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

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

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

10.1101/2020.10.28.359240 ◽

2020 ◽

Author(s):

Naser Ansari-Pour ◽

Yonglan Zheng ◽

Jason J. Pitt ◽

Stefan Dentro ◽

Toshio F. Yoshimatsu ◽

...

Keyword(s):

Breast Cancer ◽

Black Women ◽

White Women ◽

African Ancestry ◽

Clinical Intervention ◽

The Cancer Genome Atlas ◽

European Ancestry ◽

Precision Oncology ◽

Whole Genome Analysis ◽

Somatic Evolution

AbstractBlack women of African ancestry experience more aggressive breast cancer with higher mortality rates than White women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast tumors, with RNA-seq in a subset, from indigenous African patients in Nigeria in comparison to The Cancer Genome Atlas (n=76) revealed a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations and a 10.5-year younger age at diagnosis. We also found evidence for non-coding mutations in two novel drivers (ZNF217 and SYPL1) and a novel INDEL signature strongly associated with African ancestry proportion. This comprehensive analysis of an understudied population underscores the need to incorporate diversity of genomes as a key parameter in fundamental research with potential to tailor clinical intervention and promote equity in precision oncology care.

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Investigating survivin as a novel target in black women with breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.594 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 594-594

Author(s):

Andrea Walens ◽

Linnea T Olsson ◽

Sarah Van Alsten ◽

Lisa A. Carey ◽

Melissa A. Troester ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Black Women ◽

White Women ◽

Tumor Biology ◽

Survivin Expression ◽

Breast Tumors ◽

The Cancer Genome Atlas ◽

Molecular Features ◽

Apoptosis Protein

594 Background: Black women with breast cancer have higher mortality than White women. Differences in tumor biology contribute to racial disparities in breast cancer outcomes. BIRC5 gene encodes survivin, an inhibitor of apoptosis protein, and an independent marker of poor prognosis in breast cancer. Cancer patients have anti-survivin antibodies and circulating survivin-specific T cells, suggesting that survivin may be targetable. Several ongoing antibody-mediated, vaccine strategies that target survivin are being developed. Nevertheless, most survivin studies were conducted in cohorts of White women. To date, the prevalence and/or role of survivin expression in breast tumors from Black women has not been studied. Methods: Associations between BIRC5 expression, clinicopathological and molecular features were measured in the population-based Carolina Breast Cancer Study (CBCS) and The Cancer Genome Atlas (TCGA) breast cancer cohort. Gene expression was measured by Nanostring RNA counting and split into BIRC5 high (4th quartile) and low categories based on log2 gene expression values. Relative frequency differences (RFD) for the association between BIRC5 high and clinicopathologic features were estimated. RNA based p53 mutant status and homologous recombination deficiency (HRD) status were included in RFD analysis. Receiver operating characteristic (ROC) curves were used to illustrate the potential of BIRC5 expression to distinguish patients who achieved pathological complete response (pCR) after receiving neoadjuvant chemotherapy in CBCS (133 Black, 49 non-Black). Results: BIRC5 gene expression was significantly increased in tumors from 966 Black patients compared to 1,497 non-Black (p < 0.00001), adjusting for stage and subtype. BIRC5 high tumors were significantly more expressed in higher stage and basal-like breast cancer subtypes. BIRC5 high tumors were also significantly enriched for expression of genes involved in p53 loss and HRD. Furthermore, in an analysis of 182 CBCS patients, BIRC5 gene expression alone predicted pCR with similar overall AUC to ROR-PT multigene signatures (AUC 0.62 vs 0.64). Conclusions: Our study shows that survivin expression is particularly high in breast tumors from Black women. This was associated with more aggressive clinicopathological features in addition to p53 mutant and HRD status. Black women with breast cancer represent an area of unmet clinical need and could potentially benefit from anti-survivin targetable treatment strategies. Further studies are needed to help close this gap which constitutes the largest disparity among cancer-specific diseases.[Table: see text]

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Creating Models to Identify New Therapeutic Options for Aggressive African Breast Cancers

Journal of Global Oncology ◽

10.1200/jgo.18.83500 ◽

2018 ◽

Vol 4 (Supplement 2) ◽

pp. 206s-206s

Author(s):

E. Jiagge ◽

J. Bensenhaver ◽

K. Celina ◽

M. Hoenerhoff ◽

R. Gilani ◽

...

