African Ancestry–Associated Gene Expression Profiles in Triple-Negative Breast Cancer Underlie Altered Tumor Biology and Clinical Outcome in Women of African Descent

Martini, Rachel; Delpe, Princesca; Chu, Timothy R.; Arora, Kanika; Lord, Brittany; Verma, Akanksha; Bedi, Deepa; Karanam, Balasubramanyam; Elhussin, Isra; Chen, Yalei; Gebregzabher, Endale; Oppong, Joseph K.; Adjei, Ernest; Suleiman, Aisha Jibril; Awuah, Baffour; Muleta, Mahteme Bekele; Abebe, Engida; Kyei, Ishmael; Aitpillah, Francis; Adinku, Michael O.; Ankomah, Kwasi; Osei‐Bonsu, Ernest; Chitale, Dhananjay; Bensenhaver, Jessica; Nathanson, David; Jackson, LaToya; Petersen, Lindsay F.; Proctor, Erica; Stonaker, Brian; Gyan, Kofi K.; Gibbs, Lee D.; Manojlovic, Zarko; White, Jason; Yates, Clayton; Manne, Upender; Gardner, Kevin; Mongan, Nigel P.; Cheng, Esther; Ginter, Paula; Hoda, Syed A.; Elemento, Olivier; Robine, Nicolas; Sboner, Andrea; Carpten, John D.; Newman, Lisa A.; Davis, Melissa B.

doi:10.1158/2159-8290.cd-22-0138

Cited by 69 publications

(66 citation statements)

References 61 publications

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“…However, this study was mostly comprised of European ancestry populations and the mechanism by which genetic perturbations in uenced TNBC incidence was not studied. Data from other studies showed that differences in ancestry-speci c immunologic landscapes correlated with differences in TNBC biology and clinical outcomes [52]. Our data are consistent with the notion that SME biology (which encompasses immunologic response) might be a pathway by which familial factors may impact breast cancer incidence and tumor biology.…”

Section: Discussionsupporting

confidence: 89%

Associations of breast cancer etiologic factors with stromal microenvironment of primary invasive breast cancers in the Ghana Breast Health Study

Abubakar¹,

Ahearn²,

Duggan

et al. 2023

Preprint

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Background: Emerging data suggest that beyond the neoplastic parenchyma, the stromal microenvironment (SME) impacts tumor biology, including aggressiveness, metastatic potential, and response to treatment. However, the epidemiological determinants of SME biology remain poorly understood, more so among women of African ancestry who are disproportionately affected by aggressive breast cancer phenotypes. Methods: Within the Ghana Breast Health Study, a population-based case-control study in Ghana, we applied high-accuracy machine-learning algorithms to characterize biologically-relevant SME phenotypes, including tumor-stroma ratio (TSR (%); a metric of connective tissue stroma to tumor ratio) and tumor-associated stromal cellular density (Ta-SCD (%); a tissue biomarker that is reminiscent of chronic inflammation and wound repair response in breast cancer), on digitized H&E-stained sections from 792 breast cancer patients aged 17–84 years. Kruskal-Wallis tests and multivariable linear regression models were used to test associations between established breast cancer risk factors, tumor characteristics, and SME phenotypes. Results: Decreasing TSR and increasing Ta-SCD were strongly associated with aggressive, mostly high grade tumors (p-value < 0.001). Several etiologic factors were associated with Ta-SCD, but not TSR. Compared with nulliparous women [mean (standard deviation) = 28.9% (7.1%)], parous women [mean (standard deviation) = 31.3% (7.6%)] had statistically significantly higher levels of Ta-SCD (p-value = 0.01). Similarly, women with a positive family history of breast cancer [FHBC; mean (standard deviation) = 33.0% (7.5%)] had higher levels of Ta-SCD than those with no FHBC [mean (standard deviation) = 30.9% (7.6%); p-value = 0.01]. Conversely, increasing body size was associated with decreasing Ta-SCD [mean (standard deviation) = 32.0% (7.4%), 31.3% (7.3%), and 29.0% (8.0%) for slight, moderate, and large body sizes, respectively, p-value = 0.005]. These associations persisted and remained statistically significantly associated with Ta-SCD in mutually-adjusted multivariable linear regression models (p-value < 0.05). With the exception of body size, which was differentially associated with Ta-SCD by grade levels (p-heterogeneity = 0.04), associations between risk factors and Ta-SCD were not modified by tumor characteristics. Conclusions: Our findings raise the possibility that epidemiological factors may act via the SME to impact both risk and biology of breast cancers in this population, underscoring the need for more population-based research into the role of SME in multi-state breast carcinogenesis.

