Projects

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Team SAMBAI (Social, Ancestry, Molecular and Biological Analysis of Inequalities) is taking a multi-level, interdisciplinary approach to create the SAMBAI Data Repository for Cancer Equity Research. This key resource will be unprecedented in scale and scope, collecting samples and data from 40,000 people from multiple African countries, as well as people of recent African heritage in the UK and US. By capturing millions of data features for each individual, this database will allow the dissection of the complex interplay of the social, environmental, genetic, epigenetic and immunological factors that influence disparate outcomes in cancer in these underserved populations. It鈥檚 important to acknowledge that the vast majority of genomics and tumour profiling data collected to date is from people of European ancestry. SAMBAI鈥檚 repository will be the first dataset encompassing this breadth of information for populations of African descent, led in partnership with African co-investigators. Working in Ghana and South Africa, as well as other countries throughout the continent, SAMBAI will build research and training capacity, in addition to establishing new approaches to investigate cancer inequities in other underserved populations.

The team will focus on breast, pancreatic and prostate cancers 鈥� three cancer types that have a disproportionately higher rate of aggressive tumour grade and early onset in Black people. SAMBAI鈥檚 comprehensive and systematic approach spans four levels of data:

Social determinants of health

The team aims to reset the way that social determinants of health are measured, to accurately document the lived experience of Black people.

Social determinants will be assessed across multiple levels using qualitative and quantitative metrics, including individual and lifestyle behaviours; socio-cultural experiences, such as social interactions, social support, caregiving roles and encounters of racism; characteristics of the immediate environment, including housing quality, neighbourhood safety and access to healthy food; and structural-political determinants, such as government policies, laws, economic and healthcare systems, and employment opportunities.

Exposomics

To understand the biological consequences of the lived environment on health and disease, the team plans to measure and quantify, on a molecular scale, the external and internal factors that these populations are exposed to (the exposome). Using high-resolution mass spectrometry, the team will collect data on thousands of exogenous and endogenous molecules to identify risk factors relevant to these populations.

Genomics

Using short- and long-read whole-genome and RNA sequencing, the team aims to map the genetic diversity in select populations in the UK, US, and several regions of Africa to identify distinct genetic factors contributing to cancer inequities. The team will also look at epigenetics and use single-cell proteomics to determine whether external exposures based on lived experience have left imprinted epigenetic signatures.

Immune profiling

To explore the role of stress caused by structural racism, discrimination and marginalisation, the team will look at the immune cells and inflammatory proteins present in the circulation, tumours and microenvironment, of a subset of patients, to identify social and environmental mechanisms that influence cancer and systemic immunological profiles.

Looking Ahead

By building and using their extensive repository to identify factors underpinning cancer disparities among people of African descent, SAMBAI hopes its findings will inform policies and create opportunities to develop much-needed targeted cancer prevention and treatment strategies. The team鈥檚 patient advocates will play an integral role in engaging with patient communities and facilitating policy changes for effective intervention.

The DARC Side of Breast Cancer Disparities鈥�

Even with the typical delays in diagnosis, more advanced stage distribution at diagnosis, and inadequate multidisciplinary breast cancer treatment, these combined factors do not completely explain disparities in breast cancer mortality outcomes, which persist after controlling for stage at diagnosis 鈥� and have been so for the past 50 years. The approximately two-fold increased risk of TNBC in AA women has been confirmed by population-based incidence rates regionally as well as nationally and across all age intervals. Compared to non-TNBC, triple negative disease has been confirmed to be an adverse prognostic feature in AA patients, driving some of the mortality disparities. We hypothesize that altered mechanisms of tumor immune responses, which underlies TNBC tumor biology differences between SRR, are caused by population-private genetic variants among individuals with shared west African ancestry. These evolutionarily selected variants alter immune cell behavior and inflammatory mechanisms, leading to novel tumor-immune cell types and significant differences in leukocyte infiltration patterns, which may be associated with poor outcomes. We will perform an innovative multiomics investigation of African-specific gene expression in TNBC, linked to immunological tumor phenotypes. We will harness the novelty of rarely-investigated breast cancer patient populations from diverse African regions with TNBC cases from g admixed populations (i.e. African-American and Afro-Caribbean). The most impactful innovation of this study is the characterization of differential gene expression, coupled with integrated proteomics data, to identify novel tumor phenotypes that are shared among women of the African diaspora. This work will be transformative to our understanding of tumor heterogeneity and biological diversity across patient groups. We propose the follow aims: 1- Determine the ancestry- associated differential gene expression profiles of immune and inflammatory-related genes in primary tumors across an African-enriched cohort of 400 clinically annotated TNBC cases, to immune profiles linked to shared west African genetic ancestry. 2- Characterize ancestry-associated differences in pathological tumor immune response characteristics, including differences in tumor inflammation and/or tumor infiltration of specific immune cell types. 3-Create an African-enriched panel of ex vivo models to validate/investigate the ancestry-associated drivers of altered genetic pathways and immune responses. By completing these aims we expect to yield an African-enriched set of population-private, validated eQTLs, associated with TNBC immune response mechanisms that can be further interrogated by our authenticated ex vivo models.

