Cancer Risks in Heterozygous Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) DelF508 Carriers

Sugunaraj, Jaya Prakash; Mirshahi, Uyenlinh L.; Wardeh, Amr H.; Manney, Catarina; Manickam, Kandamurugu; Murray, Michael J.; Carey, David J.; Stamm, Jason

doi:10.1016/j.chest.2016.08.1242

Cited by 3 publications

(6 citation statements)

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“…There is a single report that studied 1468 individuals who were heterozygous germline carriers of F508del mutations that found an increased risk of gastric cancer in these individuals (O.R. 2.5 [CI 1.6–3.4]) [ 32 ]. There is also one report that serum CFTR levels correlated with the serum expression of the tumor biomarker CA199 in gastric cancer [ 33 ].…”

Section: Involvement Of Cftr In Gi Cancersmentioning

confidence: 99%

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CFTR and Gastrointestinal Cancers: An Update

Bhattacharya

Blankenheim

Scott

et al. 2022

JPM

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Cystic Fibrosis (CF) is a disease caused by mutations in the CFTR gene that severely affects the lungs as well as extra-pulmonary tissues, including the gastrointestinal (GI) tract. CFTR dysfunction resulting from either mutations or the downregulation of its expression has been shown to promote carcinogenesis. An example is the enhanced risk for several types of cancer in patients with CF, especially cancers of the GI tract. CFTR also acts as a tumor suppressor in diverse sporadic epithelial cancers in many tissues, primarily due to the silencing of CFTR expression via multiple mechanisms, but especially due to epigenetic regulation. This review provides an update on the latest research linking CFTR-deficiency to GI cancers, in both CF patients and in sporadic GI cancers, with a particular focus on cancer of the intestinal tract. It will discuss changes in the tissue landscape linked to CFTR-deficiency that may promote cancer development such as breakdowns in physical barriers, microbial dysbiosis and inflammation. It will also discuss molecular pathways and mechanisms that act upstream to modulate CFTR expression, such as by epigenetic silencing, as well as molecular pathways that act downstream of CFTR-deficiency, such as the dysregulation of the Wnt/β-catenin and NF-κB signaling pathways. Finally, it will discuss the emerging CFTR modulator drugs that have shown promising results in improving CFTR function in CF patients. The potential impact of these modulator drugs on the treatment and prevention of GI cancers can provide a new example of personalized cancer medicine.

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Section: Involvement Of Cftr In Gi Cancersmentioning

confidence: 99%

“…Germline heterozygous carriers of CFTR F508del have an increased risk of developing gastric cancers [ 32 , 33 ].…”

Section: Figurementioning

confidence: 99%

CFTR and Gastrointestinal Cancers: An Update

Bhattacharya

Blankenheim

Scott

et al. 2022

JPM

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Section: Introductionmentioning

confidence: 99%

“…1 The genome-first approach coupled with deep phenotyping demonstrated its utility and accuracy in ascertainment of the predictive value of CFTR [OMIM 602421] screening and cystic fibrosis. 2 Previous analyses of these data have focused on more common genetic disorders (eg, BRCA1/2 [OMIM 113705] and hypercholesterolemia). 3,4 Heterozygous germline pathogenic variants in DICER1 [OMIM 606421], an essential component of the microRNA (miRNA) processing pathway, underlie an autosomal dominant tumor-predisposition disorder that confers increased risk of a variety of rare and common neoplasms in children and adults.…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, the Geisinger-Regeneron DiscovEHR collaboration links electronic health records (EHRs) to population-scale exome sequencing to create a platform for genomic discovery, drug development, and clinical genomic implementation . The genome-first approach coupled with deep phenotyping demonstrated its utility and accuracy in ascertainment of the predictive value of CFTR [OMIM 602421] screening and cystic fibrosis . Previous analyses of these data have focused on more common genetic disorders (eg, BRCA1/2 [OMIM 113705] and hypercholesterolemia) …”

Section: Introductionmentioning

confidence: 99%

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A Genome-First Approach to Characterize DICER1 Pathogenic Variant Prevalence, Penetrance, and Phenotype

et al. 2021

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Key Points Question What are the prevalence, risk, and phenotypic spectrum of individuals with a germline putative loss-of-function (pLOF) variant in DICER1 according to a genome-first approach in a population-scale cohort? Findings In this cohort study, DICER1 pLOF variants were more than twice as common (even after adjustment for relatedness) than previously observed. Malignant tumors were observed in 16% of participants with a DICER1 pLOF variant, which is comparable to the frequency of neoplasms in the largest phenotype-first DICER1 studies published to date. Meaning The genome-first approach complements more traditional approaches to syndrome delineation and may be an efficient approach for risk estimation in monogenic disorders.

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The CFTR Gene Germline Heterozygous Pathogenic Variants in Russian Patients with Malignant Neoplasms and Healthy Carriers: 11,800 WGS Results

Makarova

Nemtsova

Danishevich

et al. 2023

IJMS

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More than 275 million people in the world are carriers of a heterozygous mutation of the CFTR gene, associated with cystic fibrosis, the most common autosomal recessive disease among Caucasians. Some recent studies assessed the association between carriers of CFTR variants and some pathologies, including cancer risk. The aim of this study is to analyze the landscape of germline pathogenic heterozygous CFTR variants in patients with diagnosed malignant neoplasms. For the first time in Russia, we evaluated the frequency of CFTR pathogenic variants by whole-genome sequencing in 1800 patients with cancer and compared this with frequencies of CFTR variants in the control group (1825 people) adjusted for age and 10,000 healthy individuals. In the issue, 47 out of 1800 patients (2.6%) were carriers of CFTR pathogenic genetic variants: 0.028 (42/1525) (2.8%) among breast cancer patients, 0.017 (3/181) (1.7%) among colorectal cancer patients and 0.021 (2/94) (2.1%) among ovarian cancer patients. Pathogenic CFTR variants were found in 52/1825 cases (2.85%) in the control group and 221 (2.21%) in 10,000 healthy individuals. Based on the results of the comparison, there was no significant difference in the frequency and distribution of pathogenic variants of the CFTR gene, which is probably due to the study limitations. Obviously, additional studies are needed to assess the clinical significance of the heterozygous carriage of CFTR pathogenic variants in the development of various pathologies in the future, particularly cancer.

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Cancer Risks in Heterozygous Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) DelF508 Carriers

Cited by 3 publications

References 0 publications

CFTR and Gastrointestinal Cancers: An Update

CFTR and Gastrointestinal Cancers: An Update

A Genome-First Approach to Characterize DICER1 Pathogenic Variant Prevalence, Penetrance, and Phenotype

The CFTR Gene Germline Heterozygous Pathogenic Variants in Russian Patients with Malignant Neoplasms and Healthy Carriers: 11,800 WGS Results

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