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Section: Discussionsupporting

confidence: 89%

Associations of breast cancer etiologic factors with stromal microenvironment of primary invasive breast cancers in the Ghana Breast Health Study

Abubakar¹,

Ahearn²,

Duggan

et al. 2023

Preprint

Self Cite

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“…Given that human ancestry has a substantial impact on gene expression (see Fig. 1C) in healthy and disease tissues [30][31][32][33], it is essential that we consider population-specific variation when modeling disease in order to improve cancer treatment for all populations. Access to diverse data is critical for creating robust precision medicine and answering scientific questions in the field [2].…”

Section: Global Population Diversity Impacts Disease Genomicsmentioning

confidence: 99%

Equitable machine learning counteracts ancestral bias in precision medicine, improving outcomes for all

Graim

Smith

Cahill

2023

Preprint

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Gold standard genomic datasets severely under-represent non-European populations, leading to inequities and a limited understanding of human disease [1–8]. Therapeutics and outcomes remain hidden because we lack insights that we could gain from analyzing ancestry-unbiased genomic data. To address this significant gap, we present PhyloFrame, the first-ever machine learning method for equitable genomic precision medicine. PhyloFrame corrects for ancestral bias by integrating big data tissue-specific functional interaction networks, global population variation data, and disease-relevant transcriptomic data. Application of PhyloFrame to breast, thyroid, and uterine cancers shows marked improvements in predictive power across all ancestries, less model overfitting, and a higher likelihood of identifying known cancer-related genes. The ability to provide accurate predictions for underrepresented groups, in particular, is substantially increased. These results demonstrate how AI can mitigate ancestral bias in training data and contribute to equitable representation in medical research.

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“…The Black/AA subpopulation harbor higher expression levels of immunosuppressive markers such as PD-1, PD-L1, and CTLA-4 compared to the White/EA group [ 199 ]. In TNBC, Martini and colleagues recently showed that West African genetic ancestry is significantly associated with PD-1 expression [ 200 ]. Within the inherently aggressive TNBC subtype, Black/AAs display greater immune infiltration and inflammation compared to non-Black/AA patients [ 21 ].…”

Section: Painting a Darc Picture: Darc Immunosenescence And Neoplasti...mentioning

confidence: 99%

“…The Women’s Circle of Health Study recently reported that Black/AA patients harbor a significantly higher density of CD8 + T cell tumor infiltration but a more exhausted CD8 + T cell profile compared to White/EA breast cancer patients [ 24 , 27 ]. Martini et al recently uncovered that West African genetic ancestry is highly associated with increased immune cell migration and infiltration but simultaneous repression of immune cell activation or naïve cells in TNBC [ 200 ]. The group also discovered that shared West African genetic ancestry is highly associated with greater infiltration of CD8 + memory T cells and immunosuppressive FOXP3 + Tregs.…”

Section: Painting a Darc Picture: Darc Immunosenescence And Neoplasti...mentioning

confidence: 99%

The DARC Side of Inflamm-Aging: Duffy Antigen Receptor for Chemokines (DARC/ACKR1) as a Potential Biomarker of Aging, Immunosenescence, and Breast Oncogenesis among High-Risk Subpopulations

Jinna

Rida²,

Su³

et al. 2022

Cells

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The proclivity of certain pre-malignant and pre-invasive breast lesions to progress while others do not continues to perplex clinicians. Clinicians remain at a crossroads with effectively managing the high-risk patient subpopulation owing to the paucity of biomarkers that can adequately risk-stratify and inform clinical decisions that circumvent unnecessary administration of cytotoxic and invasive treatments. The immune system mounts the most important line of defense against tumorigenesis and progression. Unfortunately, this defense declines or “ages” over time—a phenomenon known as immunosenescence. This results in “inflamm-aging” or the excessive infiltration of pro-inflammatory chemokines, which alters the leukocyte composition of the tissue microenvironment, and concomitant immunoediting of these leukocytes to diminish their antitumor immune functions. Collectively, these effects can foster the sequelae of neoplastic transformation and progression. The erythrocyte cell antigen, Duffy antigen receptor for chemokines(DARC/ACKR1), binds and internalizes chemokines to maintain homeostatic levels and modulate leukocyte trafficking. A negative DARC status is highly prevalent among subpopulations of West African genetic ancestry, who are at higher risk of developing breast cancer and disease progression at a younger age. However, the role of DARC in accelerated inflamm-aging and malignant transformation remains underexplored. Herein, we review compelling evidence suggesting that DARC may be protective against inflamm-aging and, therefore, reduce the risk of a high-risk lesion progressing to malignancy. We also discuss evidence supporting that immunotherapeutic intervention—based on DARC status—among high-risk subpopulations may evade malignant transformation and progression. A closer look into this unique role of DARC could glean deeper insight into the immune response profile of individual high-risk patients and their predisposition to progress as well as guide the administration of more “cyto-friendly” immunotherapeutic intervention to potentially “turn back the clock” on inflamm-aging-mediated oncogenesis and progression.

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African Ancestry–Associated Gene Expression Profiles in Triple-Negative Breast Cancer Underlie Altered Tumor Biology and Clinical Outcome in Women of African Descent

Cited by 69 publications

References 61 publications

Associations of breast cancer etiologic factors with stromal microenvironment of primary invasive breast cancers in the Ghana Breast Health Study

Associations of breast cancer etiologic factors with stromal microenvironment of primary invasive breast cancers in the Ghana Breast Health Study

Equitable machine learning counteracts ancestral bias in precision medicine, improving outcomes for all

The DARC Side of Inflamm-Aging: Duffy Antigen Receptor for Chemokines (DARC/ACKR1) as a Potential Biomarker of Aging, Immunosenescence, and Breast Oncogenesis among High-Risk Subpopulations

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