Juxtaglomerular cell tumor (JxGCT) is a rare type of renal neoplasm demonstrating morphologic overlap with some mesenchymal tumors such as glomus tumor (GT) and solitary fibrous tumor (SFT). Its oncogenic drivers remain elusive, and only a few cases have been analyzed with modern molecular techniques. In prior studies, loss of chromosomes 9 and 11 appeared to be recurrent. Recently, whole-genome analysis identified alterations involving genes of MAPK-RAS pathway in a subset, but no major pathogenic alterations have been discovered in prior whole transcriptome analyses. Considering the limited understanding of the molecular features of JxGCTs, we sought to assess a collaborative series with a multiomic approach to further define the molecular characteristics of this entity. Fifteen tumors morphologically compatible with JxGCTs were evaluated using immunohistochemistry for renin, single-nucleotide polymorphism array (SNP), low-pass whole-genome sequencing, and RNA sequencing (fusion assay). In addition, methylation analysis comparing JxGCT, GT, and SFT was performed. All cases tested with renin (n=11) showed positive staining. Multiple chromosomal abnormalities were identified in all cases analyzed (n=8), with gains of chromosomes 1p, 10, 17, and 19 and losses of chromosomes 9, 11, and 21 being recurrent. A pathogenic HRAS mutation was identified in one case as part of the SNP array analysis. Thirteen tumors were analyzed by RNA sequencing, with 2 revealing in-frame gene fusions: TFG::GPR128 (interpreted as stochastic) and NAB2::STAT6 . The latter, originally diagnosed as JxGCT, was reclassified as SFT and excluded from the series. No fusions were detected in the remaining 11 cases; of note, no case harbored NOTCH fusions previously described in GT. Genomic methylation analysis showed that JxGCT, GT, and SFT form separate clusters, confirming that JxGCT represents a distinct entity (ie, different from GT). The results of our study show that JxGCTs are a distinct tumor type with a recurrent pattern of chromosomal imbalances that may play a role in oncogenesis, with MAPK-RAS pathway activation being likely a driver in a relatively small subset.
- MeSH
- dospělí MeSH
- epigeneze genetická MeSH
- epigenomika MeSH
- fúze genů * MeSH
- genetická predispozice k nemoci MeSH
- genomika MeSH
- imunohistochemie MeSH
- jednonukleotidový polymorfismus MeSH
- juxtaglomerulární aparát patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- metylace DNA MeSH
- nádorové biomarkery * genetika MeSH
- nádory ledvin * genetika patologie chemie MeSH
- sekvenování celého genomu MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer's Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10-8) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10-6). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.
- MeSH
- Alzheimerova nemoc * genetika MeSH
- celogenomová asociační studie metody MeSH
- genetická predispozice k nemoci genetika MeSH
- inaktivace chromozomu X genetika MeSH
- jednonukleotidový polymorfismus genetika MeSH
- lidé MeSH
- lidské chromozomy X * genetika MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BIDrs9604789 variant with an increased risk of developing the disease (ORMeta = 1.31, p = 9.67 × 10-6). We also confirmed the association of TP63rs1515496 and TP63rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10-8 and OR = 1.16, p = 2.74 × 10-5). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10-4 and p = 1.56 × 10-3), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10-4). These results were in agreement with research suggesting that the TP63rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC.