Keyword(s):

Breast Cancer ◽

Drug Screening ◽

White Women ◽

African Ancestry ◽

Gene Expression Signature ◽

Breast Tumors ◽

Therapeutic Options ◽

Stem Cell Marker ◽

Breast Cancers ◽

Background Population

Background: Population-based incidence rates of breast cancer (BC) that does not express the estrogen receptor (ER), progesterone receptor (PR) or overexpress the human epidermal growth factor 2 HER2/ neu (triple negative breast cancer, TNBC) are higher among Africans compared with white women. However the underlying biologic and genetic differences among different ethnicities are poorly understood and there are currently very few ethnically diverse BC models available for identifying new therapeutic options. Aim: Establish an international collaboration to: i, characterize African breast tumors ii, create models for studying these tumors and iii, identify biomarkers for early detection and treatment personalization. Methods: We have collected tumors from 154 white Americans WA, 76 African Americans, AA, 190 Ethiopians, Eth, and 286 Ghanaian (Gh) BC patients. We then established a unique resource of patient derived xenografts (PDX) from these tumors. The PDXs were then fully characterized using whole exome and RNA sequencing for the primary tumor, matched normal DNA, and corresponding low passage PDXs. Using immunohistochemistry, we evaluated the ER, PR, HER2/ neu, androgen receptor (AR), and ALDH1 (cancer stem cell marker) expression among these tumors. Based on biomarker expression the PDXs were then tested against a panel of IND drugs, either alone or in combinations, in an ex vivo organoid culture system to discover potential new therapeutic options. Results: Mean age at BC diagnosis was 43; 49; 60; and 57 years for the Eth; Gh; AA; and WA patients, respectively. The proportion of TNBC was significantly higher for the AA and Gh patients (41% and 54%, respectively) compared with the WA and Eth patients (23% and 15%, respectively); P < 0.001. Significant differences were observed for distribution of AR positivity, which was 71%; 55%; 42% and 50% for the WA; AA; Gh; and Eth cases, respectively ( P = 0.008). The Gh breast tumors exhibited the highest number of loss of function and missense mutations that are likely to impact therapy with a high frequency of P53, APC, and FGFR mutations. These mutations were maintained in the corresponding PDXs that were developed, and were thus used as biomarkers for drug screening. These tumors exhibited a gene expression signature based on the ethnicity of the patients with 2385 genes differentially expressed between Gh and AA, 1573 between AA and CA and 1317 between GH and CA. Results from our ongoing drug screening and biomarker identification will be available soon. Conclusions: Establishing the molecular and genetic platform of aggressive breast cancers occurring in women with African ancestry will help in identifying biomarkers for early cancer detection and targeted treatment stratification for optimum patient outcome. The availability of tumor models based on tumors from diverse African populations is the important missing pieces that have to be incorporated into current drug discovery efforts.

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Breast Cancer Screening Recommendations: African American Women Are at a Disadvantage

Journal of Breast Imaging ◽

10.1093/jbi/wbaa067 ◽

2020 ◽

Vol 2 (5) ◽

pp. 416-421

Author(s):

Murray Rebner ◽

Vidya R Pai

Keyword(s):

Breast Cancer ◽

African American ◽

Black Women ◽

Cancer Screening ◽

African American Women ◽

Breast Cancer Screening ◽

White Women ◽

Breast Cancers ◽

American Women ◽

Younger Age

Abstract Since 1990, breast cancer mortality has decreased by 40% in white women but only 26% in African American women. The age at diagnosis of breast cancer is younger in black women. Breast cancer diagnosed before age 50 represents 23% of all breast cancers in African American women but only 16% of all breast cancers in white women. White women have a higher incidence of breast cancer over the age of 60. Tumor subtypes also vary among racial and ethnic groups. The triple-negative (TN) subtype, which has a poorer outcome and occurs at a younger age, represents 21% of invasive breast cancers in black women but only 10% of invasive breast cancers in white women. The hormone receptor–positive subtype, which is more common in older women and has the best outcome, has a higher incidence in white women (70%) than in black women (61%). The BRCA2 mutation is also more common in black women than in white women (other than those who are of Ashkenazi Jewish ancestry). There are also many barriers to screening. Major ones include the lack of contact with a primary health care provider as well as a decreased perceived risk of having breast cancer in the African American population. Given the younger age of onset and the higher incidence of the TN molecular subtype, following breast cancer screening guidelines that do not support screening before the age of 50 may disadvantage black women.

