||5R21CA256749-02 Interpret this number
||University Of Minnesota
||Role of Genetic and Epigenetic Alterations in Cftr in Colorectal Cancer
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.
Lower Expression of CFTR Is Associated with Higher Mortality in a Meta-Analysis of Individuals with Colorectal Cancer.
, Wang S.
, Onyeaghala G.
, Pankratz N.
, Starr T.
, Prizment A.E.
Cancers, 2023-02-03; 15(3), .