- MeSH
- autofagie * genetika MeSH
- běloši genetika MeSH
- duktální karcinom slinivky břišní * genetika patologie MeSH
- forkhead transkripční faktory MeSH
- genetická predispozice k nemoci * MeSH
- hepatocytární jaderný faktor 3-alfa genetika metabolismus MeSH
- jednonukleotidový polymorfismus * MeSH
- kohortové studie MeSH
- lidé MeSH
- nádorové biomarkery * genetika MeSH
- nádorové supresorové proteiny * genetika MeSH
- nádory slinivky břišní * genetika patologie MeSH
- studie případů a kontrol MeSH
- transkripční faktory genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
BACKGROUND: Colorectal cancer (CRC) is a common, fatal cancer. Identifying subgroups who may benefit more from intervention is of critical public health importance. Previous studies have assessed multiplicative interaction between genetic risk scores and environmental factors, but few have assessed additive interaction, the relevant public health measure. METHODS: Using resources from CRC consortia, including 45,247 CRC cases and 52,671 controls, we assessed multiplicative and additive interaction (relative excess risk due to interaction, RERI) using logistic regression between 13 harmonized environmental factors and genetic risk score, including 141 variants associated with CRC risk. RESULTS: There was no evidence of multiplicative interaction between environmental factors and genetic risk score. There was additive interaction where, for individuals with high genetic susceptibility, either heavy drinking (RERI = 0.24, 95% confidence interval [CI] = 0.13, 0.36), ever smoking (0.11 [0.05, 0.16]), high body mass index (female 0.09 [0.05, 0.13], male 0.10 [0.05, 0.14]), or high red meat intake (highest versus lowest quartile 0.18 [0.09, 0.27]) was associated with excess CRC risk greater than that for individuals with average genetic susceptibility. Conversely, we estimate those with high genetic susceptibility may benefit more from reducing CRC risk with aspirin/nonsteroidal anti-inflammatory drugs use (-0.16 [-0.20, -0.11]) or higher intake of fruit, fiber, or calcium (highest quartile versus lowest quartile -0.12 [-0.18, -0.050]; -0.16 [-0.23, -0.09]; -0.11 [-0.18, -0.05], respectively) than those with average genetic susceptibility. CONCLUSIONS: Additive interaction is important to assess for identifying subgroups who may benefit from intervention. The subgroups identified in this study may help inform precision CRC prevention.
- MeSH
- dieta MeSH
- dospělí MeSH
- genetická predispozice k nemoci * MeSH
- index tělesné hmotnosti MeSH
- interakce genů a prostředí * MeSH
- jednonukleotidový polymorfismus MeSH
- kolorektální nádory * genetika epidemiologie MeSH
- kouření škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- logistické modely MeSH
- pití alkoholu MeSH
- rizikové faktory MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
In advanced prostate cancer (PC), in particular after acquisition of resistance to androgen receptor (AR) signaling inhibitors (ARSI), upregulation of AR splice variants compromises endocrine therapy efficiency. Androgen receptor splice variant-7 (ARV7) is clinically the most relevant and has a distinct 3' untranslated region (3'UTR) compared to the AR full-length variant, suggesting a unique post-transcriptional regulation. Here, we set out to evaluate the applicability of the ARV7 3'UTR as a therapy target. A common single nucleotide polymorphism, rs5918762, was found to affect the splicing rate and thus the expression of ARV7 in cellular models and patient specimens. Serine/arginine-rich splicing factor 9 (SRSF9) was found to bind to and increase the inclusion of the cryptic exon 3 of ARV7 during the splicing process in the alternative C allele of rs5918762. The dual specificity protein kinase CLK2 interferes with the activity of SRSF9 by regulating its expression. Inhibition of the Cdc2-like kinase (CLK) family by the small molecules cirtuvivint or lorecivivint results in the decreased expression of ARV7. Both inhibitors show potent anti-proliferative effects in enzalutamide-treated or -naive PC models. Thus, targeting aberrant alternative splicing at the 3'UTR of ARV7 by disturbing the CLK2/SRSF9 axis might be a valuable therapeutic approach in late stage, ARSI-resistant PC.
