Breast Cancer In Latinas Research Articles

Abstract 3631: Transcriptome-wide association study identifies novel genes associated with breast cancer susceptibility in Latinas

Abstract Background: Genetic susceptibility to breast cancer has been studied extensively in European ancestry populations, but few studies have addressed genetic susceptibility in non-European women. Latinas are a genetically diverse group with contributions from European, African, and Indigenous American ancestries. Genome-wide association studies (GWAS) have identified unique variants in this population, particularly at the 6q25 locus. We conducted a transcriptome-wide association study (TWAS) to identify novel genes associated with risk of breast cancer in Latinas. Methods: We used individual level GWAS data from 2,396 Latina cases and 6,505 Latina controls from the studies in Northern California (San Francisco Bay Area Breast Cancer Study, Northern California Breast Cancer Family Registry and Kaiser Permanente Genetic Epidemiology Research on Aging Cohort), Southern California (Multi-ethnic Cohort) and Mexico (CAMA study). We analyzed the association between genetically predicted whole blood (WB) gene expression and breast cancer risk using newly developed TWAS models based on 784 Mexican American individuals. We also conducted parallel analyses using breast mammary tissue (BT) TWAS models from GTEx v8. All analyses were adjusted for age, ancestry, and study. Associations with false discovery rate (FDR) probability <0.05 were considered statistically significant. Results: At FDR<0.05, we identified 20 genes from BT and 39 genes from WB. Seven of the genes were significantly associated in both the WB models and GTEx BT models. Increased expression of MIB2 (pFDR = 4.74x10-17 (WB) and 1.22x10-4 (BT)), NBPF26 (pFDR = 1.30x10-7 (WB) and 7.43x10-8 (BT)), SLC35E2B (pFDR = 1.12x10-4 (WB) and 5.47x10-5 (BT)), and FAM30A (pFDR = 1.18x10-10 (WB) and 9.27x10-3 (BT)) was associated with increased risk of breast cancer risk, whereas increased expression of SLC35E2A (pFDR = 8.17x10-6 (WB) and 1.55x10-3 (BT)) and HCP5B (pFDR = 1.84x10-3 (WB) and 2.19x10-3 (BT)) was associated with decreased breast cancer risk. Increased expression of PDGFA was associated with increased risk (pFDR = 1.30x10-7) in GTEx BT reference models but decreased risk (pFDR = 2.34x10-10) in the ancestry-specific WB model. Conclusion: Our study is the first TWAS investigating the relationship between genetically predicted gene expression and breast cancer risk in Latinas. By leveraging gene expression prediction models that capture eQTLs that are more common in populations with Indigenous American ancestry, we have identified some novel genes associated with breast cancer risk in Latinas. Of these, MIB2 is a strong candidate for a mechanistic role in breast carcinogenesis in Latinas. MIB2 is involved in Notch signaling which plays an important role in breast carcinogenesis via its mismatched receptor-ligand interaction. Our study highlights the role of ancestry-based prediction models in TWAS analyses. Citation Format: Pooja Middha Kapoor, Angel C. Mak, Linda Kachuri, Donglei Hu, Scott Huntsman, Lawrence H. Kushi, Christopher Haiman, Esther M. John, Gabriela Torres-Mejia, Esteban G. Burchard, Susan L. Neuhausen, Laura Fejerman, Elad Ziv. Transcriptome-wide association study identifies novel genes associated with breast cancer susceptibility in Latinas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3631.