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Ancestry-associated transcriptomic profiles of breast cancer in patients of African, Arab, and European ancestry

npj Breast Cancer ◽

10.1038/s41523-021-00215-x ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Jessica Roelands ◽

Raghvendra Mall ◽

Hossam Almeer ◽

Remy Thomas ◽

Mahmoud G. Mohamed ◽

...

Keyword(s):

Breast Cancer ◽

Survival Data ◽

Breast Cancer Subtype ◽

African Ancestry ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

European Ancestry ◽

Breast Cancer Dataset ◽

Breast Cancer Patients ◽

Ampk Signaling

AbstractBreast cancer largely dominates the global cancer burden statistics; however, there are striking disparities in mortality rates across countries. While socioeconomic factors contribute to population-based differences in mortality, they do not fully explain disparity among women of African ancestry (AA) and Arab ancestry (ArA) compared to women of European ancestry (EA). In this study, we sought to identify molecular differences that could provide insight into the biology of ancestry-associated disparities in clinical outcomes. We applied a unique approach that combines the use of curated survival data from The Cancer Genome Atlas (TCGA) Pan-Cancer clinical data resource, improved single-nucleotide polymorphism-based inferred ancestry assignment, and a novel breast cancer subtype classification to interrogate the TCGA and a local Arab breast cancer dataset. We observed an enrichment of BasalMyo tumors in AA patients (38 vs 16.5% in EA, p = 1.30E − 10), associated with a significant worse overall (hazard ratio (HR) = 2.39, p = 0.02) and disease-specific survival (HR = 2.57, p = 0.03). Gene set enrichment analysis of BasalMyo AA and EA samples revealed differences in the abundance of T-regulatory and T-helper type 2 cells, and enrichment of cancer-related pathways with prognostic implications (AA: PI3K-Akt-mTOR and ErbB signaling; EA: EGF, estrogen-dependent and DNA repair signaling). Strikingly, AMPK signaling was associated with opposing prognostic connotation (AA: 10-year HR = 2.79, EA: 10-year HR = 0.34). Analysis of ArA patients suggests enrichment of BasalMyo tumors with a trend for differential enrichment of T-regulatory cells and AMPK signaling. Together, our findings suggest that the disparity in the clinical outcome of AA breast cancer patients is likely related to differences in cancer-related and microenvironmental features.

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Distant metastases after diagnosis: Racial disparities in breast cancer outcomes.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.1084 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 1084-1084

Author(s):

Julia Blanter ◽

Ilana Ramer ◽

Justina Ray ◽

Emily J. Gallagher ◽

Nina A. Bickell ◽

...

Keyword(s):

