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Asian Journal of Andrology 2022During recent decades, the association between mutations in ubiquitin-specific protease 26 (USP26) and male infertility remains doubtful. We conducted this meta-analysis... (Meta-Analysis)
Meta-Analysis
During recent decades, the association between mutations in ubiquitin-specific protease 26 (USP26) and male infertility remains doubtful. We conducted this meta-analysis to evaluate the association between mutations in USP26 and male infertility according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. It was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42021225251). PubMed, Web of Science, and Scopus were systematically searched for comparative clinical studies, which were written in English and provided eligible data. Studies were included when they compared USP26 mutations in azoospermic, oligozoospermic, and asthenozoospermic patients with controls with normal sperm parameter values or whose partners had experienced spontaneous pregnancy. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated with random effect models. Overall, twelve studies with 3927 infertility patients and 4648 healthy controls were included. The association between overall USP26 mutations and infertility was not significant (OR = 1.60, 95% CI: 0.51-5.01). For specific mutations, the pooled ORs were 1.65 (95% CI: 1.02-2.69) for cluster mutation (including 370-371insACA, 494T>C, and 1423C>T), 1.80 (95% CI: 0.35-9.15) for c.576G>A, 1.43 (95% CI: 0.79-2.56) for c.1090C>T, and 3.59 (95% CI: 2.30-5.59) for c.1737G>A. Our results suggest that several mutations (cluster mutation, c.1737G>A) may play roles in male infertility, while others (c.576G>A and c.1090C>T) do not show notable associations with male infertility. More high-quality clinical researches are needed for validation.
Topics: Cysteine Endopeptidases; Female; Humans; Infertility, Male; Male; Mutation; Pregnancy; Semen; Ubiquitin-Specific Proteases
PubMed: 35074940
DOI: 10.4103/aja2021109 -
Molecular Diagnosis & Therapy Jan 2023Data on molecular alterations harbored by melanoma brain metastases (MBMs) are limited, and this has hampered the development of more effective therapeutic strategies.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Data on molecular alterations harbored by melanoma brain metastases (MBMs) are limited, and this has hampered the development of more effective therapeutic strategies. We conducted a systematic review and meta-analysis of all the studies reporting DNA sequencing data of MBMs, in order to identify recurrently mutated genes and molecular pathways significantly enriched for genetic alterations.
METHODS
We searched PubMed, Embase and Scopus for articles published from the inception of each database to June 30, 2021. We included in the analysis all the studies that reported individual patient data on DNA sequencing of MBMs, assessing single nucleotide variants (SNVs) and/or gene copy number variations (CNVs) in at least five tumor samples. Meta-analysis was performed for genes evaluated for SNVs and/or CNVs in at least two studies. Pooled proportions of samples with SNVs and/or CNVs was calculated by applying random-effect models based on the DerSimonian-Laird method. Gene-set enrichment analysis (GSEA) was performed to identify molecular pathways significantly enriched for mutated genes.
RESULTS
Ten studies fulfilled the inclusion criteria and were included in the analysis, for a total of 531 samples of MBMs evaluated. Twenty-seven genes were found recurrently mutated with a meta-analytic rate of SNVs higher than 5%. GSEA conducted on the list of these 27 recurrently mutated genes revealed vascular endothelial growth factor-activated receptor activity and transmembrane receptor protein tyrosine kinase activity to be among the top 10 gene ontology (GO) molecular functions significantly enriched for mutated genes, while regulation of apoptosis and cell proliferation were among the top 10 significantly enriched GO biological processes. Notably, a high meta-analytic rate of SNVs was found in several actionable cancer-associated genes, such as all the vascular endothelial growth factor (VEGF) receptor isoforms (i.e., Flt1 and Flt2 genes, for both SNV rate: 0.22, 95% CI 0.04-0.49; KDR gene, SNV rate: 0.1, 95% CI 0.05-0.16). Finally, two tumor suppressor genes were characterized by a high meta-analytic rate of CNVs: CDKN2A/B (CNV rate: 0.59, 95% CI 0.23-0.90) and PTEN (CNV rate: 0.31, 95% CI 0.02-0.95).
CONCLUSION
MBMs harbored actionable molecular alterations that could be exploited as therapeutic targets to improve the poor prognosis of patients.
