||5R01CA201407-04 Interpret this number
||Fred Hutchinson Cancer Research Center
||Using Functional Genomics to Inform Gene Environment Interactions for Colorectal Cancer
Colorectal cancer (CRC) is a complex disease with both genetic (G) and environmental (E) risk factors
contributing to susceptibility. Genome-wide GxE interaction scans (GWIS) can help identify novel susceptibility
loci and biologically meaningful GxE interactions that point to new carcinogenic mechanisms. Limited statistical
power remains a primary concern in GxE analyses. To maximize the statistical power in a GWIS, it is essential
to have the largest possible sample size by pooling resources across studies. In this project, we will combine
the resources of three existing CRC consortia (approximately 53,600 cases and 52,400 controls of European
descent): the Colorectal Cancer Family Registry (CCFR), the Colorectal Cancer Transdisciplinary (CORECT)
Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) for interaction testing
with 8 environmental and lifestyle factors: alcohol, calcium, folate, hormone replacement therapy (HRT), non-
steroidal anti-inflammatory drugs (NSAIDs), red meat, processed meat, and smoking. To improve statistical
power and enhance our ability to discover true GxE associations, we will as part of Aim 1 incorporate functional
genomics data in two forms: (1) enhancer/promoter profiles derived from ChIPseq and DNase I hypersensitive
sites (DHS) data publicly available from Roadmap or from our own experiments in normal colon tissue; and (2)
our newly generated RNA-Seq results from normal colon biopsies with detailed environmental and lifestyle risk
factor information, and gene expression measured in normal human 3D colon organoids (“mini guts”) in
response to environmental exposures. In Aim 2 we will use our novel statistical methods that can incorporate
the CR and E-specific functional genomics data generated in Aim 1 to discover new GxE interaction for CRC
with rare and common single nucleotide variants (down to MAF 0.1%) in up to 53,600 cases and 52,400
controls. To narrow in on the underlying causal variant(s) for any identified novel GxE interaction, we will
conduct fine-mapping analyses using a trans-ethnic meta-analysis (23,500 non-European and 106,000
European). To follow-up on identified significant GxE interactions, we will functionally validate our strongest
GxE interactions (including previously published findings) to provide support for the novel GxE interactions
such as knock down in CRC cell lines and normal human 3D colon epithelial organoids.
Our large and well-characterized study population, combined with our experienced research team, and
integration of functional genomics data into our novel statistical methods provide opportunities to better
understand how genetic and environmental risk factors, combined, contribute to individual risk of CRC.
Discovering GxE interactions will provide insight into the underlying mechanisms that drive gene-CRC
associations impacted by established environmental risk factors. Since genetic profiles are fixed, modifying
environmental exposures to alter deleterious effects of alleles remains an important preventive strategy.
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