Perceived Interpersonal Racism in Relation to Incident Coronary Heart Disease Among Black Women.

BACKGROUND: Racism is highly prevalent in the United States. Few data exist about whether perceived interpersonal racism is associated with risk of coronary heart disease (CHD). METHODS: We followed 48 305 participants in the Black Women's Health Study through biennial mailed and Internet-based health questionnaires from 1997, when they provided information on perceived interpersonal racism and were free of cardiovascular disease and cancer, until the end of 2019. We averaged participant responses to 5 validated questions about perceived interpersonal racism in everyday activities, such as "people act as if they think you are dishonest." We summed the positive responses to 3 questions about perceived racism in interactions that involved jobs, housing, and police; scores ranged from 0 (no to all) to 3 (yes to all). CHD cases were defined as nonfatal myocardial infarctions confirmed through medical records, fatal cases identified through the National Death Index, and self-reported revascularization events. We used Cox proportional hazard models adjusting for major confounders to estimate hazard ratios (HRs). RESULTS: During 22 years of follow-up, we identified 1947 incident CHD cases. For women who reported experiences of racism in employment, housing, or involving the police relative to women who reported no such experiences, the age-adjusted HR for CHD was 1.35 (95% CI, 1.13-1.61; Ptrend=0.006), and the multivariable HR for CHD was 1.26 (95% CI, 1.05-1.51; Ptrend=0.05). For women in the highest quartile of perceived interpersonal racism in daily life relative to women in the lowest quartile, the age-adjusted HR for CHD was 1.25 (95% CI, 1.07-1.46; Ptrend=0.006). After multivariable adjustment, the HR was attenuated and no longer statistically significant. CONCLUSIONS: Perceived experiences of interpersonal racism in employment, in housing, and with the police were associated with higher incidence of CHD among Black women, whereas perceived racism in everyday life was not associated with higher risk.

Addition of polygenic risk score to a risk calculator for prediction of breast cancer in US Black women.

BACKGROUND: Previous work in European ancestry populations has shown that adding a polygenic risk score (PRS) to breast cancer risk prediction models based on epidemiologic factors results in better discriminatory performance as measured by the AUC (area under the curve). Following publication of the first PRS to perform well in women of African ancestry (AA-PRS), we conducted an external validation of the AA-PRS and then evaluated the addition of the AA-PRS to a risk calculator for incident breast cancer in Black women based on epidemiologic factors (BWHS model). METHODS: Data from the Black Women's Health Study, an ongoing prospective cohort study of 59,000 US Black women followed by biennial questionnaire since 1995, were used to calculate AUCs and 95% confidence intervals (CIs) for discriminatory accuracy of the BWHS model, the AA-PRS alone, and a new model that combined them. Analyses were based on data from 922 women with invasive breast cancer and 1844 age-matched controls. RESULTS: AUCs were 0.577 (95% CI 0.556-0.598) for the BWHS model and 0.584 (95% CI 0.563-0.605) for the AA-PRS. For a model that combined estimates from the questionnaire-based BWHS model with the PRS, the AUC increased to 0.623 (95% CI 0.603-0.644). CONCLUSIONS: This combined model represents a step forward for personalized breast cancer preventive care for US Black women, as its performance metrics are similar to those from models in other populations. Use of this new model may mitigate exacerbation of breast cancer disparities if and when it becomes feasible to include a PRS in routine health care decision-making.

Body size and risk of multiple myeloma in the Black Women's Health Study.

BACKGROUND: Obesity is an established risk factor for multiple myeloma (MM). Relatively few prior studies, however, have evaluated associations in Black populations. METHODS: Among 55,276 participants in the Black Women's Health Study, a prospective U.S. cohort established in 1995, we confirmed 292 incident diagnoses of MM over 26 years of follow-up. Multivariable Cox proportional hazard models, adjusted for age and putative MM risk factors, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of usual body mass index (BMI), BMI at age 18, height, and waist-to-hip ratio with MM. RESULTS: Compared to women with a usual adult BMI < 25 kg/m2, the HR associated with a usual adult BMI ≥ 35 kg/m2 was 1.38 (95% CI: 0.96, 1.98). For early adult BMI, the HR comparing women with BMI ≥ 25 vs. <25 kg/m2 was 1.57 (95% CI: 1.08, 2.28). Women who were heavy in both early and later life had the highest risk compared to those who were lean at both time points (HR: 1.60; 95% CI: 1.02, 2.52). Height was also associated with the risk of MM; the HR per 10 cm was 1.21 (95% CI: 1.02, 1.43). CONCLUSIONS: These results indicate that high early adult BMI is associated with a 57% increased risk of MM in Black women and potentially highlight the importance of weight control as a preventive measure.

