Wednesday, May 1, 2024
5/1/2024
ABSTRACT The benefits of precision oncology advances in colorectal cancer (CRC) have not been shared by all individuals. Prognosis among minority groups remains stubbornly low in comparison to non-Hispanic White (NHW) individuals. Immunotherapy has arguably been the most important advance in treatment for CRC in this past decade. This is particularly relevant for microsatellite instable tumors that harbor high mutational and neoantigen burden, where immune checkpoint inhibitors (ICIs) are highly effective and FDA-approved. However, despite dramatic activity in some CRC patients (including evidence that African American (AA) patients may exhibit better responses to ICIs), a much larger fraction of patients do not respond. As a result, extensive efforts to understand and manipulate the tumor immune microenvironment features that influence response to ICIs and other targeted therapies are ongoing and forthcoming. Also needed are studies to identify unique molecular targets for developing new precision medicine interventions. An underexplored molecular mechanism with potential to advance the fields of immune-oncology and targeted therapy is RNA splicing, a key step in gene expression that generates multiple ‘alternative’ mRNA transcripts, encoding functionally distinct protein isoforms that expands the functional repertoire of the genome. When dysregulated, in cancer, RNA splicing can result in pathogenic variants and immunogenic neoantigens. When neoantigens are present in high abundance, ICIs are most effective. The significance of RNA splicing in CRC is supported by a study demonstrating that splice neoantigens enhanced ICI blockade in a mouse model and studies showing that pathogenic RNA splice variants can drive every hallmark of cancer, with potential to be therapeutically targeted. Mounting evidence demonstrates that RNA splicing events are influenced by genetic ancestry and are important in CRC, including our recent work identifying race- and ancestry-related RNA splicing associated with cancer biology, therapeutic response and survival. Our goal is to understand the contribution of RNA splicing events to disparities in treatment response and outcomes in CRC. Quantifying how race, ethnicity and ancestry influence the transcriptome and outcomes will generate much-needed knowledge in CRC disparities. Our proposal leverages existing diverse cohorts with biospecimens and annotated data including the Latino Colorectal Cancer Consortium (LC3), the Detroit Research on Cancer Survivors (ROCS), and The Cancer Genome Atlas (TCGA). We will address three aims: (1) characterize expression patterns of alternative mRNAs and genes encoding splicing factors by genetic ancestry and across self-reported racial and ethnic groups (250 AA, 250 Hispanic/Latino and 250 NHW patients); (2) examine the role of RNA splicing in tumor-associated immune responses; and (3) determine the functional consequences of expression of prioritized RNA splice variants with respect to CRC biology in vitro and in vivo (using CRISPR/Cas9 genome edited CRC cell lines). This project will be the first of its kind to relate alternative mRNA species, neoantigens, and CRC outcomes considering the influence of genetic ancestry.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
