Role of genetic and epigenetic alterations in CFTR in colorectal cancer

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SUMMARY Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the U.S. Despite advances in screening, ~50% of CRC cases are detected at later, less treatable stages. There is a need to identify new cancer-causing genetic alterations in CRC. Our group has recently shown a critical role for the cystic fibrosis transmembrane conductance regulator (CFTR) gene as a tumor suppressor in CRC. Epidemiological studies demonstrated that individuals with CF have six times greater risk of CRC than the general population, leading to recent classification of CF as a hereditary colon cancer syndrome. Further, our animal studies as well as a recent human study, suggested that heterozygous CF-carriers may also be at CRC risk. If confirmed, these findings have implications for the general population because more than 10 million Americans carry one copy of germline CF-causing mutations. In addition, we showed that lower CFTR expression in CRC tumors is associated with decreased overall and disease-free survival of CRC patients. In these tumors decreased CFTR expression is associated with increased promoter DNA methylation which suggests that DNA methylation may drive decreased CFTR expression in CRC tumors. Our central hypothesis is that germline and epigenetic alterations in the CFTR gene contribute to increased CRC risk and mortality. In Aim 1, we will determine associations of germline CFTR variants with CRC incidence and survival of CRC patients using existing genetic data, including high-quality whole genome sequencing, whole exome sequencing and genome-wide association studies, from large population-based studies – TOPMed, GECCO, and UK Biobank. In Aim 2, we will examine the association of DNA methylation in CFTR promoter with CFTR expression and survival of CRC patients using publically available data from the Cancer Genome Atlas Program (TCGA) and Gene Expression Omnibus (GEO) datasets. The findings from this study could lead to CFTR mutation-based screening for early CRC detection in general population and testing CFTR-targeting therapies to improve survival of CRC patients with CFTR dysfunction.