Topics: Humans; DNA Copy Number Variations; Vascular Endothelial Growth Factor A; Melanoma; Mutation; Brain Neoplasms
PubMed: 36401787
DOI: 10.1007/s40291-022-00623-0 -
Journal of Surgical Oncology Nov 2022Germline BRCA1/2 mutations lead to malfunction of DNA damage repair pathways and predispose to pancreatic ductal adenocarcinoma (PDAC). The aim of this study is to... (Meta-Analysis)
Meta-Analysis Review
Germline BRCA1/2 mutations lead to malfunction of DNA damage repair pathways and predispose to pancreatic ductal adenocarcinoma (PDAC). The aim of this study is to synthesise the available research on this topic. Four studies reporting risk ratio (RR) were included in the final meta-analysis to minimise misrepresenting our results by combining separate risk estimates. Our meta-analysis revealed a statistically significant increased risk of PDAC in BRCA carriers overall (RR: 2.65, 95% confidence interval: 1.43-4.91, p = 0.002).
Topics: BRCA1 Protein; BRCA2 Protein; Carcinoma, Pancreatic Ductal; Germ-Line Mutation; Humans; Mutation; Pancreatic Ducts; Pancreatic Neoplasms
PubMed: 35770919
DOI: 10.1002/jso.26994 -
Journal of Assisted Reproduction and... Sep 2016This is a comprehensive review of the literature in this field attempting to put the FMR1 gene and its evaluation into context, both in general and for the reproductive... (Review)
Review
PURPOSE
This is a comprehensive review of the literature in this field attempting to put the FMR1 gene and its evaluation into context, both in general and for the reproductive health audience.
METHODS
Online database search of publications with systematic review of all papers relevant to ovarian reserve and assisted reproduction was done.
RESULTS
Relevant papers were identified and assessed, and an attempt was made to understand, rationalize and explain the divergent views in this field of study. Seminal and original illustrations were employed.
CONCLUSIONS
FMR1 is a highly conserved gene whose interpretation and effect on outcomes remains controversial in the reproductive health setting. Recent re-evaluations of the commonly accepted normal range have yielded interesting tools for possibly explaining unexpected outcomes in assisted reproduction. Fragile X investigations should perhaps become more routinely assessed in the reproductive health setting, particularly following a failed treatment cycle where oocyte quality is thought to be a contributing factor, or in the presence of a surprise finding of diminished ovarian reserve in a young patient.
Topics: Female; Fragile X Mental Retardation Protein; Humans; Mutation; Ovarian Reserve; Reproduction; Reproductive Techniques, Assisted
PubMed: 27432256
DOI: 10.1007/s10815-016-0765-6 -
Molecular Biology Reports Mar 2012A number of molecular epidemiological studies have been conducted the screening for BRCA1 and BRCA2 mutations in breast cancer patients with a positive family history of... (Meta-Analysis)
Meta-Analysis Review
A number of molecular epidemiological studies have been conducted the screening for BRCA1 and BRCA2 mutations in breast cancer patients with a positive family history of breast and/or ovarian cancer and reported many common mutations in BRCA1 and BRCA2 associated in breast cancer in different population and different ethnicity. However, it's still lack of a systematic analysis on these mutations. To comprehensively evaluate the frequency and distribution of common BRCA1 and BRCA2 mutations which associated with breast cancer risk, we address this issue through system review and meta-analysis on 29 relevant published studies by conducting a literature search on PubMed and CNKI. 20 common founder germline mutations were identified from all 29 studies and 4 of BRCA1 (5382insC, 185delAG, 3819del5 and 4153delA) and 2 of BRCA2 (4075delGT, 5802del4) mutations were repeatedly reported twice or more in different articles, respectively. For the BRCA1, after conducting meta-analysis, we found that the overall frequency of 5382insC was 0.09 (95% CI 0.06-0.12), the frequency of 185delAG was 0.07 (95% CI 0.01-0.13), the frequency of 3819del5 was 0.02 (95% CI 0.01-0.04) and the frequency of 4153delA was 0.06 (95% CI 0.03-0.09). For the BRCA2, the overall frequency of 4075delGT was 0.02 (95% CI 0.00-0.03) and the frequency of 5802del4 was 0.07 (95% CI 0.04-0.11). This article provides a set of common mutations for BRCA1 and BRCA2 mutation carriers and the results may help to explore frequencies of BRCA1 and BRCA2 mutations in a given population and will be of significance both for diagnostic testing and for epidemiological studies.
