have severe side effects, highlighting a need for new therapies. Drug repurposing can accelerate improvements to care, as FDA-approved drugs have known safety and pharmacological profiles. Some drugs for other conditions, such as metformin, an antidiabetic, have been tested in clinical trials for repurposing for breast cancer. Here, we exploit the genetics of breast cancer and linked predisposing diseases to propose novel drug repurposing opportunities. We hypothesize that if a predisposing disease contributes to breast cancer pathology, identifying the pleiotropic genes related to the risk of cancer could prioritize drugs, among all drugs treating a predisposing disease. We aim to develop a method to not only prioritize drugs for repurposing, but also to highlight shared etiology explaining repurposing.MethodsWe compile breast cancer’s predisposing diseases from literature. For each predisposing disease, we use GWAS summary statistics data to identify genes in loci showing genetic correlation with breast cancer. Then, we use a network approach to link these shared genes to canonical pathways. Similarly, for all drugs treating the predisposing disease, we link their targets to pathways. In this manner, we are able to prioritize a list of drugs based on each predisposing disease, with each drug linked to a set of implicating pathways. Finally, we evaluate our recommendations against drugs currently under investigation for breast cancer.ResultsWe identify 84 loci harboring mutations with positively correlated effects between breast cancer and its predisposing diseases; these contain 194 identified shared genes. Out of the 112 drugs indicated for the predisposing diseases, 74 drugs can be linked to shared genes via pathways (candidate drugs for repurposing). Fifteen out of these candidate drugs are already in advanced clinical trial phases or approved for breast cancer (OR = 9.28, p = 7.99e-03, one-sided Fisher’s exact test), highlighting the ability of our approach to identify likely successful candidate drugs for repurposing.ConclusionsOur novel approach accelerates drug repurposing for breast cancer by leveraging shared genetics with its known predisposing diseases. The result provides 59 novel candidate drugs alongside biological insights supporting each recommendation.

Abstract A021: Development of cross-ancestry polygenic risk. scores for breast cancer in women of African ancestry

Abstract Introduction: Polygenic risk scores (PRSs) predict breast cancer (BC) risk and have shown utility for screening in European ancestry women (EUR). However, PRSs developed for non-European ancestry, particularly African American (AA) women, have limited predictive accuracy. Methods: We analyzed data from 17,454 BC cases and 19,093 controls in the African American Breast Cancer Genetics (AABCG) consortium, split into training (70%), tuning (10%), and testing (20%) sets. Genome-wide association analyses for overall BC, ER-positive BC, ER- negative BC and triple-negative BC (TNBC) were performed in the training dataset, controlling for age, genotyping platform, and the top 10 principal components. We built single-ancestry PRS models using forward stepwise selection (FSS), PRSice-2, PLINK C+T, Lassosum2, and LDpred2-auto. These were combined with published EUR 313-SNP models (330-SNP for TNBC) in the tuning set to obtain cross-ancestry models. Genome-wide cross-ancestry PRS methods, including CT-SLEB and PRScsx, were also used. We created an ensemble model by combining different PRS models across subtypes using ensemble-based approaches. All developed PRS models were then evaluated in the independent testing set. Additional validation was performed using the All of Us (AoU) study with 834 BC cases and 29,122 controls from the AA population. Results: The observed-scale SNP-based heritability was estimated at 0.29 (SE: 0.12) for overall BC risk, 0.43 (SE: 0.18) for ER-positive BC, 0.44 (SE: 0.24) for ER-negative BC, and 1.13 (SE: 0.40) for TNBC. The best models showed good discriminating capacity: ensemble-based models for overall (AUC=0.626) and ER-positive BC (AUC=0.626), and combined cross-subtype and cross-ancestry FSS models for ER-negative (AUC=0.647) and TNBC (AUC=0.654). The odds ratio per standard deviation was 1.63 (95% CI: 1.55, 1.71) for the ensemble-based PRS of overall BC risk, with an estimated life risk of 28% for the top 1%. The cross-ancestry model using CT-SLEB combined with the EUR 313-SNP model was validated (AUC=0.61) among AA women in the AoU study. Conclusion: We developed PRSs with improved discriminating ability for BC risk in women with African ancestry. Cross- ancestry and subtype learning enhanced model performance. These findings indicate common variation has a larger role in BC in AA women than previously reported, warranting further validation in external AA populations and clinical evaluation. Citation Format: James L. Li, Haoyu Zhang, Julian C McClellan, Guimin Gao, Kevin Wang, Julie R. Palmer, Olufunmilayo I. Olopade, Christopher A. Haiman, Dezheng Huo. Development of cross-ancestry polygenic risk. scores for breast cancer in women of African ancestry [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A021.

