Cystic fibrosis (CF) is a life-limiting genetic disease that affects multiple organ systems. It is caused by a mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which results in the absence or damage of a relevant protein. If left untreated, it causes death in early childhood. The advent of more efficacious treatments has resulted in a notable increase in the life expectancy of CF patients. This has, in turn, led to an elevated risk of developing specific types of cancer. This review commences with an examination of CF from the standpoint of its etiology and therapeutic modalities. Subsequently, it presents a list of epidemiological studies that suggest an altered predisposition to certain cancers. A heightened risk is well documented, particularly in relation to the gastrointestinal tract. The following section addresses the role of CFTR in view of its potential involvement in the progression of various types of cancer. Several studies have indicated that the levels of the CFTR protein are reduced in many tumors and that this reduction is associated with the progression of the tumors. These decreased expressions are known to occur in the gastrointestinal tract, lungs, bladder, and/or prostate cancer. Conversely, ovarian, stomach, and cervical cancer are connected with its higher expression. The final section of the review focuses on the molecular mechanism of action of the CFTR protein in signaling pathways that affect cell proliferation and the process of carcinogenesis. This section attempts to explain the increased predisposition to cancer observed in patients with CF.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Primary ciliary dyskinesia (PCD) represents a group of rare hereditary disorders characterised by deficient ciliary airway clearance that can be associated with laterality defects. We aimed to describe the underlying gene defects, geographical differences in genotypes and their relationship to diagnostic findings and clinical phenotypes. METHODS: Genetic variants and clinical findings (age, sex, body mass index, laterality defects, forced expiratory volume in 1 s (FEV1)) were collected from 19 countries using the European Reference Network's ERN-LUNG international PCD Registry. Genetic data were evaluated according to American College of Medical Genetics and Genomics guidelines. We assessed regional distribution of implicated genes and genetic variants as well as genotype correlations with laterality defects and FEV1. RESULTS: The study included 1236 individuals carrying 908 distinct pathogenic DNA variants in 46 PCD genes. We found considerable variation in the distribution of PCD genotypes across countries due to the presence of distinct founder variants. The prevalence of PCD genotypes associated with pathognomonic ultrastructural defects (mean 72%, range 47-100%) and laterality defects (mean 42%, range 28-69%) varied widely among countries. The prevalence of laterality defects was significantly lower in PCD individuals without pathognomonic ciliary ultrastructure defects (18%). The PCD cohort had a reduced median FEV1 z-score (-1.66). Median FEV1 z-scores were significantly lower in CCNO (-3.26), CCDC39 (-2.49) and CCDC40 (-2.96) variant groups, while the FEV1 z-score reductions were significantly milder in DNAH11 (-0.83) and ODAD1 (-0.85) variant groups compared to the whole PCD cohort. CONCLUSION: This unprecedented multinational dataset of DNA variants and information on their distribution across countries facilitates interpretation of the genetic epidemiology of PCD and indicates that the genetic variant can predict diagnostic and phenotypic features such as the course of lung function.

• MeSH
• axonemální dyneiny genetika   MeSH
• cytoskeletální proteiny MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp * MeSH
• genetická variace MeSH
• genetické asociační studie * MeSH
• genotyp * MeSH
• Kartagenerův syndrom genetika   patofyziologie   MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace MeSH
• předškolní dítě MeSH
• proteiny MeSH
• registrace MeSH
• senioři MeSH
• usilovný výdechový objem MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• axonemální dyneiny MeSH
• CCDC39 protein, human MeSH Prohlížeč
• CCDC40 protein, human MeSH Prohlížeč
• cytoskeletální proteiny MeSH
• DNAH11 protein, human MeSH Prohlížeč
• proteiny MeSH

As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development.

• Klíčová slova
• CFTR modulators, Clinical trials, Drug development, Global perspective,
• MeSH
• cystická fibróza farmakoterapie   genetika   MeSH
• lidé MeSH
• mezinárodní spolupráce * MeSH
• protein CFTR účinky léků   MeSH
• vyvíjení léků organizace a řízení   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• CFTR protein, human MeSH Prohlížeč
• protein CFTR MeSH