Topics: BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; Female; Gene Frequency; Genetic Association Studies; Genetic Testing; Humans; INDEL Mutation; Models, Statistical
PubMed: 21643751
DOI: 10.1007/s11033-011-0958-0 -
Neurotoxicology Jul 2017Although amyotrophic lateral sclerosis (ALS) was identified as a neurological condition 150 years ago, risk factors related to the onset and progression of ALS remain... (Meta-Analysis)
Meta-Analysis Review
Although amyotrophic lateral sclerosis (ALS) was identified as a neurological condition 150 years ago, risk factors related to the onset and progression of ALS remain largely unknown. Monogenic mutations in over 30 genes are associated with about 10% of ALS cases. The age at onset of ALS and disease types has been found to influence ALS progression. The present study was designed to identify additional putative risk factors associated with the onset and progression of ALS using systematic review and meta-analysis of observational studies. Risk factors that may be associated with ALS include: 1) genetic mutations, including the intermediate CAG repeat expansion in ATXN2; 2) previous exposure to heavy metals such as lead and mercury; 3) previous exposure to organic chemicals, such as pesticides and solvents; 4) history of electric shock; 5) history of physical trauma/injury (including head trauma/injury); 6) smoking (a weak risk factor for ALS in women); and 6) other risk factors, such as participating in professional sports, lower body mass index, lower educational attainment, or occupations requiring repetitive/strenuous work, military service, exposure to Beta-N-methylamino-l-alanin and viral infections. Risk factors that may be associated with ALS progression rate include: 1) nutritional status, including vitamin D deficiency; 2) comorbidities; 3) ethnicity and genetic factors; 4) lack of supportive care; and 4) smoking. The extent to which these associations may be causal is discussed, with further research recommended to strengthen the evidence on which determinations of causality may be based.
Topics: Age of Onset; Amyotrophic Lateral Sclerosis; Databases, Bibliographic; Disease Progression; Environmental Exposure; Humans; Mutation; Nerve Tissue Proteins; Nutritional Status; Pesticides; Risk Factors; Vitamin D Deficiency
PubMed: 27377857
DOI: 10.1016/j.neuro.2016.06.015 -
Acta Oncologica (Stockholm, Sweden) Nov 2022Osimertinib is a recently approved third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Osimertinib is a recently approved third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR-T790M resistance mutations. The aim of the present meta-analysis was to investigate the efficacy and safety of osimertinib for patients with EGFR-mutated non-small-cell lung cancer (NSCLC).
MATERIALS AND METHODS
Databases were searched for randomized controlled studies that reported the efficacy and safety of osimertinib versus other treatments (chemotherapy, other EGFR-TKIs, etc.) in treating EGFR-mutated NSCLC. The measured effects included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), central nervous system progression-free survival (CNS-PFS), and overall survival (OS). Additional outcome was the incidence of adverse event. Relative risk (RR) for incidence and hazard ratio (HR) for survival outcomes were pooled.
RESULTS
Seven studies containing 3335 participants were finally included. Osimertinib tended to improve ORR and DCR (RRs >1) as compared with other treatments. Osimertinib was also a significant protective factor for PFS, CNS-PFS, and OS (HRs <1 and < .05). Osimertinib showed similar advantages in improving tumor response and patient survival when used as first-line, second-line, and third-line/adjuvant therapy, respectively, as compared with other treatments (RRs >1 for ORR and DCR; HRs <1 for PFS, CNS-PFS, and OS). Osimertinib also had better therapeutic effects as compared with chemotherapy, other EGFR TKIs, docetaxel + bevacizumab, and placebo, respectively. The five most common adverse events with pooled incidence > 20% were diarrhea, rash, nail effects, dry skin, and stomatitis, yet the pooled incidence of serious adverse events was less than 2%.
CONCLUSIONS
This meta-analysis suggests that osimertinib has a positive effect in disease control and survival for patients with EGFR-mutated NSCLC with acceptable toxicities.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic
PubMed: 36240432
DOI: 10.1080/0284186X.2022.2132116 -
In Vivo (Athens, Greece) Jan 2017Mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain (TKD) are associated with response and resistance to targeted therapy. The EGFR mutation... (Review)
Review
BACKGROUND
Mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain (TKD) are associated with response and resistance to targeted therapy. The EGFR mutation status in patients with advanced oral and oropharyngeal squamous cell carcinoma (OOSCC) was evaluated. A systematic literature review was undertaken to summarize current evidence and estimate the overall prevalence of EGFR TKD mutations in patients with head and neck squamous cell carcinoma (HNSCC).
MATERIALS AND METHODS
Genomic DNA was extracted from formalin-fixed, paraffin-embedded tumor samples of 113 patients with OOSCC. Pyrosequencing was performed to investigate mutations in EGFR exons 18 to 21. Medline databases were searched for relevant studies. Studies reporting mutations in the EGFR TKD in HNSCC were eligible for inclusion in the systematic review.