ThP1.7 - Moving to a specialist nurse-led service for genetic testing in breast cancer

Abstract Aims To assess the impact of a genetics nurse led clinic in breast cancer patients treatment. Methods A specialist, nurse-led breast cancer genetics service was set up in September 2022 for patients meeting the R208 and R444 criteria. A prospective data collection was performed from September 2022 to October 2023 and included patient demographics, test result and if the result led to any alteration in management of patient. Results 78 eligible patients, with a mean age of 52.8 (31-90) years. 4 (5.1%) were male. 1 (1.3%) patient declined testing, a further 1 (1.3%) patient was undecided and 1 (1.3%) wished for storage only. Patients waited 1-2 weeks following a breast cancer diagnosis to see the nurse specialist and 4-6 weeks for urgent results. The pathogenic variants identified were BRCA1 (5.3%), BRCA2 (6.7%), CHEK2 (2.7%) and PALB2 (1.3%). Of the remainder 84% of patients tested negative. Altered management occurred in 8 (10.7%) patients, 4 (50%) received risk reducing surgery, 2 (25%) received Olaparib and 2 (25%) received Olaparib and underwent risk reducing surgery. Conclusion The move to a nurse-led service has proved to be successful in terms of reduced waiting times for genetic testing appointments and results. It also ensured that all appropriate patients with breast cancer were offered genetic testing, leading to more effective and efficient treatment decisions, such as risk reducing surgery and tailored chemotherapy which could improve long-term health outcomes.

Shared genetics between breast cancer and predisposing diseases identifies novel breast cancer treatment candidates.

Current effective breast cancer treatment options have severe side effects, highlighting a need for new therapies. Drug repurposing can accelerate improvements to care, as FDA-approved drugs have known safety and pharmacological profiles. Some drugs for other conditions, such as metformin, an antidiabetic, have been tested in clinical trials for repurposing for breast cancer. Here, we exploit the genetics of breast cancer and linked predisposing diseases to propose novel drug repurposing. We hypothesize that if a predisposing disease contributes to breast cancer pathology, identifying the pleiotropic genes related to the risk of cancer could prioritize drug targets, among all drugs treating a predisposing disease. We aim to develop a method to not only prioritize drug repurposing, but also to highlight shared etiology explaining repurposing. We compile breast cancer's predisposing diseases from literature. For each predisposing disease, we use GWAS summary statistics to identify genes in loci showing genetic correlation with breast cancer. Then, we use a network approach to link these shared genes to canonical pathways, and similarly for all drugs treating the predisposing disease, we link their targets to pathways. In this manner, we are able to prioritize a list of drugs based on each predisposing disease, with each drug linked to a set of implicating pathways. Finally, we evaluate our recommendations against drugs currently under investigation for breast cancer. We identify 84 loci harboring mutations with positively correlated effects between breast cancer and its predisposing diseases; these contain 194 identified shared genes. Out of the 112 drugs indicated for the predisposing diseases, 76 drugs can be linked to shared genes via pathways (candidate drugs for repurposing). Fifteen out of these candidate drugs are already in advanced clinical trial phases or approved for breast cancer (OR = 9.28, p = 7.99e-03, one-sided Fisher's exact test), highlighting the ability of our approach to identify likely successful candidate drugs for repurposing. Our novel approach accelerates drug repurposing for breast cancer by leveraging shared genetics with its known risk factors. The result provides 59 novel candidate drugs alongside biological insights supporting each recommendation.

