Examining the Impact of Structural Racism on African American Non-Small Cell Lung Cancer Mutational Signatures and Outcomes

ABSTRACT Non-Hispanic Black/African American (AA) individuals develop non-small cell lung cancer (NSCLC) 5-years earlier than their non-Hispanic White (NHW) counterparts. AAs also have a higher lung cancer incidence and mortality rates. The role of structural racism in the development and maintenance of these disparities has been

understudied. Our long-term goal is to achieve health equity within NSCLC through investigations that benefit the AA community. The objective of this proposal is to determine the impact of racism-related socio- environmental factors, including air pollution and residential segregation on the mutagenic process in NSCLC

tumors of AA patients. The central hypothesis is that measurable structural racism stressors induce changes in mutational processes that negatively impact disease progression in AA patients with early-stage NSCLC. Our study rationale is that genomic data from AA NSCLC specimens is lacking, which hinders understanding of the

disease etiology and progression in this vulnerable population. For example, only 82 of 1,053 patients in The Cancer Genome Atlas reported identifying as African American. In addition, it is imperative to determine the extent to which racism-related socio-environmental factors affect the distribution of mutational signatures in

NSCLC tumors in AA patients in order to identify specific pathways linking structural racism stressors to worse outcomes and yield targets for intervention and biomarkers for risk stratification. We propose to survey 200 AA patients with stage I–II NSCLC identified from California and Georgia Cancer Registries and 100 AA from

Detroit to determine their exposure to structural racism stressors, which we will correlate with data from the whole-genome sequencing (WGS) of their tumor tissue. Our aims are to: (1) determine the extent to which exposure to structural racism over time is linked with differences in NSCLC tumor evolution by characterizing

the types of mutations, the order of their acquisition, and the activity of mutational processes; (2) define the effect of structural racism stressors on early recurrence (within 2-years of surgery) in stage I-II AA NSCLC patients and (3) determine the distribution of the genomics of never-smoking AAs with NSCLC compared to the

Sherlock-Lung study and if this distribution is affected by the stressors of interest. This innovative study will be one of the first to use WGS, tumor evolution, and geospatial analysis techniques to identify causal pathways linking structural racism stressors to the mutagenic processes of NSCLC, providing a much-needed integration

of social science with molecular outcomes. We expect that the structural racism stressors will induce differences in timing of driver mutation development that promote early NSCLC recurrence. This study will elucidate how racism-related socio-environmental factors affect AA NSCLC biology, which is expected to

reveal the mechanisms underlying disparate race-based NSCLC outcomes, ultimately leading to identification of new targets and development of novel interventions to reduce health disparities.