Dataset Information

Cystic Fibrosis, CFTR, and Colorectal Cancer.

ABSTRACT: Cystic fibrosis (CF), caused by biallelic inactivating mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, has recently been categorized as a familial colorectal cancer (CRC) syndrome. CF patients are highly susceptible to early, aggressive colorectal tumor development. Endoscopic screening studies have revealed that by the age of forty 50% of CF patients will develop adenomas, with 25% developing aggressive advanced adenomas, some of which will have already advanced to adenocarcinomas. This enhanced risk has led to new CF colorectal cancer screening recommendations, lowering the initiation of endoscopic screening to age forty in CF patients, and to age thirty in organ transplant recipients. The enhanced risk for CRC also extends to the millions of people (more than 10 million in the US) who are heterozygous carriers of CFTR gene mutations. Further, lowered expression of CFTR is reported in sporadic CRC, where downregulation of CFTR is associated with poor survival. Mechanisms underlying the actions of CFTR as a tumor suppressor are not clearly understood. Dysregulation of Wnt/?-catenin signaling and disruption of intestinal stem cell homeostasis and intestinal barrier integrity, as well as intestinal dysbiosis, immune cell infiltration, stress responses, and intestinal inflammation have all been reported in human CF patients and in animal models. Notably, the development of new drug modalities to treat non-gastrointestinal pathologies in CF patients, especially pulmonary disease, offers hope that these drugs could be repurposed for gastrointestinal cancers.

SUBMITTER: Scott P

PROVIDER: S-EPMC7215855 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Cystic Fibrosis, CFTR, and Colorectal Cancer.

Scott Patricia P Anderson Kyle K Singhania Mekhla M Cormier Robert R

International journal of molecular sciences 20200421 8

Cystic fibrosis (CF), caused by biallelic inactivating mutations in the <i>cystic fibrosis transmembrane conductance regulator</i> (<i>CFTR</i>) gene, has recently been categorized as a familial colorectal cancer (CRC) syndrome. CF patients are highly susceptible to early, aggressive colorectal tumor development. Endoscopic screening studies have revealed that by the age of forty 50% of CF patients will develop adenomas, with 25% developing aggressive advanced adenomas, some of which will have a ...[more]

PMID: 32326161

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Project description:Cystic fibrosis (CF) is an autosomal recessive genetic disease characterized by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is a chloride channel responsible for ion flow across epithelial surfaces of lung, sinuses, pancreas, intestine, and liver. Researchers have grouped CFTR genetic mutations into various protein defects: reduced protein synthesis (class 1 mutations), abnormal protein folding and maturation (class 2 mutation), and abnormal gating (class 3 mutation). These mutations usually present as severe forms of CF due to complete absence of CFTR at cell surfaces. Milder forms (eg, protein maturation and conductance defects, classes 4-6) present as less severe forms of CF related to the presence of CFTR at the cell surface. Differences in severity are directly due to CFTR function which is based on the severity of CFTR mutation. This knowledge has proven useful for designing therapy for individual mutations and mutation classes. The discovery and US Food and Drug Administration approval of Kalydeco® (ivacaftor) in early 2011 marked the beginning of a new era of therapies that are focused on improving defective CFTR protein function. However, due to its specificity for the G551D mutation, ivacaftor only benefit?5% of CF patients. Approximately 50% of CF patients have two copies of the F508Del mutation, while other CF patients carry only one copy of this gene. More recently, Orkambi®, a two compound medication composed of lumacaftor and ivacaftor, has provided the foundation necessary to further build on molecular concepts of: correction of trafficking, potentiation, and amplification of defective CFTR. These new concepts will form the basis of future CF therapies and extend CFTR treatment to almost 50% of CF patients. Evolving knowledge of the molecular mechanisms responsible for defective CFTR has prompted new research focused on "repair" of each phase of CFTR expression and function, thus creating a new class of combination "CFTR correctors" referred to as "triplet CFTR compounds." This article will review how patients can be selected and treated with these newer agents that are based on specific mutations. In the future, many CF practitioners have expectations that initiation of treatment for CF patients will occur simply by use of biomarkers of CFTR expression (eg, sweat chloride, nasal potential difference, rectal organoids) rather than testing for specific mutations. As continued research identifies biomarkers with greater specificity and which predict clinical response, therapies can potentially be tailored to individual responses.

Dataset Information

Cystic Fibrosis, CFTR, and Colorectal Cancer.

Publications

Cystic Fibrosis, CFTR, and Colorectal Cancer.

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