- MeSH
- 3' nepřekládaná oblast genetika MeSH
- alternativní sestřih genetika účinky léků MeSH
- androgenní receptory * metabolismus genetika MeSH
- jednonukleotidový polymorfismus genetika MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory prostaty * genetika metabolismus patologie farmakoterapie MeSH
- protein - isoformy genetika metabolismus MeSH
- protein-serin-threoninkinasy genetika metabolismus antagonisté a inhibitory MeSH
- regulace genové exprese u nádorů * účinky léků MeSH
- serin-arginin sestřihové faktory * metabolismus genetika MeSH
- sestřih RNA genetika MeSH
- tyrosinkinasy * genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: The etiopathogenesis of atopic dermatitis is complicated, and it includes aspects such as dysfunction of the skin barrier, changes in immune responses, IgE-mediated hypersensitivity, and many characteristics of the environment. Regarding skin barrier dysfunction, a number of genetic changes have been described. This genetic predisposition could be related to the phenotypes of atopic dermatitis. AIM: In this study, several polymorphisms in five proinflammatory genes were associated with certain phenotypes of AD patients (genotype-phenotype study). METHODS: In total, 89 unrelated AD Czech (Caucasian) patients were genotyped regarding five proinflammatory gene polymorphisms (angiotensinogen AGT M235T, AGT-6 G/A, TNF-α-238 G/A, TNF-β Fok1, IL-6-174 C/G and IL-6-596 G/A). Genotyping was performed using PCR and restriction analysis. For phenotypes, patients' sex, age and personal and family history of atopy, aero- and food allergies and other complex diseases were evaluated. RESULTS: A significant association with transepidermal water loss (TEWL) measured on the forearm was found with the AGT M235T polymorphism (p = 0.02). For the AG genotype of TNF-α-238 G/A, a six-times higher risk for a family history of diabetes mellitus compared to other examined aspects of family history was found (p = 0.02). A family history of thyreopathy was associated with the IL-6-174 G/C polymorphism when compared to a family history of other complex diseases. The GG genotype had a ten-times higher risk for a family history of thyreopathy compared to the other genotypes (p = 0.004). This result was highly specific (0.914). The GG genotype of IL-6-596 G/A was associated with a family history of thyreopathy, with the same result (p = 0.004). Moreover, the G allele of IL-6-174 G/C was associated with a family history of thyreopathy compared to AD patients without a positive family history of complex diseases (p = 0.03). In AD men, the MM genotype of the AGT M235T gene was found to be associated with food allergies (p = 0.004). This result was highly sensitive (0.833). A family history of cardiovascular disease in AD men was associated with AGT-6 G/A variability. The A allele was found to be six times more frequent in patients with a positive family history of cardiovascular disease (p = 0.02, with high sensitivity and specificity (0.700 and 0.735, respectively)). A family history of diabetes mellitus was associated with the TNF-β Fok1 polymorphism, where the B1 allele was almost six times more frequent in AD men with a positive family history of diabetes mellitus (p = 0.02), with high sensitivity (0.85). A significant association between TEWL measured on the forearm and the AGT M235T polymorphism was found when AD women were carriers of the MM genotype, with a median of 25 and range 4-61; those patients with the MT genotype had a median of 10 and range of 0.3-39; and patients with the TT genotype had a median of 5 and range of 3-40, p = 0.003. The polymorphism AGT-6 G/A was associated with different ages of eczema onset. The AG genotype was almost nine times more risky for the youngest group (0-7 years) compared to the oldest group (more than 18 years) (p = 0.02), with high specificity for this result. CONCLUSIONS: Our results in the field of cytokine signaling in the immune system in patients with atopic dermatitis are in agreement with those of GWASs. We suggest that cost-effective and simple PCR tests may be the best approach for the rapid and optimal collection of valid genetic information in clinical practice.