Abstract 6119: Association of genetic African ancestry and triple-negative breast cancer risk: Findings from the African-ancestry breast cancer genetics consortium

Abstract Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that lacks target treatments. It has been reported that African-American women have a higher incidence of TNBC and are diagnosed at an earlier age than women of European ancestry. This disparity may be attributed to both genetic and non-genetic risk factors that are associated with the African ancestry. In this study, we investigated whether genotype-derived African ancestry might be related to an elevated risk of TNBC, with adjustments for several known genetic and non-genetic risk factors. Included in the study are self-reported Black breast cancer patients diagnosed with TNBC (n =2,292) or estrogen receptor (ER)-positive cancer (n =7,863) and 9,324 controls included in the African-ancestry Breast Cancer Genetics (AABCG) Consortium. We estimated the global ancestry by Admixture and the local ancestry by FLARE, using reference of the European- and African-ancestry samples from the 1000 Genome Project. Odds ratios (OR) and 95% confidence interval (CI) per ten percent increase of the global African ancestry proportion were estimated using logistic regressions comparing TNBC with controls (case-control analyses) or with ER-positive cases (case-case analyses), adjusted for age. Similar analyses were conducted for the local African ancestry proportion at each of the 12 genomic regions that were identified in AABCG in relation to TNBC risk. Results for each participating study were meta-analyzed using fixed or random effect models. We further adjusted for non-genetic risk factors including body mass index (BMI), number of live births, breastfeeding, and menopausal status. A polygenic risk score (PRS) was constructed using 13 independent risk variants at the 12 TNBC risk loci. The PRS was additionally adjusted to investigate whether these risk variants mediated the association of African ancestry with TNBC risk. No significant association was observed between TNBC risk and global African ancestry proportion (OR: 1.03, 95% CI: 0.98-1.08) in case-control comparisons. Compared with ER-positive cases, however, TNBC cases had a higher global African ancestry, resulted in an OR of 1.09 (95% CI: 1.04, 1.13, P =5.35×10-5). A similar association was observed with additional adjustment for non-genetic risk factors, with an OR of 1.08 (95% CI: 1.03, 1.12, P =0.003). Similar patterns were also found for local ancestry proportion at six of the 12 TNBC risk loci (P <0.05). Further adjustment for the PRS attenuated the association between global ancestry and a TNBC diagnosis in case-case comparisons (OR: 1.05, 95% CI: 1.01, 1.10, P =0.013). Our study suggests that women with a higher African ancestry are more likely to be diagnosed with a TNBC than ER-positive breast cancer and genetic factors identified to date partially explain this association. Citation Format: Guochong Jia, Lili Liu, Julie R. Palmer, Christopher A. Haiman, Wei Zheng. Association of genetic African ancestry and triple-negative breast cancer risk: Findings from the African-ancestry breast cancer genetics consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6119.

Roll-out of an educational workshop to improve knowledge and self-confidence of healthcare professionals engaged in mainstreaming of breast cancer genetics.

There are calls worldwide for the mainstreaming of genetic testing in breast cancer (BC) clinics, but health care professionals (HCPs) are not always familiar with nor confident about genetic counselling. TRUSTING (Talking about Risk & uncertainties of Testing in Genetics is an educational programme shown to significantly improve HCPs' knowledge, communication, self-confidence, and self-awareness. We rolled out TRUSTING workshops across the UK and probed their influence on mainstreaming within BC clinics. 1 surgeon, 3 oncologists, and 1 nurse specialist who had attended the original TRUSTING evaluation project were trained to facilitate the 8-hour programme in pairs. The participants (all health care professionals) attending their workshops completed 3 questionnaires: - 1) the Intolerance to Uncertainty Scale, 2) an 18-item multiple choice knowledge questionnaire about BRCA 1/2 gene testing, incidence and risk reducing interventions and 3) a 10-item questionnaire exploring self-confidence when advising patients and their families about these issues. Both knowledge and self-confidence were re-tested post workshop together with evaluation of the facilitators' approach and overall satisfaction with the event. Follow-up questionnaires 3-12 months later examined impact of workshops on HCPs' own practice and how mainstreaming was working in their clinics. 120 HCPs (61 surgeons; 41 nurses; 9 oncologists; 9 other) attended 12 workshops. Knowledge scores (mean change = 6.58; 95% CI 6.00 to 7.17; p<0.001), and self-confidence (mean change = 2.64; 95% CI 2.33 to 2.95; p<0.001) improved significantly post workshop. Ratings for the facilitators' approach were uniformly high (mean range 9.6 to 9.9 /10). Most delegates found the workshops useful, enjoyable, and informative and 98% would definitively recommend them to colleagues. Follow-up data (n = 72/96) showed that 57% believed attendance had improved their own practice when discussing genetic testing with their patients. When asked about mainstreaming more generally, 78% reported it was working well, 18% had not yet started, and 3% thought it was problematic in their centre. Discussing the implications that having a pathogenic gene alteration has for patients' treatment and risk-reducing interventions is complex when patients are already coming to terms with a breast cancer diagnosis. Training facilitators enhanced the wider roll-out of the TRUSTING educational programme and is an effective means of helping HCPs now involved in the mainstreaming of genetic testing.