Abstract PO-164: Pathogenic variants in breast cancer risk genes in Latinas

Abstract Introduction: Pathogenic variants (PVs) in high- and intermediate-penetrance breast cancer susceptibility genes have large effects on disease risk. While individual PVs are rare, in aggregate, they markedly contribute to breast cancer risk in women of European ancestry in the general population. We examined the association with risk of developing breast cancer in Latinas. Methods: We conducted a pooled case-control analysis of breast cancer in Latinas from the San Francisco Bay Area, Los Angeles, and Mexico (4,172 cases and 3,692 controls). Case ascertainment included 2,095 participants from high-risk breast cancer studies (age below 50 years at breast cancer diagnosis, family history, or bilateral breast cancer) and 5,769 from general population studies. We determined presence of a rare PV in nine known breast cancer risk genes (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, PTEN, RAD51C, and TP53). We examined associations between PVs in each gene and breast cancer using multivariable logistic regression models, adjusted for age and ancestry. Secondary analyses were stratified by age, family history, or Indigenous American (IA) ancestry. Results: PVs in known risk genes were detected in 7.0% of cases and 1.7% of controls in participants from general population studies. Odds ratios (OR) for breast cancer in those with PVs in BRCA1, BRCA2, CHEK2, PALB2, and TP53 were 15.7 (95% CI: 5.7-64.8), 7.0 (95% CI: 3.7-14.4), 1.9 (95% CI: 1.0-4.0), 6.1 (95% CI: 3.1-13.9), and 3.7 (95% CI: 1.1-16.2) respectively. PVs in ATM (OR: 1.2, 95% CI: 0.7-2.1), BARD1 (OR: 1.5, 95% CI: 0.3-10.4), PTEN (PVs in 4 cases and 0 controls), and RAD51C (OR: 1.5, 95% CI: 0.2-11.5) were not significantly associated with breast cancer. Among cases, those with age<50 at diagnosis or with family history of breast cancer had increased odds of having a PV, with ORs of 1.4 (95% CI: 1.0-1.9) and 2.3 (95% CI: 1.4-4.0), respectively. IA above the median was associated with increased odds of having a PV among cases (OR: 1.8; 95% CI: 1.4-2.5) but not among controls. Discussion: Among Latina participants, having a PV in any of the nine genes was associated with increased risk of breast cancer. As expected, cases who were younger or had a family history of breast cancer were more likely to have a PV. In addition, cases but not controls with high IA were more likely to have a PV. The higher prevalence of PVs among high IA cases but not controls may be due to the younger age of these women and/or lower prevalence of other environmental risk factors. Our PV prevalence estimates among Latinas were similar to those previously found among European ancestry participants. Our results suggest that there may be clinical utility in testing for rare PVs in breast cancer risk genes among those in the general population. Citation Format: Jovia L Nierenberg, Aaron Adamson, Yuan C. Ding, Yiwey Shieh, Donglei Hu, Scott Huntsman, Esther M. John, Gabriela Torres-Mejia, Christopher A. Haiman, Lawrence H. Kushi, Charite N. Ricker, Linda Steele, Robin Lee, Jeffrey N. Weitzel, Laura Fejerman, Elad Ziv, Susan L. Neuhausen. Pathogenic variants in breast cancer risk genes in Latinas [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-164.

Abstract 4615: Admixture mapping and gene expression analysis to identify candidate genes associated with HER2 positive breast cancer in Latinas