- MeSH
- atopická dermatitida * genetika patologie MeSH
- dospělí MeSH
- fenotyp MeSH
- genetická predispozice k nemoci MeSH
- genotyp MeSH
- interleukin-6 genetika MeSH
- jednonukleotidový polymorfismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- TNF-alfa genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
The aim of this study was to analyse the allelic distribution of selected genes in the Czech and Vietnamese populations. We analysed samples from 94 Vietnamese volunteers and 2,859 Czech population-based subjects (2,559 from the Czechs post-MONICA and 300 volunteers from the South region of the Czech Republic). There were significant differences between the two populations for most, but not all, of the SNPs analysed. In particular, the prevalence of risk alleles in the analysed polymorphisms tended to be lower in the Vietnamese community compared to the Czech population, especially within the FTO (rs17817449; associated with obesity risk, P < 0.0001), TCF7L2 (rs7903146; linked to type 2 dia-betes, P < 0.0001) and ADH1B (rs1229984; related to alcohol consumption, P < 0.0001) genes. The genotype within the MCM6/LCT cluster (rs4988235) associated with lactase persistence was not present in the Vietnamese population. Slight genotype differences were detected for one HFE polymorphism (rs1799945 with P = 0.005; but not for rs1800562). Only the genotype frequencies within the MC4R and APOE genes were almost identical in both populations. We conclude that the Vietnamese population may have a lower genetic predisposition to the non-communicable diseases such as obesity or diabetes mellitus.
- MeSH
- Asijci * genetika MeSH
- dospělí MeSH
- frekvence genu genetika MeSH
- genotyp MeSH
- jednonukleotidový polymorfismus genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- menšiny * MeSH
- obyvatelé jihovýchodní Asie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
- Vietnam MeSH
The ABCB1 gene, encoding the ATP-dependent translocase ABCB1, plays a crucial role in the clearance of amyloid-beta (Aβ) peptides and the transport of cholesterol, implicating it in the pathogenesis of Alzheimer's disease. The study aims to investigate the association between polymorphisms in the ABCB1 gene and cognitive decline in individuals with mild cognitive impairment (MCI), particularly focusing on language function. A longitudinal cohort study involving 1 005 participants from the Czech Brain Aging Study was conducted. Participants included individuals with Alzheimer's disease, amnestic MCI, non-amnestic MCI, subjective cognitive decline, and healthy controls. Next-generation sequencing was utilized to analyze the entire ABCB1 gene. Cognitive performance was assessed using a comprehensive battery of neuropsychological tests, including the Boston Naming Test and the semantic verbal fluency test. Ten ABCB1 polymorphisms (rs55912869, rs56243536, rs10225473, rs10274587, rs2235040, rs12720067, rs12334183, rs10260862, rs201620488, and rs28718458) were significantly associated with cognitive performance, particularly in language decline among amnestic MCI patients. In silico analyses revealed that some of these polymorphisms may affect the binding sites for transcription factors (HNF-3alpha, C/EBPβ, GR-alpha) and the generation of novel exonic splicing enhancers. Additionally, polymorphism rs55912869 was identified as a potential binding site for the microRNA hsa-mir-3163. Our findings highlight the significant role of ABCB1 polymorphisms in cognitive decline, particularly in language function, among individuals with amnestic MCI. These polymorphisms may influence gene expression and function through interactions with miRNAs, transcription factors, and alternative splicing mechanisms.
- MeSH
- Alzheimerova nemoc genetika MeSH
- jednonukleotidový polymorfismus * MeSH
- kognitivní dysfunkce * genetika MeSH
- lidé MeSH
- longitudinální studie MeSH
- neuropsychologické testy MeSH
- P-glykoproteiny genetika MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
A potential association of endogenous circadian rhythm disruption with risk of cancer development has been suggested, however, epidemiological evidence for the association of sleep traits with colorectal cancer (CRC) is limited and often contradictory. Here we investigated whether genetically predicted chronotype, insomnia and sleep duration are associated with CRC risk in males, females and overall and according to CRC anatomical subsites using Mendelian randomization (MR). The two-sample inverse variance weighted (IVW) method was applied using summary-level data in up to 58,221 CRC cases and 67,694 controls and genome-wide association data of genetic variants for self-reported sleep traits. Secondary analyses using alternative instruments and sensitivity analyses assessing potential violations of MR assumptions were conducted. Genetically predicted morning preference was associated with 13% lower risk of CRC in men (ORIVW = 0.87, 95% CI = 0.78, 0.97, P = 0.01), but not in women or in both sexes combined. Τhis association remained consistent in some, but not all, sensitivity analyses and was very similar for colon and rectal cancer. There was no evidence of an association for any other sleep trait. Overall, this study provides little to no evidence of an association between genetically predicted sleep traits and CRC risk.