The Dark Genome鈥�

The New York Genome Center (NYGC) announced the launch of the MacMillan Center for the Study of the Non-Coding Cancer Genome (MCSNCG) in January 2023, it is a major new initiative in cancer research to study the role and function of the non-coding genome and epigenome in the evolution, progression, and treatment of multiple cancer types, including breast, ovary, pancreas, gastrointestinal, lung, and hematologic cancers.

, commented: 鈥淭his Center, with its leading-edge multidisciplinary approach 鈥撯€� bringing together experts in genomics, engineering, mathematics, computational biology, and cancer biology 鈥撯€� will dramatically advance the understanding of the role of the non-coding genome in cancer.鈥�

The non-coding 鈥渄ark鈥� genome constitutes 98% of the human genome and it plays an essential regulatory role across all molecular layers of biological complexity (i.e. genome, epigenome, transcriptome, proteome), influencing DNA organization and structure, genome accessibility to regulatory proteins and RNA, and intracellular organelle organization. The molecular mechanisms by which cell functions are carried out hold extraordinary promise for understanding how cellular identity is encoded in individual cell types and cell states; how cells are altered by intercellular interactions within the microenvironment, including immune cells; and how they are disrupted in various disease states, most specifically in cancer.

While extraordinary progress has been made through individual, gene-focused research projects, the biomedical research community has historically lacked the technology and collaborative framework to systematically study the causality of the non-coding genome in cancer. Therefore, foundational questions regarding the role of the non-coding genome in the development and progression of many cancer types remain unanswered.

Established by a generous gift from the MacMillan Family Foundation, the MCSNCG will seek to answer these questions through an inter-institutional, multi-disciplinary research program that brings together engineers, data scientists, mathematicians, technologists and biological experts. This range of expertise from the NYGC鈥檚 collaborative network will allow the MCSNCG to engage in coordinated efforts to understand how behavior is encoded in cells and unravel the intricacy of intercellular interactions involved in the development of cancerous cells, metastasis, and drug resistance.

Education and Outreach to promote diversity and representation in genomics and cancer research, engage the broader scientific community, and educate the public on the value and benefit of this important work is another critical component of the Center. To that end, the MCSNCG will offer internship and post-baccalaureate training opportunities, workshops and seminars for both scientific and public audiences, and will broadly disseminate the Center鈥檚 scientific findings through the publication of protocols, analytic methods, genomic data, and discoveries.

To maximize the impact of this research, the MCSNCG will also leverage existing regional cancer and genomic technology research initiatives anchored by the NYGC collaborative network such as the (P-1000) initiative. The researchers of the P-1000 initiative study cancer genomes of under-represented minority populations with the goal of understanding the role of genetic diversity in cancer, improving the application and outcome of precision medicine for these populations, and addressing the stark ethnic disparities in cancer research and diagnosis.

, says, 鈥淒ecoding causality is fundamental to providing interpretable quantitative explanations of elements of the non-coding genome in cancer. Biological problems of this nature require cross-cutting programs where investigators with a broad range of expertise are supported to collaborate and focus on building new measurement methods and computational frameworks to understand the complex dynamics of cancer biology.鈥�

The NYGC and the MacMillan Family Foundation share a mutual commitment to meaningfully and measurably advancing our understanding of cancer biology by innovating and applying new technologies, methodologies, and analytics. This new collaborative initiative brings together leading researchers from eight institutions including the BC Cancer Research Institute, Cold Spring Harbor Laboratory, Columbia University, Morehouse School of Medicine, Memorial Sloan Kettering Cancer Center, Northwell Health, New York University, and Weill Cornell Medicine.

Geo-Spatial to Tumor-Spatial: Resolving Influences of Ancestry and Race in Outcome Disparities鈥�

Our research question addresses the persistence of mortality disparities among racial/ethnic groups, where marginalized populations suffer the highest breast cancer mortality rates, due to both social and biological determinants. Generally, we seek to characterize the distinctions of tumor variation across patient groups and discover the mechanisms that are driving these differences, with aspirations to create interventions that leverage this new knowledge. While there have been decades of studies focused on the social factors, there are significant gaps in our understanding of the biological mechanisms that may be driving disparate outcomes. Intriguingly, the intersection of social and biological determinants are the real-world scenarios that are largely understudied and could hold the key to ameliorating disparate outcomes (1). Our recent work has implicated genetic ancestry-associated mechanisms related to immune response in the disparities of African and African American women with Triple Negative Breast Cancer (TNBC). In these studies, we also uncovered race-specific differences that were related to comorbidities that tend to have higher prevalence in marginalized racialized populations. Through the BCRF grant, we are utilizing multiple 鈥榦mics鈥� approaches to characterize the single-cell spatial landscapes of tumor biology across patients of African ancestry to determine how individual-level vs area-level factors may influence or correlate with tumor phenotypes. Our concept, called Oncologic Anthropology, initially suggested by Dr. Lisa Newman (Co-Investigator), will allow us to study the social history of patient populations to fully understand the circumstances surrounding their risk and disease progression.

Genentech鈥�

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Variants of Unknown Significance in Cancer Disparities