A joint transcriptome-wide association study across multiple tissues identifies candidate breast cancer susceptibility genes

Genome-wide association studies (GWASs) have identified more than 200 genomic loci for breast cancer risk, but specific causal genes in most of these loci have not been identified. In fact, transcriptome-wide association studies (TWASs) of breast cancer performed using gene expression prediction models trained in breast tissue have yet to clearly identify most target genes. To identify candidate genes, we performed a GWAS analysis in a breast cancer dataset from UK Biobank (UKB) and combined the results with the GWAS results of the Breast Cancer Association Consortium (BCAC) by a meta-analysis. Using the summary statistics from the meta-analysis, we performed a joint TWAS analysis that combined TWAS signals from multiple tissues. We used expression prediction models trained in 11 tissues that are potentially relevant to breast cancer from the Genotype-Tissue Expression (GTEx) data. In the GWAS analysis, we identified eight loci distinct from those reported previously. In the TWAS analysis, we identified 309 genes at 108 genomic loci to be significantly associated with breast cancer at the Bonferroni threshold. Of these, 17 genes were located in eight regions that were at least 1 Mb away from published GWAS hits. The remaining TWAS-significant genes were located in 100 known genomic loci from previous GWASs of breast cancer. We found that 21 genes located in known GWAS loci remained statistically significant after conditioning on previous GWAS index variants. Our study provides insights into breast cancer genetics through mapping candidate target genes in a large proportion of known GWAS loci and discovering multiple new loci.

A new population screening program for BRCA mutations in Israel – Attitudes and barriers among Ashkenazi Jewish women

Israeli Jewish women of Ashkenazi ancestry have a high BRCA mutation carrier rate. Therefore, recently, Israel included free genetic testing among all Jewish women with Ashkenazi ancestry, 25 yrs. and older in its public health system. The aim of this study was to assess the intention of eligible women to be tested for BRCA mutations, and to find factors that may affect their decision. We distributed an online survey to a panel of participants in a commercial research institute. The survey included socio-demographic characteristics, attitudes towards preventive actions, views related to benefits and limitations of performing the BRCA test, worry regarding cancer morbidity, knowledge about breast cancer morbidity and hereditary breast cancer genetics. The survey concluded with a question regarding the woman’s interest in undergoing the BRCA test. The results showed that among the 506 respondents, 250 (49%) were interested in BRCA testing, 42 (8%) objected and 214 (43%) were undecided. In comparing the undecided to the other groups, we found that most presented a positive attitude towards screening tests and preventive medicine, they showed acceptable knowledge about the proposed test, and yet were interested in learning and further expanding the knowledge and the consequences of doing the test. Most respondents of all groups expressed concern of breast cancer morbidity and were reluctant to perform the test for reasons of reducing uncertainty, implications for children and implications for their own health. Within all groups, many women expressed their desire to consult with a medical professional about the test. We conclude that aiming to improve the performance of BRCA genetic testing, women need a thorough explanation about its implications. The main way to inform them would be by medical professionals, especially in primary care. This implies that front line nurses and physicians need to become more knowledgeable and committed to this subject.

An Overview of Breast Cancer Epidemiology, Risk Factors, Classification, Genetics, Diagnosis and Treatment

An Overview of Breast Cancer Epidemiology, Risk Factors, Classification, Genetics, Diagnosis and Treatment

Abstract 4677: A preclinical platform of breast cancer PDX and derived cellular models as a tool for pharmacological screening and functional studies

