Colorectal cancer (CRC), the second most commonly diagnosed cancer, is a biologically heterogeneous disease. Molecular characterization of tumors, including somatic mutations in BRAF and KRAS, microsatellite instability (MSI), and CpG island methylator phenotype (CIMP), has provided evidence of multiple tumor subtypes that develop through activation of diverse neoplastic pathways. More recently, new technologies, such as next-generation sequencing as applied in The Cancer Genome Atlas (TCGA) Project1, have enabled further characterization by identifying mutated genes in colorectal tumors, including well known genes, such as APC, SMAD4, and PIK3CA as well as some that are less well known, such as SOX9 or ACVR1B. These discoveries highlight the importance of a number of key pathways, including MAPK, Wnt, or TGF? signaling pathways. These detailed molecular data now allow us to better define tumor subtypes by mutated genes and pathways. Knowledge of the relationship between etiologic factors for CRC-such as germline genetic, lifestyle, and environmental risk factors- and tumor subtype is critical to improve our understanding of the underlying carcinogenic mechanisms that result in different molecular subtypes of CRC;however, these relations have not been comprehensively studied. To address this, we propose to use existing resources of the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colon Cancer Family Registry (CCFR). These consortia are based on well-characterized cohort and population-based case-control studies and have available extensive germline genetic, clinical, and epidemiologic data. In addition, a large subset of cases has already undergone molecular characterization for BRAF and KRAS mutations, MSI, and CIMP. We will harmonize these existing tumor characteristics in Aim 1 in up to 11,900 CRC cases to investigate associations between defined CRC subtypes and a) common and rare germline genetic variants across the genome (Aim 1a), as well as b) lifestyle and environmental risk factors, such as alcohol, smoking, obesity, hormone use, or dietary factors (Aim 1b).
In Aim 2 we will use the tumor DNA of 4,200 CRC cases by deeply sequencing approximately 100 genes identified through existing and ongoing CRC tumor tissue sequencing studies (e.g., TCGA) to define new CRC subtypes based on mutated pathways, such as Wnt, PI3K, or TGF? signaling. We will investigate associations between these subtypes and common and rare germline genetic variants across the genome (Aim 2a), as well as lifestyle and environmental risk factors (Aim 2b). This integrated approach addresses important gaps in knowledge about the risk-factor profile of existing and newly-defined molecular subtypes of CRC. Our large and well characterized study population provides a unique opportunity to define new molecular classifications with improved precision. This precision is needed to better understand how genetic and environmental risk factors, together, contribute to individual risk of CRC. These insights on carcinogenic mechanisms can help optimize prevention measures and will have an important public health impact.

Public Health Relevance

In this large consortium comprising multiple studies we will harmonize existing data on molecular tumor characteristics, as well as define new molecular subtypes of CRC by identifying acquired somatic alterations using targeted sequencing of key cancer genes. We will examine inherited genetic variation as well as lifestyle and environmental risk factors in relation to these CRC tumor subtypes, which is critical to improving our understanding of the underlying carcinogenic mechanisms that drive CRC-associations with established risk factors.

National Institute of Health (NIH)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Mechanic, Leah E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Fred Hutchinson Cancer Research Center
United States
Zip Code
Ananthakrishnan, Ashwin N; Du, Mengmeng; Berndt, Sonja I et al. (2015) Red meat intake, NAT2, and risk of colorectal cancer: a pooled analysis of 11 studies. Cancer Epidemiol Biomarkers Prev 24:198-205
Song, Mingyang; Gong, Jian; Giovannucci, Edward L et al. (2015) Genetic variants of adiponectin and risk of colorectal cancer. Int J Cancer 137:154-64
Qi, Qibin; Chu, Audrey Y; Kang, Jae H et al. (2014) Fried food consumption, genetic risk, and body mass index: gene-diet interaction analysis in three US cohort studies. BMJ 348:g1610
Cheng, Iona; Kocarnik, Jonathan M; Dumitrescu, Logan et al. (2014) Pleiotropic effects of genetic risk variants for other cancers on colorectal cancer risk: PAGE, GECCO and CCFR consortia. Gut 63:800-7
Auer, Paul L; Teumer, Alexander; Schick, Ursula et al. (2014) Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits. Nat Genet 46:629-34
Jiao, Shuo; Peters, Ulrike; Berndt, Sonja et al. (2014) Estimating the heritability of colorectal cancer. Hum Mol Genet 23:3898-905
Passarelli, Michael N; Newcomb, Polly A; Makar, Karen W et al. (2014) No association between germline variation in catechol-O-methyltransferase and colorectal cancer survival in postmenopausal women. Menopause 21:415-20
Wang, Hansong; Burnett, Terrilea; Kono, Suminori et al. (2014) Trans-ethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A. Nat Commun 5:4613
Kantor, Elizabeth D; Hutter, Carolyn M; Minnier, Jessica et al. (2014) Gene-environment interaction involving recently identified colorectal cancer susceptibility Loci. Cancer Epidemiol Biomarkers Prev 23:1824-33
Hiraki, Linda T; Joshi, Amit D; Ng, Kimmie et al. (2014) Joint effects of colorectal cancer susceptibility loci, circulating 25-hydroxyvitamin D and risk of colorectal cancer. PLoS One 9:e92212

Showing the most recent 10 out of 23 publications