Breast Cancer ◽

Multivariate Analysis ◽

Black Women ◽

Racial Disparities ◽

Late Stage ◽

White Women ◽

Univariate Analysis ◽

Distant Metastases ◽

Stage At Diagnosis

1084 Background: Black women diagnosed with breast cancer are more likely to have a poor prognosis, regardless of breast cancer subtype. Despite having a lower incidence rate of breast cancer when compared to white women, black women have the highest breast cancer death rate of all racial and ethnic groups, a characteristic often attributed to late stage at diagnosis. Distant metastases are considered the leading cause of death from breast cancer. We performed a follow up study of women with breast cancer in the Mount Sinai Health System (MSHS) to determine differences in distant metastases rates among black versus white women. Methods: Women were initially recruited as part of an NIH funded cross-sectional study from 2013-2020 to examine the link between insulin resistance (IR) and breast cancer prognosis. Women self-identified as black or white race. Data was collected via retrospective analysis of electronic medical records (EMR) between September 2020-January 2021. Distant metastases at diagnosis was defined as evidence of metastases in a secondary organ (not lymph node). Stage at diagnosis was recorded for all patients. Distant metastases after diagnosis was defined as evidence of metastases at any time after initiation of treatment. Univariate analysis was performed using Fisher’s exact test, multivariate analysis was performed by binary logistic regression, and results expressed as odds ratio (OR) and 95% confidence interval (CI). A p value <0.05 was considered statistically significant. Results: We identified 441 women enrolled in the IR study within the MSHS (340 white women, 101 black women). Median follow up time for all women was 2.95 years (median = 3.12 years for white and 2.51 years for black women (p=0.017)). Among these patients, 11 developed distant metastases after diagnosis: 4 (1.2%) white and 7 (6.9%) black (p=0.004). Multivariate analysis adjusting for age, race and stage at diagnosis revealed that black women were more likely to have distant metastasis (OR 5.8, CI 1.3-25.2), as were younger women (OR for age (years) 0.9, CI 0.9-1.0), and those with more advanced stage at diagnosis. Conclusions: Black women demonstrated a far higher percentage of distant metastases after diagnosis even when accounting for age and stage. These findings suggest that racial disparities still exist in the development of distant metastases, independent from a late-stage diagnosis. The source of existing disparities needs to be further understood and may be found in surveillance, treatment differences, or follow up.

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Geographical disparities of incidence and prevalence of triple-negative breast cancers: Multistate study data analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e12599 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e12599-e12599

Author(s):

Hyein Jeon ◽

Myeong Lee ◽

Mohammed Jaloudi

Keyword(s):

Breast Cancer ◽

Black Women ◽

Significant Relationship ◽

White Women ◽

Triple Negative ◽

The State ◽

Luminal A ◽

Black Females ◽

Black And White ◽

State Effect

e12599 Background: Higher prevalence of triple negative breast cancer (TNBC) in black women with associated poor outcomes due to various disparities is well documented within a single state. We examine multiple states to better understand the state effect on such differences in incidence and prevalence of TNBC in black women. Methods: Female patients of ages 19 years old and above with breast cancer from the Surveillance, Epidemiology and End Results (SEER) Program across 13 states (608 counties) from 2015 (n = 66,444) and 2016 (n = 66,122) were examined. The relationships between the proportion of black and white women and the rate of patients with different tumor subtypes (luminal A, luminal B, HR-HER2+, and triple negative) were examined at the county level using ordinary least-square regression models. In parallel, due to consideration of various state-specific healthcare policies, socio-cultural norms, and socio-economic disparities, multi-level regression models were applied to examine the nested, random effect of each state on TNBC prevalence in each county. Bonferroni correction was applied to reduce the Type I error caused by repeated use of the same variables in multiple tests. Results: The baseline breast cancer rates between black and white women were similar in the population (0.171% for black and 0.168% for white). Consistent to previous studies, we demonstrate a significant positive correlation (p < 0.001) in TNBC in black females in both years. Surprisingly, when accounted for the random effects on states, 38.2% (2015) and 34.3% (2016) increase in incidence of TNBC in black females were seen, suggestive of state-specific disparity affecting race-specific health. In 2015, other subtypes of breast cancer in both black and white females did not result in significant relationship. Interestingly, in 2016, there was a significant relationship seen between the TNBC rate in white females and the white female population rate only after adjusting for the state effect (p = 0.026). This indicates the impact of non-biological factors such as state-wide health policies. Additionally, HR-HER2+ black females had a significant relationship against respective population rate only after adjusting for the state effect as well (p = 0.0394). For luminal A white females, a 15% decrease in incidence was seen after adjusting for state effect (p = 0.0424). Conclusions: This is the first known across-state examination of breast cancer subtypes by race with random effects on state. This study shows the role of state-specific factors affecting incidence in black and white females and potentially indicates the importance of state-level management for breast cancer on health disparities in addition to race-driven effects. Further studies are needed to elucidate comparable differences between states affecting the rates of various subtypes of breast cancer and thus health outcomes.

