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Frontiers in Cardiovascular Medicine 2022Mutations in the gene-encoding for the major Ca channel of the heart-may exhibit a variety of clinical manifestations. These include typical or atypical Timothy...
Geno- and phenotypic characteristics and clinical outcomes of gene mutation associated Timothy syndrome, "cardiac only" Timothy syndrome and isolated long QT syndrome 8: A systematic review.
BACKGROUND
Mutations in the gene-encoding for the major Ca channel of the heart-may exhibit a variety of clinical manifestations. These include typical or atypical Timothy syndromes (TS) which are associated with multiple organ manifestations, and cardiac involvement in form of malignant arrhythmias, QTc prolongation, or AV block. "Cardiac only" Timothy syndrome (COTS) shows no extracardiac manifestation, whereas some gene mutations are associated with QTc prolongation alone (isolated long QT syndrome 8, LQT8).
METHODS
A systematic search of the literature reporting cases of gene mutation associated syndromes, including TS, COTS and isolated LQT8 major databases published from 2004 through 2019 was performed. Detailed patient-level phenotypic and genotypic characteristics, as well as long-term outcome measures were collected and compared between pre-specified patient groups, defined both on phenotype and genotype.
RESULTS
A total of 59 TS, 6 COTS, and 20 isolated LQT8 index cases were identified. Apart of syndactyly or baldness, there were no major differences regarding clinical manifestations or outcome measures between TS subtypes, either defining TS subtypes on the genotype or based on the phenotype. Both subtypes were characterized by an extreme degree of QTc prolongation (median ≥600 ms) which were reflected in high major adverse cardiac event rate. On the other hand, there were marked differences between TS, COTS, and isolated LQT8. Timothy syndrome was characterized by a much earlier disease onset, much more pronounced QTc prolongation and much higher mortality rate than COTS or isolated LQT8. Similar differences were observed comparing exon 8/8A vs. non-exon 8/8A mutation carriers. TS showed a high degree of genetic homogeneity, as the p.Gly406Arg mutation either in exon 8 or exon 8A alone was responsible for 70% of the cases.
CONCLUSIONS
Clinical phenotypes associated with mutations in the gene show important clinical differences. Timothy syndrome is associated with the most severe clinical phenotype and with the highest risk of morbidity and mortality. However, distinguishing TS subtypes, in any form, are not supported by our data.
SYSTEMATIC REVIEW REGISTRATION
[https://www.crd.york.ac.uk/prospero/], identifier [CRD42020184737].
PubMed: 36523353
DOI: 10.3389/fcvm.2022.1021009 -
JCO Precision Oncology Aug 2022Non-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers and can be classified... (Meta-Analysis)
Meta-Analysis
PURPOSE
Non-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers and can be classified into three classes according to molecular characteristics. Consensus treatment strategies for class 2 and 3 BRAF mutations have not yet been established.
METHODS
We performed a systematic review and meta-analysis with published reports of individual patients with cancer harboring class 2 or 3 BRAF mutations from 2010 to 2021, to assess treatment outcomes with US Food and Drug Administration-approved mitogen-activated protein kinase (MAPK) pathway targeted therapy (MAPK TT) according to BRAF class, cancer type, and MAPK TT type. Coprimary outcomes were response rate and progression-free survival.
RESULTS
A total of 18,167 studies were screened, identifying 80 studies with 238 patients who met inclusion criteria. This included 167 patients with class 2 and 71 patients with class 3 BRAF mutations. Overall, 77 patients achieved a treatment response. In both univariate and multivariable analyses, response rate and progression-free survival were higher among patients with class 2 compared with class 3 mutations, findings that remain when analyses are restricted to patients with melanoma or lung primary cancers. MEK ± BRAF inhibitors demonstrated greater clinical activity in class 2 compared with class 3 BRAF-mutant tumors than BRAF or EGFR inhibitors.
CONCLUSION
This meta-analysis suggests that MAPK TTs have clinical activity in some class 2 and 3 BRAF-mutant cancers. BRAF class may dictate responsiveness to current and emerging treatment strategies, particularly in melanoma and lung cancers. Together, this analysis provides clinical validation of predictions made on the basis of a mutation classification system established in the preclinical literature. Further evaluation with prospective clinical trials is needed for this population.
