Functional variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are associated with increased risk of colorectal cancer

Anna Prizment; Abby Standafer; Conghui Qu; Kathleen M Beutel; Shuo Wang; Wen-Yi Huang; Annika Lindblom; Rachel Pearlman; Bethany Van Guelpen; Alicja Wolk; Daniel D Buchanan; Robert C Grant; Stephanie L Schmit; Elizabeth A Platz; Corinne E Joshu; David J Couper; Ulrike Peters; Timothy K Starr; Patricia Scott; Nathan Pankratz

doi:10.1093/hmg/ddaf007

Functional variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are associated with increased risk of colorectal cancer

Hum Mol Genet. 2025 Jan 17:ddaf007. doi: 10.1093/hmg/ddaf007. Online ahead of print.

Authors

Anna Prizment^{1

2}, Abby Standafer¹, Conghui Qu³, Kathleen M Beutel¹, Shuo Wang¹, Wen-Yi Huang⁴, Annika Lindblom^{5

6}, Rachel Pearlman⁷, Bethany Van Guelpen⁸, Alicja Wolk⁹, Daniel D Buchanan¹⁰, Robert C Grant¹¹, Stephanie L Schmit^{12

13}, Elizabeth A Platz^{14

15}, Corinne E Joshu^{14

15}, David J Couper¹⁶, Ulrike Peters³, Timothy K Starr^{2

17}, Patricia Scott^{2

18}, Nathan Pankratz¹

Affiliations

¹ Laboratory Medicine and Pathology, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN, 55455, USA.
² Masonic Cancer Center, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN, 55455, USA.
³ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, 98019, USA.
⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, MSC 9776, Bethesda, MD, 20892, USA.
⁵ Department of Molecular Medicine and Surgery, Karolinska Institutet, K1 Molekylär medicin och kirurgi, K1 MMK Klinisk genetik, 171 76 Stockholm, Sweden.
⁶ Department of Clinical Genetics, Karolinska University Hospital, Eugeniavägen 3, 171 64 Solna, Sweden.
⁷ Department of Internal Medicine, Division of Human Genetics, The Ohio State University Comprehensive Cancer Center, 2012 Kenny Rd, Columbus, OH, 43221, USA.
⁸ Department of Radiation Sciences, Oncology Unit, 27C, Målpunkt QC11, NUS, Norrlands universitetssjukhus, Umeå University, 901 85 Umeå, Sweden.
⁹ Institute of Environmental Medicine, Karolinska Institutet, C6 Institutet för miljömedicin, C6 CVD-NUT-EPI Wolk, 171 77 Stockholm, Sweden.
¹⁰ Department of Clinical Pathology, University of Melbourne Center for Cancer Research, University of Melbourne, 305 Grattan Street, Melbourne, Victoria, 3010, Australia.
¹¹ UHN-Princess Margaret Cancer Centre, University of Toronto, 7-811 700 University Ave, Toronto, Ontario, M5G 1X6, Canada.
¹² Genomic Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, Mail Code NE50, Cleveland, OH, 44195, USA.
¹³ Population and Cancer Prevention Program, Case Comprehensive Cancer Center, 10900 Euclid Ave, Cleveland, OH, 44106, USA.
¹⁴ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe Street, Baltimore, MD, 21205, USA.
¹⁵ Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 615 N Wolfe Street, Baltimore, MD, 21205, USA.
¹⁶ Department of Biostatistics, University of North Carolina at Chapel Hill, 123 W Franklin Street, Suite 450, CB #8030, Chapel Hill, NC, 27516, USA.
¹⁷ Department of Obstetrics and Gynecology, Medical School, University of Minnesota, 515 Delaware St SE, Minneapolis, MN, 55455, USA.
¹⁸ Department of Biomedical Sciences, University of Minnesota Medical School Duluth, 1035 University Drive, Duluth, MN, 55812, USA.

PMID: 39825500
DOI: 10.1093/hmg/ddaf007

Abstract

Background: Individuals with cystic fibrosis (CF; a recessive disorder) have an increased risk of colorectal cancer (CRC). Evidence suggests individuals with a single CFTR variant may also have increased CRC risk.

Methods: Using population-based studies (GECCO, CORECT, CCFR, and ARIC; 53 785 CRC cases and 58 010 controls), we tested for an association between the most common CFTR variant (Phe508del) and CRC risk. For replication, we used whole exome sequencing data from UK Biobank (UKB; 5126 cases and 20 504 controls matched 4:1 based on genetic distance, age, and sex), and extended our analyses to all other heterozygous CFTR variants annotated as CF-causing.

Results: In our meta-analysis of GECCO-CORECT-CCFR-ARIC, the odds ratio (OR) for CRC risk associated with Phe508del was 1.11 (P = 0.010). In our UKB replication, the OR for CRC risk associated with Phe508del was 1.28 (P = 0.002). The sequencing data from UKB also revealed an association between the presence of any other single CF-causing variant (excluding Phe508del) and CRC risk (OR = 1.33; P = 0.030). When stratifying CFTR variants by functional class, class I variants (no protein produced) had a stronger association (OR = 1.77; p = 0.002), while class II variants (misfolding and retention of the protein in the endoplasmic reticulum) other than Phe508del (OR = 1.75; p = 0.107) had similar effect size as Phe508del, and variants in classes III-VI had non-significant ORs less than 1.0 and/or were not present in cases.

Conclusions: CF-causing heterozygous variants, especially class I variants, are associated with a modest but statistically significant increased CRC risk. More research is needed to explain the biology underlying these associations.

Keywords: colorectal cancer; haploinsufficiency; heterozygous CFTR variants; rare variant burden test; whole exome sequencing data.

Abstract

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