Abstract The incidence of Human Epidermal Growth Factor Receptor 2 positive (HER2+) breast cancer is higher in Latinas, both in the U.S. and in Latin America. Preliminary analyses of the Peruvian Genetics and Genomics of Breast Cancer (PEGEN-BC) study data set showed a strong association between the Indigenous American (IA) component of ancestry and HER2 status independently of stage at diagnosis and other factors. The aim of this study was to identify genetic loci associated with genetic ancestry and HER2+ breast cancer in patients with high IA ancestry. To achieve this aim we used admixture mapping and gene-expression guided fine mapping. Breast cancer patients were recruited at the Instituto Nacional de Enfermedades Neoplásicas in Lima, Peru. A total of 1,850 patients have been recruited to date. DNA samples are currently available for a total of 1,380 patients. Genome wide genotypes were obtained with the Affymetrix Precision Medicine Research Array. After quality control, genome wide genotype data was available for 1,312 patients. After LD pruning and exclusion of SNPs with minor allele frequency <0.05, we estimated global ancestry with the program ADMIXTURE and locus-specific ancestry using RFMix. Tumor subtypes were classified using immunohistochemistry markers for estrogen, progesterone and HER2 receptors. Admixture mapping was conducted using logistic regression models. The outcome variable was HER2 status (HER2+ =1, HER2- =0). Global Individual IA ancestry and age at diagnosis were included as covariates. For transcriptomic analysis within regions of interest we used exome sequencing data (Illumina NextSeq500 system) for total RNA extracted from 79 FFPE tumor tissues from the same cohort. Genes within regions with suggestive admixture mapping signals were further analyzed by comparing normalized RNA read counts by HER2+ status using the DEseq2 R package. Admixture mapping analysis revealed two regions associated with IA ancestry in two chromosomal regions: 2q11-2q12 (OR=0.6, p=0.00009) and 3p14 (OR=1.5, p= 0.0004). Of the 44 genes within the 2q region, TGFBRAP1, member of the heat shock protein 90 family, was the only gene with suggestive differential expression by HER2 status (p=0.032). Of the 28 genes within the 3p14 region, we found significant differential expression for FLNB (lower expression in HER2+ tumours, 5%FDR= 0.03), which has been shown to supress tumour growth and metastasis. Combining admixture mapping and transcriptomics is a promising approach to discover candidate genes associated with subtype-specific breast cancer risk. We are currently working to replicate suggestive findings and expand our sample size to increase power. Citation Format: Valentina Zavala, Katie M. Marker, Tatiana Vidaurre, Jeannie Navarro-Vasquez, Sandro Casavilca, Mónica Calderon, Julio Abugattas, Henry Gómez, Hugo Fuentes, Ruddy Liendo-Picoaga, Jose M. Cotrina, Silvia P. Neciosup, Carlos A. Castaneda, Zaida Morante, Fernando Valencia, Silvia J. Serrano-Gomez, Jovanny Zabaleta, Laura Fejerman. Admixture mapping and gene expression analysis to identify candidate genes associated with HER2 positive breast cancer in Latinas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4615.

Abstract B080: Assessment of the molecular mechanisms of a protective variant for breast cancer in Latinas

Abstract The incidence of breast cancer is lower in women of Latin American origin in the U.S. compared to European American and African American women. Among Latinas, the rs140068132A>G variant, which is common in women with IAA, has been associated to a lower risk of breast cancer. The frequency of the G allele is 0% for non-Latinos while 12% in Latinos, being highest in the Peruvian population (23%). This variant is located on chromosome 6 near the Estrogen Receptor 1 gene (ESR1) and even though experimental evidence suggests that this variant might be functional, the molecular mechanisms that explain its protective effect are unknown. We hypothesize that the rs140068132-G variant decreases ESR1 expression, which affects the expression or function of genes involved in associated pathways. We aim to test the association of the rs140068132 variant and gene expression in breast cancer tumors from patients with high IAA. We collected 47 breast tumors and blood samples from the Instituto Nacional de Enfermedades Neoplásicas in Lima, Peru. These patients were genotyped for IAA estimation and determination of the rs140068132 genotype. Total RNA was extracted from tumor samples and used for a paired-end sequencing (2 × 75bp paired-end,100 million reads per sample) in the Illumina NextSeq500. Differential gene expression between genotypes was performed by DEseq2 R package and statistical significance was determined using FDR<0.05 for samples with at least log2 1.5-fold change. Differentially expressed isoforms were detected by EBseq R package using FDR<0.05. Tumor intrinsic subtypes were obtained using PAM50 as implemented in the genefu R package. The average IAA for the 47 Peruvian patients was 77% (SD=0.17). Twenty-seven patients were homozygous AA, 19 heterozygous AG and 1 GG for the rs140068132 variant. According to PAM50 classification, 10 tumors were Luminal A, 12 Luminal B, 15 HER2+ and 10 Basal. Among luminal tumors there was a suggestive trend towards lower expression of the ESR1 gene in patients carrying the protective allele (p=0.16). Including all subtypes, 27 genes were differentially expressed according to the rs140068132 genotype. Four of these genes are ER dependent or associated with ER status. The expression of the top gene, which is a transcriptional target of ER, is lost in patients with the protective allele. This association is mainly driven by its expression in luminal tumors and remained significant after adjusting for IAA. ESR1 isoforms were not differentially expressed by genotype, however significant differences were detected in the expression of isoforms for 115 genes, of which 18% have been reported to be transcriptional targets of ER or functionally related. Our preliminary results suggest that the rs140068132 variant decreases ER expression and affects the expression of functionally associated genes in luminal tumors. Further allele-specific expression analysis will elucidate if this variant is part of a cis-regulatory module. Note: This abstract was not presented at the conference. Citation Format: Valentina A. Zavala, Tatiana Vidaurre, Katie Marker, Sandro Casavilca, Lizeth Tamayo, Carlos Castañeda, Jeannie Vásquez, Fernando Valencia, Zaida Morante, M. Calderon, J. Abugattas, H. Gomez, H. Fuentes, C. Monge-Pimentel, Silvia Neciosup, Jovanny Zabaleta, Laura Fejerman. Assessment of the molecular mechanisms of a protective variant for breast cancer in Latinas [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B080.