Psychosocial stressors and breast cancer gene expression in the Black Women's Health Study.

PURPOSE: Prior studies indicate that the physiologic response to stress can affect gene expression. We evaluated differential gene expression in breast cancers collected from Black women with high versus low exposure to psychosocial stressors. METHODS: We analyzed tumor RNA sequencing data from 417 Black Women's Health Study breast cancer cases with data on early life trauma and neighborhood disadvantage. We conducted age-adjusted differential gene expression analyses and pathway analyses. We also evaluated Conserved Transcriptional Response to Adversity (CTRA) contrast scores, relative fractions of immune cell types, T cell exhaustion, and adrenergic signaling. Analyses were run separately for estrogen receptor positive (ER+; n = 299) and ER- (n = 118) cases. RESULTS: Among ER+ cases, the top differentially expressed pathways by stress exposure were related to RNA and protein metabolism. Among ER- cases, they were related to developmental biology, signal transduction, metabolism, and the immune system. Targeted analyses indicated greater immune pathway enrichment with stress exposure for ER- cases, and possible relevance of adrenergic signaling for ER+ cases. CTRA contrast scores did not differ by stress exposure, but in analyses of the CTRA components, ER- breast cancer cases with high neighborhood disadvantage had higher pro-inflammatory gene expression (p = 0.039) and higher antibody gene expression (p = 0.006) compared to those with low neighborhood disadvantage. CONCLUSION: There are multiple pathways through which psychosocial stress exposure may influence breast tumor biology. Given the present findings on inflammation and immune response in ER- tumors, further research to identify stress-induced changes in the etiology and progression of ER- breast cancer is warranted.

Perceived Experiences of racism in Relation to Genome-Wide DNA Methylation and Epigenetic Aging in the Black Women's Health Study.

BACKGROUND: African American women have a disproportionate burden of disease compared to US non-Hispanic white women. Exposure to psychosocial stressors may contribute to these health disparities. Racial discrimination, a major stressor for African American women, could affect health through epigenetic mechanisms. METHODS: We conducted an epigenome-wide association study (EWAS) to examine the association of interpersonal racism (in daily life and in institutional settings) with DNA methylation in blood in 384 participants of the Black Women's Health Study (BWHS). We also evaluated whether a greater number of perceived experiences of racism was associated with epigenetic aging as measured using different methylation clocks. Models were adjusted for chronological age, body mass index, years of education, neighborhood SES, geographic region of residence, alcohol drinking, smoking, and technical covariates. RESULTS: Higher scores of racism in daily life were associated with higher methylation levels at the cg04494873 site in chromosome 5 (ß = 0.64%; 95% CI = 0.41%, 0.87%; P = 6.35E-08). We also replicated one CpG site, cg03317714, which was inversely associated with racial discrimination in a previous EWAS among African American women. In the BWHS, higher scores of racism in daily life were associated with lower methylation levels at that CpG site (ß = -0.94%; 95% CI = -1.37%, -0.51%; P = 2.2E-05). Higher racism scores were associated with accelerated epigenetic aging in more than one methylation clock. CONCLUSIONS: Exposure to discriminatory events may affect the epigenome and accelerate biological aging, which may explain in part the earlier onset of disease in African American women.

Lifecourse growth and development determinants of mammographic density in Black women.

BACKGROUND: High mammographic density is one of the strongest breast cancer risk factors; however, determinants of high mammographic density are understudied in Black women. We assessed growth and development factors across the lifecourse in relation to mammographic density. METHODS: Within the Black Women's Health Study (BWHS), we used Cumulus software to assess percent mammographic density from digital screening mammograms for 5,905 women ages 40-74. We fit linear regression models to quantify the association of lifecourse characteristics including birth weight, childhood somatotype, age at menarche, body mass index (BMI) at age 18, height, BMI at mammography, and adulthood waist-to-hip ratio with density overall and by age. We also performed a path analysis to assess the total and mediating effects of the growth and development factors on density. RESULTS: BMI at age 18, height, BMI at mammography, and waist-to-hip ratio were significantly and inversely associated with density. On path analysis, total effects of childhood somatotype (standardized  = -0.05, p <0.001), BMI at age 18 (standardized  = -0.13, p <0.001), BMI at mammography (standardized  = -0.22, p <0.001), and waist-to-hip ratio (standardized  = -0.04, p <0.001) were associated with density. CONCLUSIONS: Several factors across the lifecourse - greater childhood somatotype, BMI at age 18, height, BMI at mammography, and waist-to-hip ratio - were associated with lower mammographic density in this cohort of Black women. IMPACT: Body size closer to the time of mammography may be more meaningful in determining mammographic density, though early life adiposity also influences mammographic density.