Abstract Despite considerable progress in understanding the biology and genetics of breast cancer, the development of effective therapies needs physiological and predictive preclinical models. In this context, breast cancer (BC) patient-derived xenograft (PDX) models have become a standard tool as they reproduce the biology of tumors of origin, in term of histology, genotype and response to chemotherapy. They have proven their relevance in the study of pathways leading to the development and progression of cancer, to the mechanisms linked to tumor resistance and to the identification of novel effective therapies. We present a preclinical platform of over 60 fully characterized BC PDX models and their in vitro cell derivatives for preclinical evaluation of new treatment modalities. Our platform consists of a PDX collection of 43 TNBC, 6 ER+, 4 HER2+, 6 Luminal B models (ER+ HER2+) and 14 cellular models derived from these PDXs, representing the variety of BC. PDX models were obtained by transplantation of post-surgery tumor specimens either by grafting of tumor fragments in the interscapular region of nude mice or by injection of tumor cells into the fat pad of NOD-Scid mice. Molecular analyses were done included gene expression, gene copy number, whole exome sequencing and IHC markers staining. In vivo drug efficacy assays were performed with standards of care as single agent or in combinations. This PDX panel mostly reflects the molecular heterogeneity of breast cancer and reproduce accurately the molecular and drug response profile of human tumors. It provides an invaluable tool for translational research. It is widely used to performed standard drug evaluation but also “Mouse Clinical Trials” (MCT) in vivo screens to provide more predictive preclinical data on single-agent or combination drug efficacy. Engrafted on highly immunodeficient mice humanized with human PBMCs or CD34+ cells, these PDX models allow bispecific T-Cell engager antibody testing or immune-checkpoint inhibitors evaluation. In addition to these PDX panel, we derived cellular models (PDXDCs) to offer a time- and cost-effective preclinical screening tool. PDXDCs were obtained from dissociated PDX tumors cultured under different media and matrix conditions. They were characterized by comparison with the parental PDX by Short Tandem Repeat (STR) profiling before performing a master bank. WES and RNASeq molecular analyses were done and in vitro drug sensitivity was compared with their parental PDX in vivo drug response. Overall, the results show that this PDXDC panel reproduced in vitro the in vivo drug response profile of the original PDXs with various therapies. This BC PDX panel and in vitro cell derivatives provide a powerful preclinical platform to improve our knowledge on BC biology and to rapidly evaluate response to new treatments and translate this knowledge to the clinic. Citation Format: Delphine Nicolle, Aurore Gorce, Marie Tavernier, Elisabetta Marangoni, Didier Decaudin, Christophe Ginestier, Emmanuelle Charafe-Jaufret, Judith Passildas, Nina Robin, Robert Clarke, Erwan Corcuff, Anaïs Joachim, Bernard Malissen, Ana Zarubica, Hervé Luche, Jean-Gabriel Judde, Olivier Déas. A preclinical platform of breast cancer PDX and derived cellular models as a tool for pharmacological screening and functional studies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4677.

Abstract P2-18-01: Matched Single-Cell RNA-seq and Single-Cell ATAC-seq of Male Breast Cancers Nominate Salient Cancer-Specific Enhancers

Abstract Although male breast cancer accounts for less than 1% of all breast cancer cases, overall survival is worse for men compared to women. This is due, in part, to the older age of patients at the time of diagnosis and the increased presence of comorbidities in the male population. While male breast cancer presents with similarities to certain female breast cancers, the paucity of data available on male breast cancer makes it difficult to establish targeted therapies, and to date, most male breast cancers are treated according to the standards in place for female breast cancer. Thus, investigating the transcriptional and epigenetic landscape of male breast cancer with improved resolution is crucial for understanding the tumor heterogeneity of this rare cancer type and can lead to the discovery of new therapeutic targets. In this study, we present matched transcriptional (scRNA-seq) and epigenetic (scATAC-seq) profiles of two male breast cancer tumors at single-cell resolution. Using scRNA-seq, we determine differentially expressed genes between male and female breast cancer tumors, specifically in the malignant cell populations, and highlight several genes that may have therapeutic implications within male breast cancer. We then leverage the scATAC-seq data to link variation in chromatin accessibility to changes in gene expression and show that certain highly expressed genes in the tumor-epithelial cells of male breast tumors are linked to highly active enhancer elements that drive their expression. Finally, we examine transcription factor motifs in the tumor-epithelial regulatory regions of male breast cancer tumors to further investigate the regulatory logic of these cell types. Overall, this dataset exposes clinically relevant regulatory networks in male breast tumors, providing a useful resource to the field of breast oncology that expands on the current knowledge of male breast cancer genetics. Citation Format: Kamila Wisniewska, Hyunsoo Kim, Matthew J. Regner, Philip Spanheimer, Hector L. Franco. Matched Single-Cell RNA-seq and Single-Cell ATAC-seq of Male Breast Cancers Nominate Salient Cancer-Specific Enhancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-18-01.