Abstract B081: Common copy number aberrations in breast cancer in Latinas

Abstract Background: Latinos represent the largest and fastest-growing minority population in the US; breast cancer is the most common cancer and causes the most cancer deaths in this population. Copy number amplifications and deletions are an important determinant of the biology of breast tumors and, in some cases, may help to guide treatment. However, little is known about the copy number profile of breast tumors from Latinas. For example, in The Cancer Genome Atlas (TCGA), one of the largest publicly available tumor mutation datasets, there are data on only 31 Latina (out of a total of >1000) breast cancer cases. Therefore, we used whole exome sequencing on matched tumor/normal pairs in 146 tumors from 142 women, to investigate copy number aberrations in breast tumors from Latinas. Methods: We enrolled 142 Latinas with invasive breast cancer and obtained blood and tumor tissue (formalin-fixed paraffin embedded). We performed whole exome sequencing of 146 pairs of tumor (somatic) and normal (germline) samples resulting in 142 tumor-normal pairs for analysis. Target coverage for normal was ~30X and for tumor was ~100X. Sequence data were aligned using Burrows-Wheeler Aligner, and copy number aberrations were called using CNVkit. We estimated genetic ancestry from the germline genotype data using ADMIXTURE. Results: Age at diagnosis ranged from 31 to 75 years with a median age of 48 years. Histologically, 83% were estrogen-receptor positive, 71 % were progesterone-receptor positive, and 17% were human epidermal growth factor receptor positive; 87% were Stage 1 or 2 at diagnosis. The mean genetic ancestry in our sample was ~52.3% European, ~41.6% Indigenous American, and ~6.2% African. Large copy number amplifications were detected mostly commonly at 1q and 8q, and large deletions were detected at 11q, 16q and 17p. Genes commonly gained/amplified included MYC (43%), FGFR1 (19.2%), CCND1 (18.0%), and ERRB2 (14.4%). Genes commonly deleted in at least one chromosome include TP53, MAP2K4, BRCA1, PP2R2A, CHEK2, and PALB2. Summary: Breast tumors from Latinas display similar rates of large chromosomal copy number gains and losses at common positions and similar rates of gene-specific copy number amplifications and deletions compared non-Latina European ancestry women. Citation Format: Elad Ziv, Daniel Schmolze, Donglei Hu, Aaron Adamson, Shu Tao, Charleen Adams, Linda Steele, Scott Huntsman, Jeffrey Weitzel, Jung Byun, Kevin Gardner, Eliseo Perez-Stable, Anna Napoles-Springer, Susan Neuhausen. Common copy number aberrations in breast cancer in Latinas [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B081.