Topics: Humans; Lung Neoplasms; Melanoma; Mitogen-Activated Protein Kinases; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; United States
PubMed: 35977349
DOI: 10.1200/PO.22.00107 -
Virus Genes Apr 2022African swine fever virus (ASFV) is the causative agent of African swine fever (ASF). The virus causes an acute highly hemorrhagic disease in domestic pigs, with high... (Review)
Review
African swine fever virus (ASFV) is the causative agent of African swine fever (ASF). The virus causes an acute highly hemorrhagic disease in domestic pigs, with high mortality. Although the overall genome mutation rate of ASFV, a large DNA virus, is relatively low, ASFV exhibits genetic and antigenic diversity. ASFV can be classified into 24 genotypes on the basis of the B646L gene. Cross-protected ASFV strains can be divided into eight serogroups on the basis of antibody-mediated hemadsorption inhibition. Here, we review research progress on ASFV genotyping and serogrouping, and explain how this information assists in the rapid identification of virus origin during ASF outbreaks and will aid in the development of ASF vaccines.
Topics: African Swine Fever; African Swine Fever Virus; Animals; Genotype; Phylogeny; Serogroup; Sus scrofa; Swine
PubMed: 35061204
DOI: 10.1007/s11262-021-01879-0 -
Scientific Reports Sep 2015Many types of KIT mutations have been observed in gastrointestinal stromal tumors (GISTs), but their prognostic and predictive significance are still unclear. A... (Meta-Analysis)
Meta-Analysis Review
Many types of KIT mutations have been observed in gastrointestinal stromal tumors (GISTs), but their prognostic and predictive significance are still unclear. A meta-analysis and literature review were conducted to estimate the contribution of KIT mutations in prognostic parameters and clinic-pathological significance of GISTs. A total of 18 relevant articles from PubMed, EMBASE and Web of Science databases were included in this study. The frequency of KIT mutation was significantly increased in the GIST patients with higher mitosis (≥5/50 high-power fields (HPFs) and larger size (≥5 cm) of tumors than in those with lower MI (≤5/50HPFs) and smaller size (≤5 cm) of GISTs respectively. The rate of KIT mutation was not significantly changed between GISTs in stomachs and in small intestines. KIT mutational status has prognostic significance for patients' outcome. GIST patients with KIT exon 9 mutations have higher risk of progression than those with exon 11 mutations. 5 year relapse-free survival (RFS) rate was significantly higher in patients with KIT exon 11 deletion than in those with other type of KIT exon 11 mutations. The deletion involving KIT exon 11, particularly codons 557-558, is a valuable predictor of prognosis for patients with GISTs.
Topics: Exons; Gastrointestinal Stromal Tumors; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Mutation; Odds Ratio; Prognosis; Proto-Oncogene Proteins c-kit; Receptor, Platelet-Derived Growth Factor alpha; Risk
PubMed: 26349547
DOI: 10.1038/srep13718 -
BMC Cancer Nov 2023RAS mutations affect prognosis in patients with metastatic colorectal cancer (mCRC) and have been identified as strong negative predictive markers for anti-epidermal... (Meta-Analysis)
Meta-Analysis
BACKGROUND
RAS mutations affect prognosis in patients with metastatic colorectal cancer (mCRC) and have been identified as strong negative predictive markers for anti-epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb) therapy, but many tumors containing wild-type RAS genes still do not respond to these therapies. Some additional biomarkers may have prognostic or predictive roles, but conclusions remain controversial.
METHODS
We performed a meta-analysis and systematic review of randomized controlled trials comparing anti-EGFR mAb therapy with alternative therapy that investigated the prognostic and predictive impact of additional biomarkers in RAS wild-type (wt) mCRC patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) and odds ratios (ORs) for objective response rate (ORR) were calculated. The prognostic value of biomarkers was investigated by separately pooling HR and OR for different treatment groups in an individual study. The predictive value was assessed by pooling study interactions between treatment effects and biomarker subgroups.