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Insulin Resistance and Inflammation in Black Women with and without Breast Cancer: Cause for Concern

Ethnicity & Disease ◽

10.18865/ed.26.4.513 ◽

2016 ◽

Vol 26 (4) ◽

pp. 513 ◽

Cited By ~ 2

Author(s):

Kathleen A. Griffith ◽

Seon Yoon Chung ◽

Shijun Zhu ◽

Alice S. Ryan

Keyword(s):

Breast Cancer ◽

Insulin Resistance ◽

Black Women ◽

White Women ◽

Cancer Recurrence ◽

Control Group ◽

Study Objective ◽

Increased Risk ◽

Tnf Α ◽

History Of

Objective: After chemotherapy for breast cancer, Black women gain more weight and have an increased mortality rate compared with White women. Our study objective was to compare biomarkers associated with obesity in Black women with and without a history of breast cancer.Design: Case-controlSetting: Academic/federal institutionParticipants: Black women with a history of breast cancer (cases) and age-matched controls.Methods: We compared insulin resistance, inflammation, and lipids in overweight and obese Black women with a history of breast cancer (n=19), age similar controls (n=25), and older controls (n=32). Groups did not differ on mean body mass index (BMI), which was 35.4 kg/m2, 36.0 kg/m2, and 33.0 kg/m2, respectively.Main Outcome Measures: Insulin resistance (HOMA-IR); inflammation (TNF-α, IL-1b, IL-6, IL-8, CRP); lipids (cholesterol, triglycerides).Results: Cases had 1.6 and 1.38 times higher HOMA-IR values compared with age similar and older controls, respectively (P≤.001 for both). TNF-α and IL-1b were significantly higher in cases compared with both control groups (P<.001 for both). IL-6 was also higher in cases compared with age-similar controls (P=.007), and IL-8 was lower in cases compared with older controls (P<.05). Lipids did not differ between cases and either control group.Conclusions: Black women with breast cancer were significantly more insulin resistant with increased inflammation compared not only with age similar controls but with women who were, on average, a decade older. These biomarkers of insulin resistance and inflammation may be associated with increased risk of breast cancer recurrence and require ongoing evaluation, especially given the relatively abnormal findings compared with the controls in this underserved group. Ethn Dis. 2016;26(4):513-520; doi:10.18865/ed.26.4.513

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Lifetime Recreational Exercise Activity and Breast Cancer Risk Among Black Women and White Women

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/dji374 ◽

2005 ◽

Vol 97 (22) ◽

pp. 1671-1679 ◽

Cited By ~ 116

Author(s):

Leslie Bernstein ◽

Alpa V. Patel ◽

Giske Ursin ◽

Jane Sullivan-Halley ◽

Michael F. Press ◽

...

Keyword(s):

Breast Cancer ◽

Black Women ◽

Breast Cancer Risk ◽

Cancer Risk ◽

White Women ◽

Recreational Exercise ◽

Exercise Activity

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Molecular basis of distinct oestrogen responses in endometrial and breast cancer

Endocrine Related Cancer ◽

10.1530/erc-17-0563 ◽

2019 ◽

Vol 26 (1) ◽

pp. 31-46 ◽

Cited By ~ 6

Author(s):

Eva Baxter ◽

Karolina Windloch ◽

Greg Kelly ◽

Jason S Lee ◽

Frank Gannon ◽

...

Keyword(s):

Breast Cancer ◽

Transcriptional Activation ◽

The Cancer Genome Atlas ◽

Breast Cancers ◽

Oestrogen Receptor Alpha ◽

Limited Success ◽

Cancer Genome Atlas ◽

Using Data ◽

Oestrogen Signalling

Up to 80% of endometrial and breast cancers express oestrogen receptor alpha (ERα). Unlike breast cancer, anti-oestrogen therapy has had limited success in endometrial cancer, raising the possibility that oestrogen has different effects in both cancers. We investigated the role of oestrogen in endometrial and breast cancers using data from The Cancer Genome Atlas (TCGA) in conjunction with cell line studies. Using phosphorylation of ERα (ERα-pSer118) as a marker of transcriptional activation of ERα in TCGA datasets, we found that genes associated with ERα-pSer118 were predominantly unique between tumour types and have distinct regulators. We present data on the alternative and novel roles played by SMAD3, CREB-pSer133 and particularly XBP1 in oestrogen signalling in endometrial and breast cancer.

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