Abstract P4-09-02: Somatic tumor profiles of breast cancer in Latinas

Abstract Background: Latinos represent the largest and fastest-growing minority population in the US; breast cancer is the most common cancer and causes the most cancer deaths in this population. Precision medicine is being applied increasingly to guide breast cancer treatment decisions. However, the ability to apply precision medicine for prognosis and targeted treatments for breast cancer in Latinas is limited by insufficient data on somatic mutation and gene expression profiles in available tumor mutation datasets. In The Cancer Genome Atlas (TCGA), one of the largest publicly available tumor mutation datasets, only 31 of ~1100 total breast cancers are Latina. Therefore, we performed whole exome sequencing on matched tumor/normal pairs in 146 tumors from 142 women reporting here on their somatic mutational profile compared to non-Latino women of European ancestry from TCGA. Methods: We enrolled 142 Latinas with invasive breast cancer and obtained blood and tumor tissue (formalin-fixed paraffin embedded). After whole exome sequencing of 146 pairs of tumor (somatic) and normal (germline) samples, high quality data were available for 142 tumor-normal pairs for analysis. Target coverage for normal was ~30X and for tumor was ~100X. Sequence data were aligned using Burrows-Wheeler Aligner, genotype calls were made using GATK and Mutect2 was used to call somatic mutations including base substitutions and small insertions and deletions. We estimated genetic ancestry from the germline genotype data using ADMIXTURE. Results: Age at diagnosis ranged from 31 to 75 years with a median age of 48 years. Histologically, 83% were estrogen-receptor positive, 71 % were progesterone-receptor positive, and 17% were human epidermal growth factor receptor positive; 87% were Stage 1 or 2 at diagnosis. The mean genetic ancestry in our sample was 52.3% European, 41.6% Indigenous American, and 6.2% African. We compared the 30 genes most commonly mutated in breast cancers (e.g., PIK3CA, TP53, MAP3K1, MLL3) in non-Latina Whites in TCGA to our data both overall and by subtype and searched for additional recurrently mutated genes not commonly observed in other populations. Similar to non-Latinos, PIK3CA and TP53 were the most commonly mutated genes; mutations in PIK3CA, GATA3, MAP3K1, and RYR2 were significantly more frequent in Latinas (p-value range from 0.001-0.002). Summary: In general, breast tumors from Latinas have similar rates of somatic mutations in most of the top commonly observed genes in European-ancestry women. Citation Format: Susan Neuhausen, Daniel Schmolze, Linda Steele, Shu Tao, Aaron Adamson, Charleen Adams, Donglei Hu, Scott Huntsman, Jung Byun, Kevin Gardner, Eliseo Perez-Stable, Anna Napoles, Jeffrey Weitzel, Elad Ziv. Somatic tumor profiles of breast cancer in Latinas [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-09-02.

Abstract 2419: A polygenic risk score predicts breast cancer risk in Latinas

Abstract Background: Genome-wide association studies (GWAS) have identified over 180 single nucleotide polymorphisms (SNPs) associated with breast cancer risk. Polygenic risk scores (PRS) represent the combined effects of multiple SNPs and have been consistently shown to improve the performance of existing risk models. Most SNPs were discovered in women of European ancestry. Thus, there are limited data on how PRS perform in Latinas, whose ancestry is a mixture of European and Indigenous American. We therefore sought to validate the performance of a 184-SNP PRS in Latinas. Methods: We conducted a pooled analysis of U.S. Latina and Mexican participants from 6 existing studies. Our analysis included 3,441 women with breast cancer and 7,773 women without breast cancer. We constructed a PRS containing 184 SNPs associated with breast cancer in prior GWAS, p < 5 x 10-8. We used multivariable logistic regression to evaluate the associations between the PRS and breast cancer, adjusting for genetic ancestry and study of origin. To assess discrimination, we calculated the area under the receiver operating characteristic curve (AUROC). To test the performance of the PRS by genetic ancestry, we stratified our analysis by quartiles of Indigenous American genetic ancestry. Results: The PRS was associated with breast cancer, with an odds ratio (OR) per standard deviation increment of 1.51 (95% CI 1.44-1.59). The PRS showed intermediate discrimination for cases vs. controls, with an AUROC of 0.62 (95% CI 0.60-0.63). When we stratified the analysis by genetic ancestry, the PRS performed worse in women with higher Indigenous American/lower European ancestry. Specifically, the discrimination of the PRS was least in the top quartile of Indigenous American ancestry and greatest in the bottom quartile, with AUROC of 0.60 (95% CI 0.57-0.62) vs. 0.65 (95% CI 0.62-0.67), respectively (p = 0.01). The corresponding ORs per standard deviation of the PRS were 1.40 (95% CI 1.29-1.53) for the top quartile and 1.70 (95% CI 1.52-1.89) for the bottom quartile of Indigenous American ancestry (p = 0.006). Conclusions: A 184-SNP PRS predicts breast cancer in Latinas, with the AUROC of 0.62 in our study being comparable to previous estimates in Europeans. However, the performance of the PRS varied according to genetic ancestry. While our results suggest the PRS may be used as-is in Latinas with higher European ancestry, future efforts should focus on refining the PRS in Latinas of higher Indigenous American ancestry through discovery and replication of novel predictive SNPs in this subgroup. Citation Format: Yiwey Shieh, Laura Fejerman, Sarah D. Sawyer, Donglei Hu, Scott Huntsman, Esther M. John, Lawrence H. Kushi, Gabriela Torres-Mejia, Jeffrey N. Weitzel, Christopher A. Haiman, Elad Ziv, Susan L. Neuhausen. A polygenic risk score predicts breast cancer risk in Latinas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2419.