- MeSH
- celogenomová asociační studie MeSH
- cirkadiánní rytmus genetika MeSH
- genetická predispozice k nemoci MeSH
- jednonukleotidový polymorfismus MeSH
- kolorektální nádory * genetika epidemiologie MeSH
- lidé MeSH
- mendelovská randomizace * MeSH
- poruchy iniciace a udržování spánku genetika MeSH
- rizikové faktory MeSH
- spánek * genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
IMPORTANCE: Understanding the pathogenic mechanisms of Fuchs endothelial corneal dystrophy (FECD) could contribute to developing gene-targeted therapies. OBJECTIVE: To investigate associations between demographic data and age at first keratoplasty in a genetically refined FECD cohort. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study recruited 894 individuals with FECD at Moorfields Eye Hospital (London) and General University Hospital (Prague) from September 2009 to July 2023. Ancestry was inferred from genome-wide single nucleotide polymorphism array data. CTG18.1 status was determined by short tandem repeat and/or triplet-primed polymerase chain reaction. One or more expanded alleles (≥50 repeats) were classified as expansion-positive (Exp+). Expansion-negative (Exp-) cases were exome sequenced. MAIN OUTCOMES AND MEASURES: Association between variants in FECD-associated genes, demographic data, and age at first keratoplasty. RESULTS: Within the total cohort (n = 894), 77.3% of patients were Exp+. Most European (668 of 829 [80.6%]) and South Asian (14 of 22 [63.6%]) patients were Exp+. The percentage of female patients was higher (151 [74.4%]) in the Exp- cohort compared to the Exp+ cohort (395 [57.2%]; difference, 17.2%; 95% CI, 10.1%-24.3%; P < .001). The median (IQR) age at first keratoplasty of the Exp + patients (68.2 years [63.2-73.6]) was older than the Exp- patients (61.3 years [52.6-70.4]; difference, 6.5 years; 95% CI, 3.4-9.7; P < .001). The CTG18.1 repeat length of the largest expanded allele within the Exp+ group was inversely correlated with the age at first keratoplasty (β, -0.087; 95% CI, -0.162 to -0.012; P = .02). The ratio of biallelic to monoallelic expanded alleles was higher in the FECD cohort (1:14) compared to an unaffected control group (1:94; P < .001), indicating that 2 Exp+ alleles were associated with increased disease penetrance compared with 1 expansion. Potentially pathogenic variants (minor allele frequency, <0.01; combined annotation dependent depletion, >15) were only identified in FECD-associated genes in 13 Exp- individuals (10.1%). CONCLUSIONS AND RELEVANCE: In this multicenter cohort study among individuals with FECD, CTG18.1 expansions were present in most European and South Asian patients, while CTG18.1 repeat length and zygosity status were associated with modifications in disease severity and penetrance. Known disease-associated genes accounted for only a minority of Exp- cases, with unknown risk factors associated with disease in the rest of this subgroup. These data may have implications for future FECD gene-targeted therapy development.
- MeSH
- celogenomová asociační studie MeSH
- dospělí MeSH
- Fuchsova endoteliální dystrofie * genetika chirurgie epidemiologie diagnóza MeSH
- genetická predispozice k nemoci * MeSH
- jednonukleotidový polymorfismus * MeSH
- lidé středního věku MeSH
- lidé MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- stupeň závažnosti nemoci MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- pozorovací studie MeSH