Genetics, Treatment, and New Technologies of Hormone Receptor-Positive Breast Cancer

The current molecular classification divides breast cancer into four major subtypes, including luminal A, luminal B, HER2-positive, and basal-like, based on receptor gene expression profiling. Luminal A and luminal B are hormone receptor (HR, estrogen, and/or progesterone receptor)-positive and are the most common subtypes, accounting for around 50-60% and 15-20% of the total breast cancer cases, respectively. The drug treatment for HR-positive breast cancer includes endocrine therapy, HER2-targeted therapy (depending on the HER2 status), and chemotherapy (depending on the risk of recurrence). In this review, in addition to classification, we focused on discussing the important aspects of HR-positive breast cancer, including HR structure and signaling, genetics, including epigenetics and gene mutations, gene expression-based assays, the traditional and new drugs for treatment, and novel or new uses of technology in diagnosis and treatment. Particularly, we have summarized the commonly mutated genes and abnormally methylated genes in HR-positive breast cancer and compared four common gene expression-based assays that are used in breast cancer as prognostic and/or predictive tools in detail, including their clinical use, the factors being evaluated, patient demographics, and the scoring systems. All these topic discussions have not been fully described and summarized within other research or review articles.

Breast cancer subtype and clinical characteristics in women from Peru.

Breast cancer is a heterogeneous disease, and the distribution of the different subtypes varies by race/ethnic category in the United States and by country. Established breast cancer-associated factors impact subtype-specific risk; however, these included limited or no representation of Latin American diversity. To address this gap in knowledge, we report a description of demographic, reproductive, and lifestyle breast cancer-associated factors by age at diagnosis and disease subtype for The Peruvian Genetics and Genomics of Breast Cancer (PEGEN-BC) study. The PEGEN-BC study is a hospital-based breast cancer cohort that includes 1943 patients diagnosed at the Instituto Nacional de Enfermedades Neoplásicas in Lima, Peru. Demographic and reproductive information, as well as lifestyle exposures, were collected with a questionnaire. Clinical data, including tumor Hormone Receptor (HR) status and Human Epidermal Growth Factor Receptor 2 (HER2) status, were abstracted from electronic medical records. Differences in proportions and mean values were tested using Chi-squared and one-way ANOVA tests, respectively. Multinomial logistic regression models were used for multivariate association analyses. The distribution of subtypes was 52% HR+HER2-, 19% HR+HER2+, 16% HR-HER2-, and 13% HR-HER2+. Indigenous American (IA) genetic ancestry was higher, and height was lower among individuals with the HR-HER2+ subtype (80% IA vs. 76% overall, p=0.007; 152 cm vs. 153 cm overall, p=0.032, respectively). In multivariate models, IA ancestry was associated with HR-HER2+ subtype (OR=1.38,95%CI=1.06-1.79, p=0.017) and parous women showed increased risk for HR-HER2+ (OR=2.7,95%CI=1.5-4.8, p<0.001) and HR-HER2- tumors (OR=2.4,95%CI=1.5-4.0, p<0.001) compared to nulliparous women. Multiple patient and tumor characteristics differed by age at diagnosis (<50 vs. >=50), including ancestry, region of residence, family history, height, BMI, breastfeeding, parity, and stage at diagnosis (p<0.02 for all variables). The characteristics of the PEGEN-BC study participants do not suggest heterogeneity by tumor subtype except for IA genetic ancestry proportion, which has been previously reported. Differences by age at diagnosis were apparent and concordant with what is known about pre- and post-menopausal-specific disease risk factors. Additional studies in Peru should be developed to further understand the main contributors to the specific age of onset and molecular disease subtypes in this population and develop population-appropriate predictive models for prevention.

Targeted Gene Panel Sequencing Unveiled New Pathogenic Mutations in Patients With Breast Cancer.