Genetics, Tumor Features and Treatment Response of Breast Cancer in Latinas

Breast cancer is a heterogeneous and genetic disease that has variability according to ethnicity and race with respect to incidence, clinical characteristics and prognosis. The incidence of breast cancer is lower but mortality is higher in Latinas than Caucasians in the US series. Risk factors appear to have different prevalence and impact in Latinas. Breast cancer in Latinas has particular clinic-pathological features including younger age, higher rates of triple-negative subtype and advanced stages. Molecular studies find that Latinas from every region have a specific BRCA incidence and a recurrent mutation, as well as differences in activity of molecular pathways. Treatment response rates and toxicity have also been compared, and no difference was found between Latinas and other ethnic groups.

Abstract IA42: Genome wide association for breast cancer risk in Latinas: Analysis of known susceptibility loci

Abstract Background: Genome wide association studies have identified over 90 common variants associated with breast cancer risk. The majority of these findings have been made in populations of European ancestry. We have performed a genome wide association study of in ~2400 US Latina and Mexican breast cancer cases and ~7500 controls. Here we report on examination of previously reported loci and fine mapping within those loci. Methods: Cases and controls included women from the San Francisco Bay Area Study, the Northern California Breast Cancer Family Registry, the Multi-Ethnic Cohort and the Kaiser Permanente Research Program on Genes and the Environment on Health all based in California. In addition we included cases and controls from the CAMA study, based in Mexico and recruiting from 4 different states: Mexico City, Veracruz, Monterrey, and Puebla. Each of the samples were genotyped using an array with genome wide coverage (Affymetrix 6.0, Affymetrix Axiom, Illumina 1M, Illumina 2.5M or Illumina Oncoarray). We inferred genetic ancestry using principal components analysis. We imputed each array to the Haplotype Reference Consortium and performed association testing with breast cancer using logistic regression models, adjusting for study, array used, and principal components 1-10. Results: We have identified several signals at 6q25 which are independent of previously reported SNPs in other populations. We have also evaluated the utility of polygenic risk using data from common variants at previously reported loci. We compared a range of algorithms to enhance the predictive power of polygenic risk in Latinas, including ones that utilize fine mapping vs. ones which use the top SNPs from other populations. Conclusion: We demonstrate that a combination of new variants and judicious use of data from the known loci generates useful polygenic risk for breast cancer in Latinas. Citation Format: Joshua Hoffman, Sarah Sawyer, Laura Fejerman, Donglei Hu, Scott Huntsman, Esther John, Gabriela Torres-Mejia, Larry Kushi, Chistopher Haiman, Elad Ziv. Genome wide association for breast cancer risk in Latinas: Analysis of known susceptibility loci. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr IA42.

Genomic Disparities in Breast Cancer Among Latinas.

Breast cancer is the most common cancer diagnosed among Latinas in the United States and the leading cause of cancer-related death among this population. Latinas tend to be diagnosed at a later stage and have worse prognostic features than their non-Hispanic white counterparts. Genetic and genomic factors may contribute to observed breast cancer health disparities in Latinas. We provide a landscape of our current understanding and the existing gaps that need to be filled across the cancer prevention and control continuum. We summarize available data on mutations in high and moderate penetrance genes for inherited risk of breast cancer and the associated literature on disparities in awareness of and uptake of genetic counseling and testing in Latina populations. We also discuss common genetic polymorphisms and risk of breast cancer in Latinas. In the treatment setting, we examine tumor genomics and pharmacogenomics in Latina patients with breast cancer. As the US population continues to diversify, extending genetic and genomic research into this underserved and understudied population is critical. By understanding the risk of breast cancer among ethnically diverse populations, we will be better positioned to make treatment advancements for earlier stages of cancer, identify more effective and ideally less toxic treatment regimens, and increase rates of survival.