RESULTS
Thirty publications reporting on eighteen trials were selected, including a total of 13,507 patients. In prognostic analysis, BRAF mutations were associated with poorer PFS [HRs = 3.76 (2.47-5.73) and 2.69 (1.82-3.98)] and OS [HRs = 2.66 (1.95-3.65) and 2.45 (1.55-3.88)] in both the experimental and control arms; low miR-31-3p expression appeared to have longer PFS and OS. In terms of predictive effect, a lack of response to anti-EGFR therapy was observed in patients with BRAF mutant tumors (P < 0.01 for PFS). Patients with tumors with any mutation in the KRAS/NRAS/BRAF/PIK3CA gene also showed similar results compared with all wild-type tumors (P for PFS, OS, and ORR were < 0.01, < 0.01 and 0.01, respectively). While low miR-31-3p expression could predict PFS (P = 0.01) and OS (P = 0.04) benefit. The prognostic and predictive value regarding PIK3CA mutations, PTEN mutations or deletions, EGFR, EREG/AREG, HER2, HER3, and HER4 expression remains uncertain.
CONCLUSIONS
In RAS wt mCRC patients receiving EGFR-targeted therapy, BRAF mutation is a powerful prognostic and therapy-predictive biomarker, with no effect found for PIK3CA mutation, PTEN mutation or deletion, but the combined biomarker KRAS/NRAS/BRAF/PIK3CA mutations predict resistance to anti-EGFR therapy. Low miR-31-3p expression may have positive prognostic and therapy predictive effects. Evidence on the prognostic and predictive roles of EGFR and its ligands, and HER2/3/4 is insufficient.
Topics: Humans; Prognosis; Proto-Oncogene Proteins B-raf; Colorectal Neoplasms; Proto-Oncogene Proteins p21(ras); ErbB Receptors; Antibodies, Monoclonal; Colonic Neoplasms; Rectal Neoplasms; Biomarkers; Class I Phosphatidylinositol 3-Kinases; Mutation; MicroRNAs; Biomarkers, Tumor
PubMed: 37974093
DOI: 10.1186/s12885-023-11600-z -
Blood Coagulation & Fibrinolysis : An... Jul 2016Distribution of hereditary thrombophilic gene mutations differs globally. Prothrombin gene mutation G20210A is a common prothrombotic single-nucleotide polymorphism. In... (Review)
Review
Distribution of hereditary thrombophilic gene mutations differs globally. Prothrombin gene mutation G20210A is a common prothrombotic single-nucleotide polymorphism. In this systematic review, we provide a comprehensive report of the prevalence of prothrombin G20210A across the globe. Databases [Pubmed, Web of Science, Embase] were interrogated from their inception through December 2015 for articles reporting prothrombin G20210A prevalence rates and ethnicity. Prevalence rates were organized by continent and ethnoracial ancestry. A total of 113 articles were included with a total 61 876 participants tested for prothrombin G20210A. Reported prevalence rates varied from 0 to 15.9% among ethnic groups, with higher rates seen in the thromboembolism affected cohort compared with the unaffected cohort. Carrier rate distribution is supported by known historical migration patterns of global populations. This review of prothrombin G20210A prevalence may guide resourceful screening for identification of hereditary thrombophilia in female populations of interest with hypercoagulable states.
Topics: Asian People; Black People; Female; Gene Expression; Global Health; Heterozygote; Humans; Mutation Rate; Polymorphism, Single Nucleotide; Prevalence; Prothrombin; Thrombophilia; Venous Thromboembolism; White People; Women's Health
PubMed: 27058219
DOI: 10.1097/MBC.0000000000000562 -
Prostate Cancer and Prostatic Diseases Dec 2023The goal of precision medicine in prostate cancer (PCa) is to individualize the treatment according to the patient's germline mutation status. PCa has a very high rate... (Review)
Review
BACKGROUND
The goal of precision medicine in prostate cancer (PCa) is to individualize the treatment according to the patient's germline mutation status. PCa has a very high rate of genetic predisposition compared with other cancers in men, with an estimated rate of cancers ascribable to hereditary factors of 5-15%.
