Grant Number:	5R01CA284732-03 Interpret this number
Primary Investigator:	Figueiredo, Jane
Organization:	Cedars-Sinai Medical Center
Project Title:	Elucidating the Role of Transcriptomics in Driving Ethnicity and Ancestry-Related Disparities in Colorectal Cancer
Fiscal Year:	2026

The benefits of precision oncology advances in colorectal cancer (CRC) differ across patient groups in the United States (U.S.). Prognosis remains stubbornly low in some patients. 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, 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 immuno-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 biology, therapeutic response and survival. Our goal is to understand the contribution of RNA splicing events to differences in treatment response and outcomes in CRC. Quantifying how genetic ancestry influences the transcriptome and outcomes will generate much-needed knowledge in CRC. Our proposal leverages existing cohorts with biospecimens and annotated data. We will address three aims: (1) characterize expression patterns of alternative mRNAs and genes encoding splicing factors by genetic ancestry and across patient characteristics that broadly represent the U.S. populations; (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.




Site- and age-dependent associations between Fusobacterium nucleatum and colorectal cancer mortality.
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Source: Cancer, 2026-06-15 00:00:00.0; 132(12), p. e70484.
PMID: 42244408
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The phylum Fusobacteriota is associated with CRC-specific mortality: Results from the Translational Research Program in Cancer Differences across Populations.
Authors: Thomas C.E. , Loroña N.C. , LaBrie S.D. , Curtis K.R. , Yin H. , Ma N. , Randolph T.W. , Qu C. , Huyghe J.R. , Thomas S. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2026-04-01 00:00:00.0; , .
EPub date: 2026-04-01 00:00:00.0.
PMID: 41920180
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The Translational Research Program in Cancer Differences across Populations.
Authors: Figueiredo J.C. , Redwood D. , Li L. , Donato E. , Fort D. , Fox E.E. , Grady W.M. , Green H. , Harrison T.A. , Haupt C. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2025-06-27 00:00:00.0; , .
EPub date: 2025-06-27 00:00:00.0.
PMID: 40576634
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Colorectal Tumors in Diverse Patient Populations Feature a Spectrum of Somatic Mutational Profiles.
Authors: Matejcic M. , Teer J.K. , Hoehn H.J. , Diaz D.B. , Shankar K. , Gong J. , Nguyen N.T. , Loroña N.C. , Coppola D. , Fulmer C.G. , et al. .
Source: Cancer Research, 2025-05-15 00:00:00.0; 85(10), p. 1928-1944.
PMID: 40126181
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Building research infrastructure to advance precision medicine in colorectal cancer.
Authors: Schmit S.L. , Loroña N.C. , Sobieski D. , Matejcic M. , Nguyen N.T. , Hoehn H.J. , Diaz D.B. , Shankar K. , Cockman E.M. , Jean-Baptiste E. , et al. .
Source: Jnci Cancer Spectrum, 2025-04-30 00:00:00.0; 9(3), .
PMID: 40111849
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de novo metastases in patients with primary colorectal cancer: a Surveillance, Epidemiology, and End Results analysis.
Authors: Loroña N.C. , Sankar K. , Stern M.C. , Schmit S.L. , Figueiredo J.C. .
Source: Cancer Causes & Control : Ccc, 2025-04-19 00:00:00.0; , .
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