Abstract IA13: Understanding and preventing breast cancer disparities in Latinas

Abstract Background: Although Latinas have lower breast cancer rates compared to non-Hispanic Whites (NHW), breast cancer is the top cancer killer of Latinas. There are many reasons for this, some involve biology, types of breast cancer found in Latinas, metabolic increases thought to be due to adoption of western diets, and lack of screening for early detection. In a large breast cancer program examining such cancers in Latinas, we overcame a number of challenges in each of four studies examining the fore-named factors. Methods: Four projects and four cores made up our Center for Population Health and Health Disparities (CPHHD). Using a community-based participatory research (CBPR) model, we recruited Latinas to participate in studies investigating the various factors related to breast cancer. Projects used robust methodologies to assess the relationship between elevated risks of triple negative breast cancers; the effects of a typical US diet compared to a traditional Mexican diet; the role of genetic ancestry on breast cancer in Latinas; and the effectiveness of a lay health worker intervention to increase breast cancer screening. As part of the program, we asked investigators to identify challenges encountered and how they were resolved. Results: All four projects were completed on time. Overall results of each project will be presented. Challenges in each project will be described as well as how the challenges were overcome. The role of the Community Advisory Board will be described and how its suggestions for sending results back to participants were adopted and incorporated in the program. Discussion: Embarking on a large transdisciplinary program to understand Latinas' breast cancer risks and to translate those risks to the population of interest has been stimulating and thought-provoking. Addressing challenges as they emerged and finding solutions required a team effort. By obtaining perspectives from a variety of disciplines, we were able to solve the challenges. This team approach is recommended for similar studies. Citation Format: Beti Thompson, Shirley AA Beresford, Gloria D. Coronado, Marian Neuhouser, Christopher I. Li, Linda S. Cook, Peggy Porter. Understanding and preventing breast cancer disparities in Latinas. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr IA13.

Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25

The genetic contributions to breast cancer development among Latinas are not well understood. Here we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 5′ of the Estrogen Receptor 1 gene (ESR1; 6q25 region). The minor allele for this variant is strongly protective (rs140068132: odds ratio (OR) 0.60, 95% confidence interval (CI) 0.53–0.67, P=9 × 10−18), originates from Indigenous Americans and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for oestrogen receptor-negative disease (OR 0.34, 95% CI 0.21–0.54) than oestrogen receptor-positive disease (OR 0.63, 95% CI 0.49–0.80; P heterogeneity=0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P=0.001). rs140068132 is located within several transcription factor-binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations.

Abstract LB-299: Genome wide association study of breast cancer in Latinas identifies protective variants of Indigenous American origin on 6q25