METHODS
A systematic search (PubMed, Web of Science, and ClinicalTrials.gov) of English literature from 2000 to 2022, using the keywords "prostate cancer", "germline mutations", "family history", and "inheritance" was conducted, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.
RESULTS
The search identified 980 publications. Of these, 200 papers were removed before screening (duplicates, non-English literature, and publication year before 2000) and 245 records were excluded after title/abstract screening. Finally, 50 articles were included in the final analysis. We analyze the latest evidence on the genetic basis of PCa predisposition and clinical implications for more personalized screening protocols and therapeutic management of this high-prevalent cancer.
DISCUSSION
Emerging data show that germline mutations in homologous recombination genes (BRCA1/2, ATM, CHECK2), in mismatch repair genes (MLH1, MLH2, MSH6), and other additional genes are associated with the development and aggressiveness of PCa. Germline testing and genetic counseling have increasingly important implications in cancer screening and therapeutic decisions making for patients affected by PCa. Patients with localized PCa and some gene mutations are more likely to develop aggressive cancer, so active treatment may be preferable to active surveillance for these patients. Moreover, in patients with metastatic PCa, these gene alterations may be useful biomarkers for predicting response to specific therapy such as PARP inhibitors, recently approved for the treatment of metastatic castration-resistant PCa. The evidence supports recent guidelines and recommendations considering germline genetic testing for patients with a positive family history of PCa or men with high risk or metastatic disease.
Topics: Male; Humans; Prostatic Neoplasms; Germ-Line Mutation; BRCA1 Protein; Precision Medicine; BRCA2 Protein
PubMed: 36434163
DOI: 10.1038/s41391-022-00609-3 -
Journal of Research in Medical Sciences... Mar 2015BRCA1/2 genes mutation prevalence varies among ethnic groups and may be influenced by founder mutations. Understanding BRCA1/2 genes mutations is important for reducing... (Review)
Review
BACKGROUND
BRCA1/2 genes mutation prevalence varies among ethnic groups and may be influenced by founder mutations. Understanding BRCA1/2 genes mutations is important for reducing breast cancer (BC) incidence, accurate risk assessment and counseling. This systematic review of the literature was conducted to addressing BRCA1/2 mutations in Iranian BC patients.
MATERIALS AND METHODS
A search for relevant articles was run on before January 2014 using MedLine, PubMed, Science Iranian Database, Google, and Web sites related to the study topic. The key words included: BC and Iran with Genes, BRCA Genes, BRCA1 and BRCA2; "Cancer Genes," and "Iran."
RESULTS
Thirteen articles retrieved from this search strategy were eligible for this review. The overall BRCA1 mutation rate for Iranian female BC patients was detected 31.8% (377/1183). Although this gene mutation rate for male patients is <0.01%. Eight BRCA1 mutations (c. 4837A > G, c. 3419G > A, c. 3119G > A, c. 2612C > T, c. 3113A > G, c. 2311T > C, c. 4301T > C and c. 4308T > C in BRCA1, and one BRCA2 mutation (c. 6494G > C) were found in multiple case subjects and represent candidate founder mutations.
CONCLUSION
According to these studies, there is heterogeneity in BRCA mutations in Iranian BC patients.
PubMed: 26109977
DOI: No ID Found -
Frontiers in Oncology 2022In non-small cell lung cancer (NSCLC) patients treated by immune checkpoint inhibitors (ICIs), tumor mutation burden (TMB) has been found to have predictive potential...
Predictive Efficacy of Blood-Based Tumor Mutation Burden Assay for Immune Checkpoint Inhibitors Therapy in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.
BACKGROUND
In non-small cell lung cancer (NSCLC) patients treated by immune checkpoint inhibitors (ICIs), tumor mutation burden (TMB) has been found to have predictive potential for survival. When compared to TMB detection in tissue (tTMB), detecting TMB in the blood (bTMB) has practical advantages; yet, the results of various studies are conflicting. The question of whether bTMB can be utilized as a predictive biomarker is becoming increasingly contentious. To confirm the predictive efficacy of bTMB, researchers did a systematic review and meta-analysis to look into the relationship between ICIs and bTMB.