Pack-Year Smoking History: An Inadequate and Biased Measure to Determine Lung Cancer Screening Eligibility.

PURPOSE: Pack-year smoking history is an imperfect and biased measure of cumulative tobacco exposure. The use of pack-year smoking history to determine lung cancer screening eligibility in the current US Preventive Services Task Force (USPSTF) guideline may unintentionally exclude many high-risk individuals, especially those from racial and ethnic minority groups. It is unclear whether using a smoking duration cutoff instead of a smoking pack-year cutoff would improve the selection of individuals for screening. METHODS: We analyzed 49,703 individuals with a smoking history from the Southern Community Cohort Study (SCCS) and 22,126 individuals with a smoking history from the Black Women's Health Study (BWHS) to assess eligibility for screening under the USPSTF guideline versus a proposed guideline that replaces the ≥20-pack-year criterion with a ≥20-year smoking duration criterion. RESULTS: Under the USPSTF guideline, only 57.6% of Black patients with lung cancer in the SCCS would have qualified for screening, whereas a significantly higher percentage of White patients with lung cancer (74.0%) would have qualified (P < .001). Under the proposed guideline, the percentage of Black and White patients with lung cancer who would have qualified for screening increased to 85.3% and 82.0%, respectively, eradicating the disparity in screening eligibility between the groups. In the BWHS, using a 20-year smoking duration cutoff instead of a 20-pack-year cutoff increased the percentage of Black women with lung cancer who would have qualified for screening from 42.5% to 63.8%. CONCLUSION: Use of a 20-year smoking duration cutoff instead of a 20-pack-year cutoff greatly increases the proportion of patients with lung cancer who would qualify for screening and eliminates the racial disparity in screening eligibility between Black versus White individuals; smoking duration has the added benefit of being easier to calculate and being a more precise assessment of smoking exposure compared with pack-year smoking history.

Benign and Malignant Outcomes in the Offspring of Females Exposed In Utero to Diethylstilbestrol (DES): An Update from the NCI Third Generation Study.

BACKGROUND: Females exposed prenatally to diethylstilbestrol (DES) have an elevated risk of cervical dysplasia, breast cancer, and clear cell adenocarcinoma (CCA) of the cervix/vagina. Testicular cancer risk is increased in prenatally exposed males. Epigenetic changes may mediate the transmission of DES effects to the next ("third") generation of offspring. METHODS: Using data self-reported by third-generation females, we assessed DES in relation to the risk of cancer and benign breast and reproductive tract conditions. Using data from prenatally DES-exposed and unexposed mothers, we assessed DES in relation to cancer risk in their female and male offspring. Cancer risk was assessed by standardized incidence ratios (SIR) and 95% confidence intervals (CI); the risks of benign and malignant diagnoses were assessed by hazard ratios (HR) and 95% CI. RESULTS: In self-reported data, DES exposure was not associated with an increased risk of overall cancer (HR 0.83; CI 0.36-1.90), breast cancer, or severe cervical dysplasia. No females reported CCA. The risk of borderline ovarian cancer appeared elevated, but the HR was imprecise (3.46; CI 0.37-32.42). Based on mothers' reports, DES exposure did not increase the risk of overall cancer (HR 0.80; CI 0.49-1.32) or of other cancers in third-generation females. Overall cancer risk in exposed males appeared elevated (HR 1.41; CI 0.70-2.86), but the CI was wide. The risk of testicular cancer was not elevated in exposed males; no cases of prostate cancer were reported. CONCLUSIONS: To date, there is little evidence that DES is associated with cancer risk in third-generation females or males, but these individuals are relatively young, and further follow-up is needed.

Association of ESR1 Germline Variants with TP53 Somatic Variants in Breast Tumors in a Genome-wide Study.

In breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors. A genome-wide association study was conducted in 2,850 women of European ancestry with breast cancer using TP53 and PIK3CA mutation status (positive or negative) as well as specific functional categories [e.g., TP53 gain-of-function (GOF) and loss-of-function, PIK3CA activating] as phenotypes. Germline variants showing evidence of association were selected for validation analyses and tested in multiple independent datasets. Discovery association analyses found five variants associated with TP53 mutation status with P values <1 × 10-6 and 33 variants with P values <1 × 10-5. Forty-four variants were associated with PIK3CA mutation status with P values <1 × 10-5. In validation analyses, only variants at the ESR1 locus were associated with TP53 mutation status after multiple comparisons corrections. Combined analyses in European and Malaysian populations found ESR1 locus variants rs9383938 and rs9479090 associated with the presence of TP53 mutations overall (P values 2 × 10-11 and 4.6 × 10-10, respectively). rs9383938 also showed association with TP53 GOF mutations (P value 6.1 × 10-7). rs9479090 showed suggestive evidence (P value 0.02) for association with TP53 mutation status in African ancestry populations. No other variants were significantly associated with TP53 or PIK3CA mutation status. Larger studies are needed to confirm these findings and determine if additional variants contribute to ancestry-specific differences in mutation frequency. SIGNIFICANCE: Emerging data show ancestry-specific differences in TP53 and PIK3CA mutation frequency in breast tumors suggesting that germline variants may influence somatic mutational processes. This study identified variants near ESR1 associated with TP53 mutation status and identified additional loci with suggestive association which may provide biological insight into observed differences.

BMI and breast cancer risk around age at menopause.

BACKGROUND: A high body mass index (BMI, kg/m2) is associated with decreased risk of breast cancer before menopause, but increased risk after menopause. Exactly when this reversal occurs in relation to menopause is unclear. Locating that change point could provide insight into the role of adiposity in breast cancer etiology. METHODS: We examined the association between BMI and breast cancer risk in the Premenopausal Breast Cancer Collaborative Group, from age 45 up to breast cancer diagnosis, loss to follow-up, death, or age 55, whichever came first. Analyses included 609,880 women in 16 prospective studies, including 9956 who developed breast cancer before age 55. We fitted three BMI hazard ratio (HR) models over age-time: constant, linear, or nonlinear (via splines), applying piecewise exponential additive mixed models, with age as the primary time scale. We divided person-time into four strata: premenopause; postmenopause due to natural menopause; postmenopause because of interventional loss of ovarian function (bilateral oophorectomy (BO) or chemotherapy); postmenopause due to hysterectomy without BO. Sensitivity analyses included stratifying by BMI in young adulthood, or excluding women using menopausal hormone therapy. RESULTS: The constant BMI HR model provided the best fit for all four menopausal status groups. Under this model, the estimated association between a five-unit increment in BMI and breast cancer risk was HR=0.87 (95% CI: 0.85, 0.89) before menopause, HR=1.00 (95% CI: 0.96, 1.04) after natural menopause, HR=0.99 (95% CI: 0.93, 1.05) after interventional loss of ovarian function, and HR=0.88 (95% CI: 0.76, 1.02) after hysterectomy without BO. CONCLUSION: The BMI breast cancer HRs remained less than or near one during the 45-55 year age range indicating that the transition to a positive association between BMI and risk occurs after age 55.

Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes.

African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations.

Hypertension and Risk of Endometrial Cancer: A Pooled Analysis in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: The incidence rates of endometrial cancer are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for endometrial cancer. Hypertension, another component of metabolic syndrome, is also increasing in prevalence, and emerging evidence suggests that it may be associated with the development of certain cancers. The role of hypertension independent of other components of metabolic syndrome in the etiology of endometrial cancer remains unclear. In this study, we evaluated hypertension as an independent risk factor for endometrial cancer and whether this association is modified by other established risk factors. METHODS: We included 15,631 endometrial cancer cases and 42,239 controls matched on age, race, and study-specific factors from 29 studies in the Epidemiology of Endometrial Cancer Consortium. We used multivariable unconditional logistic regression models to estimate ORs and 95% confidence intervals (CI) to evaluate the association between hypertension and endometrial cancer and whether this association differed by study design, race/ethnicity, body mass index, diabetes status, smoking status, or reproductive factors. RESULTS: Hypertension was associated with an increased risk of endometrial cancer (OR, 1.14; 95% CI, 1.09-1.19). There was significant heterogeneity by study design (Phet < 0.01), with a stronger magnitude of association observed among case-control versus cohort studies. Stronger associations were also noted for pre-/perimenopausal women and never users of postmenopausal hormone therapy. CONCLUSIONS: Hypertension is associated with endometrial cancer risk independently from known risk factors. Future research should focus on biologic mechanisms underlying this association. IMPACT: This study provides evidence that hypertension may be an independent risk factor for endometrial cancer.

Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants That Confer Risk for Breast Cancer.