Abstract Background: Multiple breast cancer genome-wide association studies (GWAS) have been conducted, with most samples analyzed being of European or Asian origin. No GWAS has been published to date on US Latinas or Latin American women. Previous studies have demonstrated that among Latina women, those with the highest Indigenous American ancestry are protected from breast cancer. We performed the first genome-wide association study of breast cancer in Latinas in a total of 1523 cases and 3221 controls and validated the strongest associations in an additional 977 Latina cases and 1158 controls. Methods: For the discovery phase, samples were genotyped with either the 6.0 Affymetrix array or Illumina Infinitum 660W/Omni 2.5 arrays. Additional genotypes were imputed from 1000 genomes and the final analysis included ∼7 million SNPs. SNPs for replication were genotyped using Sequenom. Logistic regression analyses included the first 10 principal components as covariates. Results: We identified two new variants, located 5’ of the ESR1 gene (6q25 region), which are strongly associated with breast cancer in this population. The minor allele for these variants is strongly protective (rs140068132: OR 0.61, 95%CI 0.48-0.75, p=3x10-13 & rs147157845: OR 0.63 95% CI 0.49-0.76; p =2x10-12). These alleles are present only in Latinos, correlate with Indigenous American ancestry, and are uncorrelated with previously reported risk variants in the ESR1 region. We found a strong association for both ER-positive and ER-negative breast cancer, but significantly more protection for ER-negative disease (p=0.014). The rs140068132 variant is also associated with breast density. The average breast density among women who are homozygous for the protective allele is approximately half of that of women homozygous for the common allele [Mean (sd) density for Homozygous GG = 9 (8); Homozygous AA = 17 (14), p 0.0009]. rs140068132, is located within a putative binding region for multiple transcription factors. MAPPER predicts disruption of putative transcription factor binding sites for the rare allele at rs140068132 but not rs147157845. Electromotility shift assays showed differential binding of the two alleles at the rs140068132 locus, with the protective allele (G) showing substantially reduced binding affinity compared to the common A allele. Conclusions: The variants at this locus represent, to our knowledge, the strongest genome wide effect size on breast cancer for a common variant (frequency >0.05 in any major population). These results may help in understanding the previous observations of lower breast cancer risk among Latina women with more Indigenous American ancestry and highlight the importance of conducting GWAS in diverse populations. Citation Format: Laura Fejerman, Nasim Ahmadiyeh, Donglei Hu, Scott Huntsman, Kenneth Beckman, Jennifer Caswell, Esther M. John, Gabriela Torres-Mejia, Luis Carvajal-Carmona, Magdalena Echeverry, Anna Marie Tuazon, Carolina Ramirez, COLUMBUS Consortium, Christopher Gignoux, Celeste Eng, Esteban Gonzalez-Burchard, Brian Henderson, Loic Le Marchand, Eliseo J. Perez-Stable, Christopher A. Haiman, Elad Ziv. Genome wide association study of breast cancer in Latinas identifies protective variants of Indigenous American origin on 6q25. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-299. doi:10.1158/1538-7445.AM2014-LB-299

Breast Cancer in Latinas: Gene Expression, Differential Response to Treatments, and Differential Toxicities in Latinas Compared with Other Population Groups

Disparities in clinical outcomes of breast cancer have been described among different racial and ethnic groups in the U.S. Convincing data exist showing that Latina women have a lower incidence of breast cancer but a higher breast cancer-related mortality rate compared with white women. Noticeable differences in breast cancer incidence are present even within different Latina subsets with a higher incidence in second- and third-generation women compared with foreign born. An increasing amount of data exists pointing to significant differences in the genetics and biology of breast cancer in Latinas as a significant contributor to the higher mortality, including a higher incidence of triple-negative breast cancers (which do not overexpress HER-2 protein and are negative for estrogen receptors and progesterone receptors). Other social and environmental factors are likely to play a significant role as well, including a lower rate of screening mammography, variable access to medical care, among others. Recent data are inconclusive regarding differences among racial/ethnic groups in the response to chemotherapy. Data on racial/ethnic variations in the pharmacogenomics of chemotherapy, endocrine treatments, and toxicity are more limited, with some data suggesting differences in frequencies of polymorphisms of genes involved in the metabolism of some of these agents. Further studies are needed on this subject.

Vitamin D receptor genotype and breast cancer in Latinas (United States).

Polymorphism in the vitamin D receptor (VDR) gene has been associated with variation in bone mineral density and with prostate cancer risk. The purpose of this study was to determine whether polymorphism in the VDR gene may also influence breast cancer risk. Polymorphisms in the 5' and 3' ends of the VDR gene were genotyped for 143 Latina women with breast cancer and 300 cohort controls. Both the BsmI and poly-A polymorphisms in the 3' end of the VDR gene were associated with breast cancer risk, with a trend for increasing risk with increasing number of BsmI B alleles or short (S) poly-A alleles. Compared to subjects having two long poly-A alleles (genotype LL), odds ratios (and 95% confidence intervals) were 1.5 (1.0 2.3) and 3.2 (1.5-6.9) for subjects having genotypes SL and SS, respectively. Compared to BsmI genotype bb, odds ratios (and 95% confidence intervals) were 1.6 (1.1-2.5) and 2.2 (1.0-4.7) for genotypes Bb and BB respectively. The start codon polymorphism, FokI, was not associated with breast cancer risk. These results suggest that polymorphic variation in or near the 3' end of the VDR gene influences breast cancer risk in Latina women.