Abstract IA29: Racial differences in the lung cancer transcriptome: Insights from coding, noncoding, and alternative polyadenylated genes

Abstract

Abstract Deciphering the post-transcriptional mechanisms (PTM) regulating gene expression is an important step in understanding the molecular mechanisms underlying cancer transcriptomics and heterogeneity. Such studies are a core component of precision medicine and systems-level approaches to understanding the complexity of cancer. Historically, African Americans have been under-represented in clinical cancer research, a field that is increasingly focused on classifying patients according to molecular profiles. Thus, diversity helps to ensure equal access to new cancer therapies and better treatment for everyone. In the first analysis to study transcriptomic differences in lung cancer from European Americans and African Americans, we provided a detailed molecular analysis from paired non-small cell lung cancer tissues that identified differential coding and noncoding RNA expression in African Americans and European Americans. African American-enriched differential gene expression was characterized by stem cell and invasion pathways, while differential gene expression in lung tumors from European Americans was primarily characterized by cell proliferation pathways. Integration of noncoding RNA profiles suggested that population-specific gene expression was at least partly driven by population-specific miRNA expression profiles. Similar to other tumor types, we determined that race-enriched gene and miRNA expression signatures suggest a more aggressive disease in African Americans. Moreover, on the basis of predicted drug resistance to adjuvant chemotherapies, African Americans may not equally benefit from the same range of clinical drugs as European Americans. For example, drug susceptibility predictions using the CMAP resource revealed a strong inverse correlation between African Americans' resistance and European Americans' sensitivity to the same panel of drugs. While these are predicted findings, they demonstrate a proof of principle that population differences in gene expression could be important to consider in the context of drug development. Transcriptome profiling studies in cancer health disparities are not restricted to coding or noncoding gene expression. Alternative polyadenylation (APA) is a key PTM mechanism, whose comprehensive analysis remains an important open challenge. In our recent studies, we used a novel APA pipeline that sequences 3′ end-enriched RNA and maps polyA sites directly, an approach that is different to traditional 5′-3′ sequencing methods. We then comprehensively mapped the APA landscape in lung cancer for the first time, analyzing matched tissues derived from European American and African American patients. Consistent with previous observations and a finding that shortened 3′ UTRs are enriched in proliferating cells, we identified widespread shortening of the 3′ UTR in lung cancer. Many of these events were also associated with clinical outcome. Interestingly, we also observed racial differences in APA. Consistent with our previous findings showing that lung tumors from European Americans are enriched in cell proliferation pathways, tumors from EA were 2 times more likely to have shorter 3′ UTR transcripts. Further, we identified several genes where the 3′ UTR was lengthened in African Americans and shortened in European Americans, including PTEN, a known tumor suppressor previously linked with disparities in other cancer types. These data point towards APA as a mechanism of tumor suppressor inactivation that is independent of somatic copy number or mutational changes. Collectively, our data show that many aspects of the lung cancer transcriptome are shared between European Americans and African Americans, but that distinct patterns of expression and regulation are found in each population. Moreover, our work shows that the inclusion of patients of differing ethnicities also has the potential to inform our understanding of the biologic mechanisms of health disparities. Citation Format: Brid Ryan. Racial differences in the lung cancer transcriptome: Insights from coding, noncoding, and alternative polyadenylated genes [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr IA29.