• Department of Biostatistics and Bioinformatics, Duke University, 11028A Hock Plaza, 2424 Erwin Road Suite 1106, Durham, NC, 27705, USA. richard.barfield@duke.edu.
• Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
• National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
• Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
• Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.
• Department of Epidemiology and Population Science, Albert Einstein College of Medicine, Bronx, NY, USA.
• Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
• Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
• Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
• Department of Medical Oncology and Therapeuytic, University of Southern California, Los Angeles, CA, USA.

Colorectal cancer (CRC) is a heterogeneous disease with evidence of distinct tumor types that develop through different somatically altered pathways. To better understand the impact of the host genome on somatically mutated genes and pathways, we assessed associations of germline variations with somatic events via two complementary approaches. We first analyzed the association between individual germline genetic variants and the presence of non-silent somatic mutations in genes in 1375 CRC cases with genome-wide SNPs data and a tumor sequencing panel targeting 205 genes. In the second analysis, we tested if germline variants located within previously identified regions of somatic allelic imbalance were associated with overall CRC risk using summary statistics from a recent large scale GWAS (n≃125 k CRC cases and controls). The first analysis revealed that a variant (rs78963230) located within a CNA region associated with TLR3 was also associated with a non-silent mutation within gene FBXW7. In the secondary analysis, the variant rs2302274 located in CDX1/PDGFRB frequently gained/lost in colorectal tumors was associated with overall CRC risk (OR = 0.96, p = 7.50e-7). In summary, we demonstrate that an integrative analysis of somatic and germline variation can lead to new insights about CRC.