Abstract IA27: Understanding more about risk and prognostic factors: Lessons from the Colon Cancer Family Registry
Authors: Newcomb Polly A. 
Published: March 2017

Background: Colorectal cancer (CRC) is a heterogeneous disease with etiology associated with genetic and epidemiologic factors. Family studies have served as the cornerstone of genetic research on CRC. Studies of multiple-case families led to the discovery of the best characterized CRC susceptibility syndromes: hereditary nonpolyposis colorectal cancer (HNPCC; hereafter called Lynch syndrome) and familial adenomatous polyposis (FAP). The primary genetic bases of these dominant, relatively high-penetrance syndromes were identified. However, somatic and epigenetic alterations in these same genes are involved in sporadic CRC as well. Although these changes are established causes of CRC, many important questions remain, specifically the relation of these genetic and also environmental risk factors in relation to CRC survival. The Colon Cancer Family Registry (CCFR) is an NCI-supported international resource established in 1997 to support interdisciplinary studies on the genetic, somatic, environmental, behavioral, and lifestyle risk factors for CRC. Case subjects with incident colon or rectal cancer were identified via regional, state, and provincial cancer registries in the U.S., Canada and Australasia. Now in its 18th year, the CCFR is the largest registry of colorectal cancers world-wide. In this study, we have now leveraged this cohort to examine the epidemiology, genetics, and molecular characteristics of outcomes after a diagnosis of colorectal cancer.

Methods: Over 10,000 participants with incident CRC were recruited into the CCFR between 1998 and 2007 across six international sites; nearly 3,500 deaths have occurred. Each center had slight differences in design and sampling schemes, which ensured a resource that covers the continuum of disease risk for CRC. Risk-factor data, blood and tumor samples, and medical records were collected from participants using standardized protocols. Participants continue to be followed every 5 years for changes in common risk factors, surveillance, and new cancers. Vital status, including cause of death, is recorded. Tumors have been characterized for microsatellite instability (MSI) status, protein expression for mismatch repair mutations (MLH1, MSH2, MSH6 and PMS2), and for point mutations in BRAF V600E and KRAS codons 12 and 13. CpG Island Methylator Phenotype (CIMP) was measured in tumors demonstrating microsatellite instability and the somatic silencing of MLH1 due to DNA methylation was tested in tumors showing loss of MLH1 protein expression. Germline testing was conducted for MutYH mutations in all cases and for MMR gene mutations for all cases showing a loss of gene expression in the respective protein. Genome-wide association studies (GWAS) will soon be completed on all cases. Analyses have been conducted using the CCFR case population as a whole, or using site subsets based on appropriate design and inclusion criteria.

Results: Several factors known to be associated with a reduced risk of colorectal cancer, such as physical activity and the use of non-steroidal anti-inflammatory drugs (NSAIDs), were also associated with improved survival, while other such factors, including hormone replacement therapy, were not. Elevated pre-diagnostic BMI was associated with increased risk but modestly elevated post-diagnostic BMI was associated with improved survival. A history of smoking was associated with both increased risk and worse survival. Family history of colorectal cancer, which has consistently been associated with increased risk of disease, was not found to be associated with survival. Similarly, we found in a screen of 18 genetic susceptibility loci, one identified locus in SMAD7 was also associated with survival, but others were not. Tumor microsatellite instability was strongly associated with improved survival. Cases with CIMP positive tumors and/or mutations in BRAF, and/or KRAS were each associated with higher mortality, particularly when those characteristics were combined, where a two-fold increase was observed in cases MSS, CIMP+, and positive for BRAF when compared to cases with MSS tumors and negative for all other markers; a 70% lower mortality was observed in cases with tumors characterized as MSI-high, non-CIMP, and negative for mutations in BRAF and KRAS.

Conclusions: The CCFR has shed light on many environmental factors, genetics and tumor characteristics that are related to both incidence and survival. Information gained from studies using this resource provides insight into the biology of this common cancer and importantly may help target messaging on prevention, inform the development of interventions, or tailor recommendations for CRC survivorship care. The greater scientific community has access to this rich resource.

Citation Format: Polly A. Newcomb. Understanding more about risk and prognostic factors: Lessons from the Colon Cancer Family Registry. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr IA27.