Abstract A031: Heterozygote carriers of cystic fibrosis mutations have increased risk of colorectal cancer
Authors: Prizment Anna E. , Standafer Abigail , Wang Shuo , Qu Conghui , Peters Ulrike , Scott Patricia , Starr Timothy , Pankratz Nathan 
Published: December 2022

Background and purpose: Colorectal cancer (CRC) is the third leading cause of cancer deaths in the U.S. Establishing new genetic variants associated with CRC risk may lead to early CRC detection and novel treatment options. Recently, mouse genetic studies identified the cystic fibrosis transmembrane conductance regulator (CFTR) gene as a tumor suppressor in CRC. In line with this, a human study using MarketScan claims data showed that cystic fibrosis (CF) carriers – individuals with one copy of mutant CFTR – are at increased CRC risk. Although there are more than 10 million CF carriers in the U.S., to our knowledge, no studies comprehensively examined CFTR mutations in relation to CRC risk. Our hypothesis is that CFTR mutations are associated with an increased risk of CRC. Methods: We used whole exome sequencing (WES) data in 454,333 individuals (age 44-82 years), including 4,975 cases of CRC, in the UK Biobank study. We utilized risk set sampling to select up to four controls per CRC case based on age of diagnosis, gender, race, and year of joining the study. To examine associations between CFTR mutations and CRC risk, logistic regression (odds ratio and p-value) was used after adjusting for age, gender and 10 principal components capturing global ancestry. An aggregate burden score was constructed that included all variants listed as CF-causing in the CFTR2 online database. Results: Of the 465 CFTR variants in the CFTR2 database, 378 are classified as CF-causing, and of those 153 were observed in the UK Biobank WES data set. Individuals with two CF-causing alleles were excluded from further analysis (8 cases and 35 controls), since the association between CF and CRC is already well established. The frequency of the F508del variant, the most common CF-causing mutation, was 3.77% in cases versus 3.11% in controls, while the frequency of any other CF-causing mutation was 1.07% in cases versus 0.80% in controls. Having any CF-causing mutation was associated with a significant 24% increased CRC risk (one-sided p=0.002). Having one copy of the F508del mutation, was associated with a significant 21% increased risk of CRC (one-sided p=0.012), while having one copy of any other CF-causing mutation was associated with a slightly larger 34% increased risk of CRC (one-sided p=0.036). Conclusions: CF-causing mutations in the heterozygous state lead to a significantly increased risk of CRC. Individuals with multiple genetic risk factors, such as in CFTR, may require earlier screening for CRC.

Citation Format: Anna E. Prizment, Abigail Standafer, Shuo Wang, Conghui Qu, Ulrike Peters, Patricia Scott, Timothy Starr, Nathan Pankratz. Heterozygote carriers of cystic fibrosis mutations have increased risk of colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A031.