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Gene-Level Germline Contributions to Clinical Risk of Recurrence Scores in Black and White Patients with Breast Cancer.

ABSTRACT: Continuous risk of recurrence scores (CRS) based on tumor gene expression are vital prognostic tools for breast cancer. Studies have shown that Black women (BW) have higher CRS than White women (WW). Although systemic injustices contribute substantially to breast cancer disparities, evidence of biological and germline contributions is emerging. In this study, we investigated germline genetic associations with CRS and CRS disparity using approaches modeled after transcriptome-wide association studies (TWAS). In the Carolina Breast Cancer Study, using race-specific predictive models of tumor expression from germline genetics, we performed race-stratified (N = 1,043 WW, 1,083 BW) linear regressions of three CRS (ROR-S: PAM50 subtype score; proliferation score; ROR-P: ROR-S plus proliferation score) on imputed tumor genetically regulated tumor expression (GReX). Bayesian multivariate regression and adaptive shrinkage tested GReX-prioritized genes for associations with tumor PAM50 expression and subtype to elucidate patterns of germline regulation underlying GReX-CRS associations. At FDR-adjusted P < 0.10, 7 and 1 GReX prioritized genes among WW and BW, respectively. Among WW, CRS were positively associated with MCM10, FAM64A, CCNB2, and MMP1 GReX and negatively associated with VAV3, PCSK6, and GNG11 GReX. Among BW, higher MMP1 GReX predicted lower proliferation score and ROR-P. GReX-prioritized gene and PAM50 tumor expression associations highlighted potential mechanisms for GReX-prioritized gene to CRS associations. Among patients with breast cancer, differential germline associations with CRS were found by race, underscoring the need for larger, diverse datasets in molecular studies of breast cancer. These findings also suggest possible germline trans-regulation of PAM50 tumor expression, with potential implications for CRS interpretation in clinical settings. SIGNIFICANCE: This study identifies race-specific genetic associations with breast cancer risk of recurrence scores and suggests mediation of these associations by PAM50 subtype and expression, with implications for clinical interpretation of these scores.

SUBMITTER: Patel A

PROVIDER: S-EPMC8732329 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:INTRODUCTION:Although breast cancer incidence is higher among white women, black women are more likely to have aggressive tumors with less favorable histology, and to have a worse prognosis. Obesity and alcohol consumption have been identified as two modifiable risk factors for breast cancer, while physical activity may offer protection. Little however is known about the association of these factors with race on the severity of breast cancer. METHODS:Data collected as part of a large prospective study looking at insulin resistance and race among women with breast cancer was queried for patient characteristics, lifestyle factors and tumor characteristics. The association with Nottingham Prognostic Index (NPI) was assessed with different models using univariate and multivariate linear regression. RESULTS:Among 746 women in our cohort, 82% (n?=?615) were white and 18% (n?=?131) were black, mean age 58 years. Black patients were more likely to have high BMI (31.0 vs. 26.7, p?<?0.0001), comorbidities (69% vs 55%, p?=?0.01), self-reported poor diet (70% vs 42%, p?<?0.001), be sedentary (56% vs 46%, p?=?0.03) and were less likely to consume alcohol (8% vs 32%, p?<?0.0001) compared to white patients. Overall, 137 (18%) of the patients had poorer prognosis (NPI?>?4.4), which was significantly associated with younger age (55.6 vs 58.5 years, p?=?0.02), black race (27% vs 15%, p?=?0.001), triple negative cancer (15% vs 6%, p?=?0.003), and poor diet (54% vs 45%, p?=?0.046) compared to patients with better prognosis (NPI???4.4). On multivariate analysis, (model R2?=?0.12; p?<?0.001), age (??=?-0.011 per year, p?=?0.002), healthy diet (??=?-0.195, p?=?0.02), and exercise (??=?-0.004, p?=?0.02) were associated with better prognosis, while black race (??=?0.247, p?=?0.02) and triple negative cancer (??=?0.908, p?<?0.0001) were associated with poor prognosis. Neither alcohol use nor BMI was significantly associated with NPI. CONCLUSION:Among modifiable risk factors, diet and exercise are associated with NPI. Unmodifiable factors including race and biologic subtype remain the most important determinants of prognosis.

Project description:Importance:The high prevalence of hypertension among the US black population is a major contributor to disparities in life expectancy; however, the causes for higher incidence of hypertension among black adults are unknown. Objective:To evaluate potential factors associated with higher risk of incident hypertension among black adults. Design, Setting, and Participants:Prospective cohort study of black and white adults selected from a longitudinal cohort study of 30 239 participants as not having hypertension at baseline (2003-2007) and participating in a follow-up visit 9.4 years (median) later. Exposures:There were 12 clinical and social factors, including score for the Southern diet (range, -4.5 to 8.2; higher values reflect higher level of adherence to the dietary pattern), including higher fried and related food intake. Main Outcomes and Measures:Incident hypertension (systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or use of antihypertensive medications) at the follow-up visit. Results:Of 6897 participants (mean [SD] age, 62 [8] years; 26% were black adults; and 55% were women), 46% of black participants and 33% of white participants developed hypertension. Black men had an adjusted mean Southern diet score of 0.81 (95% CI, 0.72 to 0.90); white men, -0.26 (95% CI, -0.31 to -0.21); black women, 0.27 (95% CI, 0.20 to 0.33); and white women, -0.57 (95% CI, -0.61 to -0.54). The Southern diet score was significantly associated with incident hypertension for men (odds ratio [OR], 1.16 per 1 SD [95% CI, 1.06 to 1.27]; incidence of 32.4% at the 25th percentile and 36.1% at the 75th percentile; difference, 3.7% [95% CI, 1.4% to 6.2%]) and women (OR, 1.17 per 1 SD [95% CI, 1.08 to 1.28]; incidence of 31.0% at the 25th percentile and 34.8% at the 75th percentile; difference, 3.8% [95% CI, 1.5% to 5.8%]). The Southern dietary pattern was the largest mediating factor for differences in the incidence of hypertension, accounting for 51.6% (95% CI, 18.8% to 84.4%) of the excess risk among black men and 29.2% (95% CI, 13.4% to 44.9%) of the excess risk among black women. Among black men, a higher dietary ratio of sodium to potassium and an education level of high school graduate or less each mediated 12.3% of the excess risk of incident hypertension. Among black women, higher body mass index mediated 18.3% of the excess risk; a larger waist, 15.2%; less adherence to the Dietary Approaches to Stop Hypertension diet, 11.2%; income level of $35 000 or less, 9.3%; higher dietary ratio of sodium to potassium, 6.8%; and an education level of high school graduate or less, 4.1%. Conclusions and Relevance:In a mediation analysis comparing incident hypertension among black adults vs white adults in the United States, key factors statistically mediating the racial difference for both men and women included Southern diet score, dietary ratio of sodium to potassium, and education level. Among women, waist circumference and body mass index also were key factors.

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Gene-Level Germline Contributions to Clinical Risk of Recurrence Scores in Black and White Patients with Breast Cancer.

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