RESULTS
No mutations in the EGFR TKD were observed in 113 samples of OOSCC. A total of 53 eligible studies were included in the systematic review. In total, from the review, 117 patients harboring a total of 159 EGFR TKD mutations were reported among 4122 patients with HNSCC. The overall prevalence of EGFR TKD mutations in HNSCC was 2.8%.
CONCLUSION
Large-scale studies are warranted to provide further evidence regarding the mutation status of EGFR in patients with HNSCC.
Topics: Carcinoma, Squamous Cell; ErbB Receptors; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Mutation; Neoplasm Staging; Polymerase Chain Reaction; Prognosis; Retrospective Studies; Survival Rate
PubMed: 28064216
DOI: 10.21873/invivo.11020 -
The Laryngoscope Feb 2014To perform a systematic review of GJB2-associated hearing loss to describe genotype distributions and auditory phenotype. (Review)
Review
OBJECTIVES/HYPOTHESIS
To perform a systematic review of GJB2-associated hearing loss to describe genotype distributions and auditory phenotype.
DATA SOURCES
230 primary studies identified from Pubmed.
REVIEW METHODS
Pubmed was searched systematically to screen broadly for any study reporting on genotype and carrier frequencies for biallelic GJB2-associated hearing loss in defined populations around the world. Genotype and audiometric data were extracted and subjected to meta-analysis to determine genotype distributions, carrier frequencies, rates of asymmetric or progressive hearing loss, and imaging abnormalities.
RESULTS
A total of 216 articles comprising over 43,000 hearing-loss probands were included. The prevalence of biallelic GJB2-associated hearing loss was consistent across most of the 63 countries examined, with different mutations being predominant in different countries. Common mutations were found in greater than 3% of the general population worldwide. Meta-analysis of 48 case-control studies demonstrated a two-fold higher carrier frequency among hearing-impaired individuals compared to normal-hearing controls for truncating alleles, but not V37I. Progression, asymmetry, and imaging abnormalities were present in 14% to 19% of individuals with GJB2-associated hearing loss.
CONCLUSION
GJB2 mutations are highly prevalent around the world. The multiple predominant mutations present in different populations attest to the importance of this gene for normal cochlear function and suggests an evolutionary heterozygote advantage. The unusually high carrier rate for truncating mutations among hearing-impaired individuals is consistent with either the presence of complementary mutations or a carrier phenotype. The significant rate of asymmetry and progression highlights the importance of diagnostic workup and close follow-up for this highly variable condition.
Topics: Connexin 26; Connexins; Genotype; Global Health; Hearing Loss; Humans; Mutation; Phenotype; Prevalence
PubMed: 23900770
DOI: 10.1002/lary.24332 -
Journal Der Deutschen Dermatologischen... Dec 2019Loricrin downregulation has been associated with age-related changes as well as inherited and inflammatory skin diseases. We hypothesize that changes in loricrin could...
Loricrin downregulation has been associated with age-related changes as well as inherited and inflammatory skin diseases. We hypothesize that changes in loricrin could be more related to altered barrier function and consequently disorders that affect epithelial cells, such as psoriasis, atopic dermatitis (AD), erythrokeratoderma, loricrin keratoderma (LK) and periodontitis. The aim of this review is to summarize what is known about the association between loricrin downregulation and epithelial-related disorders (ERDs). A search was performed on the following databases: Medline, Cochrane Library, PubMed, EMBASE, Lilacs, Scopus and Google Scholar, resulting in 16 included articles. Loricrin keratoderma was the ERD most frequently associated with loricrin mutations (730insG, 709insC and 578insG; 5/7 cases - 71.44 %). Atopic dermatitis was the ERD most frequently associated with loricrin downregulation (2/7 cases - 28.6 %). Mutilating palmoplantar keratoderma, progressive symmetrical erythrokeratoderma and a new type of erythrokeratoderma were not associated with any mutations. At the gene level, periodontitis patients showed the highest decrease (-6.89x), followed by AD (-6.5x) and psoriasis patients (-0.5x). In summary, loricrin mutation and downregulation were associated with several ERDs. The diversity in disease presentation is likely related to whether there is a total loss of loricrin, mislocalization and/or if the mutant form of loricrin causes dysfunction of other proteins and/or changes in cornification.
Topics: DNA Mutational Analysis; Down-Regulation; Female; Gene Expression; Humans; Keratosis; Male; Membrane Proteins; Mucous Membrane; Mutation; Psoriasis; RNA, Messenger; Skin Diseases
PubMed: 31846220
DOI: 10.1111/ddg.14001