Enrichment of Germline Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Pathogenic Variants in Patients With Solid Tumors: Evidence for Increased Cancer Risk

Abstract

Introduction: Wide-spread use of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators has resulted in a dramatic increase in life expectancy of people with CF. Historically, CFTR carrier status has been thought to be benign; however, data are emerging that dysfunction of CFTR may play a role in cancer risk. The aims of this study were to (1) determine the frequency of germline pathogenic CFTR gene variations in a cohort of patients with cancer, and (2) investigate associations between germline pathogenic CFTR variants and established germline somatic oncogenic driver mutations. Methods: The Indiana University Adult Precision Genomics (APG) clinical database was queried for all subjects having a germline CFTR pathogenic variant (PV). The CFTR PVs observed in our cohort were compared to published population minor allele frequencies from the Allele Frequency Aggregator (ALFA) Project then scaled to reflect our APG population. Results: Data were available for 2141 patients. Based on known minor allele frequencies and the racial distribution of our cohort, we expected 33 subjects (1.5%) to have CFTR PVs. However, CFTR PVs were present in 71 subjects (3.3%), 2.1-fold higher than expected (p < 0.001). The observed enrichment of CFTR PVs varied by cancer type, with CFTR PVs being overrepresented in patients with skin and gastrointestinal cancers. Conclusions: The overall prevalence of CFTR PVs in people with solid tumors was higher than expected. These results suggest that carriers of CFTR PV may benefit from enhanced cancer screening.