Breast cancer includes several subtypes with distinct characteristic biological, pathologic, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate the development of improved prevention and treatment approaches. In this study, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case genome-wide association study (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead variants in 12 loci remained statistically significant after accounting for previously reported breast cancer susceptibility variants, among which, two were genome-wide significant. Fine mapping implicated putative functional/causal variants and risk genes at several loci, e.g., 3q26.31/TNFSF10, 8q22.3/NACAP1/GRHL2, and 8q23.3/LINC00536/TRPS1, for TNBC as compared with luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates the enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to two-fold increased risk of being diagnosed with TNBC instead of luminal cancers. The CC-GWAS PRS remained statistically significant after adjusting for TNBC PRS derived from traditional case-control GWAS in The Cancer Genome Atlas and the African Ancestry Breast Cancer Genetic Consortium. The CC-GWAS PRS was also associated with overall survival and disease-specific survival among patients with breast cancer. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC. Significance: The discovery of subtype-informative genetic risk variants for breast cancer advances our understanding of the etiologic heterogeneity of breast cancer, which could accelerate the identification of targets and personalized strategies for prevention and treatment.

Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction.

We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10-8), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.

Hypertensive Disorders of Pregnancy and Risk of Stroke in U.S. Black Women.

BACKGROUND: Black women have a disproportionately higher burden of both preeclamptic pregnancy and stroke compared with White women, but virtually all existing evidence on this possible association has been generated from women of European ancestry. METHODS: In the Black Women's Health Study, a prospective cohort of U.S. Black women who enrolled in 1995, 42,924 participants were parous and free of cardiovascular disease at baseline. Biennial questionnaires included questions on preeclampsia, gestational hypertension, and stroke. We sought the medical records for participants who reported a stroke, and we reviewed them blinded to reproductive history. Cox proportional-hazards models, with control for potential confounders, were used to estimate hazard ratios and 95% confidence intervals (CIs). RESULTS: Over a median of 22 years of follow-up, there were 1555 incident strokes, including 310 among 4938 women with a history of hypertensive disorders of pregnancy (HDOP). The multivariable hazard ratio for stroke for women with any HDOP compared with those who had never experienced HDOP was 1.66 (95% CI, 1.46 to 1.89). Comparable hazard ratios were 1.53 (95% CI, 1.29 to 1.82) for preeclampsia and 1.81 (95% CI, 1.53 to 2.13) for gestational hypertension only. Associations were similar among women under age 55 years and those aged 55 years and older. CONCLUSIONS: In this prospective study of Black women, a history of HDOP was associated with an estimated 66% increased long-term risk of stroke. This association may contribute to the disproportionately higher stroke incidence in Black women given the higher prevalence of HDOP in this population. (Funded by the U.S. National Institutes of Health.)

Association of ESR1 germline variants with TP53 somatic variants in breast tumors in a genome-wide study.

Background: In breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. HER2 positive and triple negative breast cancers (TNBC) have a higher frequency of TP53 somatic mutations than other subtypes. PIK3CA mutations are more frequently observed in hormone receptor positive tumors. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors. Methods: A genome-wide association study was conducted using breast cancer mutation status of TP53 and PIK3CA and functional mutation categories including TP53 gain of function (GOF) and loss of function mutations and PIK3CA activating/hotspot mutations. The discovery analysis consisted of 2850 European ancestry women from three datasets. Germline variants showing evidence of association with somatic mutations were selected for validation analyses based on predicted function, allele frequency, and proximity to known cancer genes or risk loci. Candidate variants were assessed for association with mutation status in a multi-ancestry validation study, a Malaysian study, and a study of African American/Black women with TNBC. Results: The discovery Germline x Mutation (GxM) association study found five variants associated with one or more TP53 phenotypes with P values <1×10-6, 33 variants associated with one or more TP53 phenotypes with P values <1×10-5, and 44 variants associated with one or more PIK3CA phenotypes with P values <1×10-5. In the multi-ancestry and Malaysian validation studies, germline ESR1 locus variant, rs9383938, was associated with the presence of TP53 mutations overall (P values 6.8×10-5 and 9.8×10-8, respectively) and TP53 GOF mutations (P value 8.4×10-6). Multiple variants showed suggestive evidence of association with PIK3CA mutation status in the validation studies, but none were significant after correction for multiple comparisons. Conclusions: We found evidence that germline variants were associated with TP53 and PIK3CA mutation status in breast cancers. Variants near the estrogen receptor alpha gene, ESR1, were significantly associated with overall TP53 mutations and GOF mutations. Larger multi-ancestry studies are needed to confirm these findings and determine if these variants contribute to ancestry-specific differences in mutation frequency.