The increasing commercialization of new gene panels based on next-generation sequencing for clinical research has significantly improved our understanding of breast cancer genetics and has led to the discovery of new mutation variants. The study included 16 unselected Moroccan breast cancer patients tested with multi-gene panel (HEVA screen panel) using Illumina Miseq, followed by Sanger sequencing to validate the most relevant mutation. Mutational analysis revealed the presence of 13 mutations (11 single-nucleotide polymorphisms [SNPs] and 2 indels), and 6 of 11 identified SNPs were predicted as pathogenic. One of the 6 pathogenic mutations was c.7874G>C, a heterozygous SNP in HD-OB domain of BRCA2 gene, which led to the arginine to threonine change at codon 2625 of the protein. This work describes the first case of a patient with breast cancer harboring this pathogenic variant and analyzes its functional impact using molecular docking and molecular dynamics simulation. Further experimental investigations are needed to validate its pathogenicity and to verify its association with breast cancer.

Abstract B088: The Alabama Hereditary Cancer Cohort – New strategies for African American recruitment

Abstract Our group has established the Alabama Hereditary Cancer Cohort and primarily investigates breast cancer genetics in African American, an underrepresented group in biomedical research. Alabama has double the national percentage of African Americans and is the location of the infamous and unethical Tuskegee Syphilis Study. Therefore, strategic protocols were developed to break research participation barriers, effectively recruiting African American hereditary breast cancer cases and families. Our initial recruitment strategies involved both hospital-based and community-based recruitment; the latter involved our recruitment bus, the Gene Machine, and focused on African American engagement. Since our initial publication, our community-based recruitment protocol has been modified. Many of the modifications were due to the pandemic, limiting in-person community engagement. In-person education seminars and enrollment sessions transitioned to virtual meetings, using various video-conferencing platforms. Regarding virtual enrollments, upon agreement to proceed with the virtual consent process, study participants are mailed an enrollment kit containing study consent forms, saliva collection kits, return mailing materials, and instructions. Once received, an enrollment appointment is made, and the consent process follows the procedure for in-person study enrollment, concluding with the saliva sample collection. Once collected, the sample is packaged with the consent forms and returned to our laboratory in the postage-paid mailer. Community-based recruitment has also been enhanced by partnering with the Alabama Department of Public Health to identify study participants through the Alabama Statewide Cancer Registry, similar to the very successful Carolina Breast Cancer Study. Furthermore, Research Champions have been added to the protocol, defined as primary healthcare providers and specialists who aid in recruitment by identifying individuals who fit the study criteria. The concept of Research Champions was developed after recognizing that the requirements to execute hospital-based recruitment are arduous on partnering hospitals. Thus, the sole function of a Research Champion is identifying prospective study participants, relieving the burden on physicians and hospital staff. Lastly, our Gene Machine Facebook page and newly designed website, tailored towards laypeople/study participants, facilitate additional engagement through ads, videos, and photos. Ultimately, these processes reduce the travel burden, aid in social distancing, and expand our reach, enhancing recruitment and enrollment efforts and breaking barriers to African American research. Citation Format: Nancy Merner, Elizabeth Stallworth, Erica Reasor, Katia Khoury, Lily Gutnik, Meagan Farmer, Brandon Johnson. The Alabama Hereditary Cancer Cohort – New strategies for African American recruitment [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B088.

Genetics of Breast Cancer Among Moroccan Women: a Literature Review

Introduction: Breast cancer (BC) is a heterogeneous disease defined by the accumulation of various molecular alterations that accord each tumor a specific phenotype. Our study aimed to summarize all studies conducted on genetic alterations associated with BC in Moroccan women. Methods: We systematically searched literature databases from the time of inception until 31 August 2021 to collect information concerning the mutation spectrum for BC in Morocco. Results: We identified twenty-three studies including 1858 cases. According to our literature search, twenty-nine mutations were detected in 92/468 (19, 66%) patients for BRCA1/BRCA2 genes. We captured eighteen mutations dispersed in the exons 2, 3, 5, 11, 16, 17, 18, and 20 of the BRCA1 gene (c.68_69delAG, c.116G&gt;A, c.181T&gt;G, c.798_799delTT, c.3279delC, c.2805delA, c.1016dupA, c.2126insA, c.3453delT, c.2884C&gt;T, c.2596C&gt;T, c.2612C&gt;T, c.1186A&gt;G, c. 1100A&gt;G, c.4942A&gt;T, c.5062-5064delGTT, c.5095C&gt;T and c.5309G&gt;T). Moreover, eleven mutations dispersed in the exons 3, 10, 11, and 14 and intron 6 of the BRCA2 gene were detected (c.289G&gt;T, c.1310_1313delAAGA, c.3381delT, c.5073dupA, c.5116_5119delAATA, c.6322C&gt;T, c.3847_3848delGT, c.5576-5579delTTAA, c.7110delA, c.7235inG and c.517-1G&gt;A). A few case-control studies have focused on the association of polymorphisms (SNPs) with the genetic susceptibility of developing BC in Moroccan cases in other genes. A significant association between MTHFR 677T allele ( OR: 2.49, 95% CI: 1.17–5.29, p?=?0.017), TP53 72Pro variant (OR 2.2, 95% CI 1.07-4.54, p = 0.03), CYP2D6*3variant (OR=2.08, CI 1.28-3.39, p=0.003) and the risk of developing BC was observed. Additionally, the rs1799793 ERCC2 polymorphism, four SNPs in APOBEC3B, and one SNP in APOBEC3A were significantly associated with BC risk (p?0.05). Conclusion: This review will allow updating the Moroccan Human Mutation Database. However, large studies including more mutations and polymorphisms are required to determine the prevalence of these mutations in the Moroccan population. This could be very beneficial to guide specific and more effective therapeutic strategies in our country. Keywords: Breast cancer, BRCA1, BRCA2, genetic alterations, Morocco.