METHOD
From the inception to March 2021, Cochrane Library, PubMed, EMBASE and other databases were systematically searched. The predictive value of bTMB in ICIs, or the efficacy of ICIs against chemotherapy, was studied. The results were presented as pooled ratio rate (RR) and hazard ratio (HR) with 95% confidence intervals for the Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Subgroup analysis, heterogeneity analyses, and sensitivity analysis were also performed.
RESULTS
A total of 2,610 NSCLC patients were studied in seven trials. There were no significant differences in OS (HR = 1.09; 95% CI: 0.62-1.91, = 0.774) or PFS (HR = 0.73; 95% CI: 0.20-2.65, = 0.629) between high and low bTMB groups in the ICIs cohort. When ICIs were compared to chemotherapy, ICIs were found to enhance OS (HR = 0.74; 95% CI: 0.59-0.92, = 0.006), but the improvement in PFS and ORR was only a numerical trend (PFS: HR = 0.83; 95% CI: 0.63-1.09, = 0.173; ORR: RR = 0.92, 95% CI: 0.77-1.10, = 0.372). NSCLC patients treated with ICIs in the high bTMB group had better survival benefits than chemotherapy patients in terms of OS (HR = 0.63; 95% CI: 0.51-0.76, 0.001), PFS (HR = 0.63; 95% CI: 0.52-0.76, 0.001), and ORR (RR = 1.86; 95% CI: 1.32-2.62, 0.001), while in the low TMB group, the results were no different or even reversed (OS: HR = 0.89; 95% CI: 0.64-1.24, = 0.485; PFS: HR = 1.21, 95% CI: 0.93-1.58, = 0.154; ORR: RR = 0.68, 95% CI: 0.54-0.85, = 0.001).
CONCLUSIONS
TMB could predict the enhanced survival benefit of NSCLC patients treated with ICIs; however the role of bTMB is limited at this stage. For NSCLC patients with high TMB, ICIc may be a better option than chemotherapy.
PubMed: 35223476
DOI: 10.3389/fonc.2022.795933 -
Journal of Gastroenterology and... Jun 2015A number of studies have confirmed that antiviral therapy with nucleotide analogs (NAs) can improve the prognosis of hepatitis B virus (HBV)-related hepatocellular... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIMS
A number of studies have confirmed that antiviral therapy with nucleotide analogs (NAs) can improve the prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative therapy. However, what factors affected the prognosis of HBV-HCC after removal of the primary tumor and inhibition of HBV replication? A meta-regression analysis was conducted to explore the prognostic factor for this subgroup of patients.
METHODS
MEDLINE, EMBASE, Web of Science, and Cochrane library were searched from January 1995 to February 2014 for clinical trials evaluating the effect of NAs on the prognosis of HBV-HCC after curative therapy. Data were extracted for host, viral, and intervention information. Single-arm meta-analysis was performed to assess overall survival (OS) rates and HCC recurrence. Meta-regression analysis was carried out to explore risk factors for 1-year OS rate and HCC recurrence for HBV-HCC patients after curative therapy and antiviral therapy.
RESULTS
Fourteen observational studies with 1284 patients met the inclusion criteria. Influential factors for prognosis of HCC were mainly baseline HBeAg positivity, cirrhotic stage, advanced Tumor-Node-Metastasis (TNM) stage, macrovascular invasion, and antiviral agent type. The 1-year OS rate decreased by more than four times (coefficient -4.45, P<0.001) and the 1-year HCC recurrence increased by more than one time (coefficient 1.20, P=0.003) when lamivudine was chosen for HCC after curative therapy, relative to entecavir for HCC.
CONCLUSIONS
HBV mutation may play a role in HCC recurrence. Entecavir or tenofovir, a high genetic barrier to resistance, should be recommended for HBV-HCC patients.
Topics: Antiviral Agents; Carcinoma, Hepatocellular; Combined Modality Therapy; Databases, Bibliographic; Female; Guanine; Hepatitis B; Hepatitis B virus; Humans; Liver Neoplasms; Male; Middle Aged; Mutation; Neoplasm Recurrence, Local; Prognosis; Regression Analysis; Tenofovir
PubMed: 25689418
DOI: 10.1111/jgh.12917