Keynote Presentation: RNA Splicing and Ancestry-related Molecular Targets in Precision Oncology and Cancer Disparities

Individuals of under-represented minority ancestry are at disproportional risk for higher incidence and mortality rates for particular cancers. The unequal burden of cancer in certain racial and ethnic groups, known as “cancer disparities”, can be attributed to a multilevel interplay among neighborhood and population-wide social, psychosocial, lifestyle, environmental, health system, and biological determinants of health. ARS is a key step in gene expression enabling individual genes to encode multiple proteins, and is emerging as a major driver of abnormal phenotypic heterogeneity including gaining aggressive characteristics and tolerance to anticancer therapy. RNA splicing–related genetic and genomic variation in tumors includes oncogenes dysregulated by ARS, spliceosome-dependent transformation, RNA splicing–related immunogenic epitopes and race–related cancer aggressiveness and drug response. Our laboratory has conducted a number of studies in multiple cancers stratified by race (both self-identified and by ancestral genotyping) using either deep RNAseq or array-based technologies on retro- and prospectively banked tissue samples, as well as computational analysis of publicly available databases such as TCGA. We have shown that the burden of race-related differential ARS (D-ARS) is much higher than differential gene expression, and that many of the D-ARS are functionally involved in oncogenic signaling pathways and statistically associate with survival. We have built an application, “CanSplice”, to mine genomic datasets for D-ARS by patient race and ethnicity. We have also begun to identify and test, preclinically and clinically, approaches to modulate and exploit ARS for therapeutic application, including splice-switching oligonucleotides, small molecules targeting RNA splicing or RNA splice variants, and combination regimens with immunotherapies. Our findings identify race-related ARS targets that may aid in the development of new biomarkers and precision therapeutic agents that have the potential to mitigate cancer disparities.

Learning Objectives:

1. Define the various contributors to cancer health disparities and some points of intersectionality between them

2. Explain the potential role of RNA splicing in the biology of ancestry-related difference in the molecular etiology of cancer in different populations

3. Identify approaches to pharmacologically target RNA splicing to mitigate cancer aggressiveness