Genotype and phenotype correlation of breast cancer in young Kazakh women

Breast cancer occupies a leading position in incidence and mortality from cancer among women worldwide and in Kazakhstan. Currently, modern genotyping methods are widely used for more accurate diagnosis and successful treatment of the disease. In this study, we analyzed the contribution of genetic variants of the BRCA2 gene to the pathogenesis and clinical heterogeneity of breast cancer among young ethnic Kazakh women under 40 years of age. 200 patients were examined. Using next-generation sequencing (NGS) and subsequent bioinformatic analysis, rare pathogenic variants were found in patients with breast cancer. All pathogenic variants met in the heterozygous state. 12 pathogenic variants in the BRCA2 gene were identified in 22 patients, among which were nonsense, frameshift indels, and inframe deletions. An analysis of the association between the mutational status and the disease's clinical features showed a relationship between the manifestation of a number of clinical and morphological features and the presence of pathogenic mutations in the BRCA2 gene in patients. Further research in the field of breast cancer genetics will contribute to obtaining a more accurate picture of the interaction of genotype and phenotype in this disease. Key words: breast cancer, next-generation sequencing, pathogenic mutations, BRCA2.

Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics

By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p<5.0×10-8 and a Bonferroni-corrected p<4.6×10-6, respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy.

Breast cancer and cancer genetics - Volume 82 multiple choice answers

Breast cancer and cancer genetics - Volume 82 multiple choice answers

Impact of BRCA1/2 cascade testing on anxiety, depression, and cancer worry levels among unaffected relatives in a multiethnic Asian cohort.

Cascade testing for families with BRCA pathogenic variants is important to identify relatives who are carriers. These relatives can benefit from appropriate risk management and preventative strategies arising from an inherited increased risk of breast, ovarian, prostate, melanoma, and pancreatic cancers. Cascade testing has the potential to enable cost-effective cancer control even in low- and middle-income settings, but few studies have hitherto evaluated the psychosocial impact of cascade testing in an Asian population, where the cultural and religious beliefs around inheritance and destiny have previously been shown to influence perception and attitudes toward screening. In this study, we evaluated the short- and long-term psychosocial impact of genetic testing among unaffected relatives of probands identified through the Malaysian Breast Cancer Genetics Study and the Malaysian Ovarian Cancer Study, using validated questionnaires (Hospital Anxiety and Depression Scale and Cancer Worry Scale) administered at baseline, and 1-month and 2-year post-disclosure of results. Of the 305 unaffected relatives from 98 independent families who were offered cascade testing, 256 (84%) completed predictive testing and family history of cancers was the only factor significantly associated with uptake of predictive testing. We found that the levels of anxiety, depression, and cancer worry among unaffected relatives decreased significantly after result disclosure and remained low 2-year post-result disclosure. Younger relatives and relatives of Malay descent had higher cancer worry at both baseline and after result disclosure compared to those of Chinese and Indian descent, whereas relatives of Indian descent and those with family history of cancers had higher anxiety and depression levels post-result disclosure. Taken together, the results from this Asian cohort highlight the differences in psychosocial needs in different communities and inform the development of culture-specific genetic counseling strategies.