Cancer Prevention Program

Hormones and Colon Cancer: Epigenetic Subtypes, Risk and Survival

PI: Polly A. Newcomb, PhD

Hormones appear to play a central, largely protective, role in colorectal cancer in women. The use of exogenous estrogens has been consistently associated with a 40% decrease in risk of colorectal cancer, and increased levels of circulating estrogens, such as occurs in obese women, also appear to modify risk. The mechanisms that confer this protective effect, however, are not clear. While older theses on this association related to perturbations in bile-acid profiles and local effects mediated by the estrogen receptor, emerging data may implicate a role for epigenetic changes.  As an extension to our recently completed case-control study (CA 76366) of colorectal cancer in women, we propose to examine different tumor subtypes defined by epigenetic changes and their relationship with estrogen exposures, as well as how these effects may impact upon prognosis by evaluating: 1) the relationship of pre-diagnosis exposures with colorectal cancer outcomes (new colon neoplasia and survival); 2) the methylation of CpG island promoters (CIMP) in several genes (a phenotype reflective of widespread genomic silencing) and its relationship with estrogen; and 3) the association between CIMP subtype of the primary tumor and colorectal cancer outcomes. To accomplish these specific aims, we will follow-up a cohort of women diagnosed with colorectal cancer who were participants in our population-based case-control study of postmenopausal hormones and colorectal cancer risk. In this study, we will have information from 1,017 women aged 50-74 years with invasive colorectal cancer identified from the Puget Sound SEER registry. From diagnostic material for a subset of 500 women, tumor DNA has been extracted and methylation will be assessed using Methylight. Passive follow-up will be completed approximately 5 years after diagnosis to collect new primary information and vital status. This research will permit a better understanding of some of the epigenetic pathways for the protection conferred by hormones against colorectal cancer, and provide practical information for women and their physicians about lifestyle and psychosocial factors that may prevent colorectal cancer and/or improve prognosis.