Panel Of Candidate Genes Research Articles

Exploring the Impact of Genetics in a Large Cohort of Moebius Patients by Trio Whole Exome Sequencing.

Moebius syndrome (MBS) is a rare congenital disorder characterized by non-progressive facial palsy and ocular abduction paralysis. Most cases are sporadic, but also rare familial cases with autosomal dominant transmission and incomplete penetrance/variable expressivity have been described. The genetic etiology of MBS is still unclear: de novo pathogenic variants in REV3L and PLXND1 are reported in only a minority of cases, suggesting the involvement of additional causative genes. With the aim to uncover the molecular causative defect and identify a potential genetic basis of this condition, we performed trio-WES on a cohort of 37 MBS and MBS-like patients. No de novo variants emerged in REV3L and PLXND1. We then proceeded with a cohort analysis to identify possible common causative genes among all patients and a trio-based analysis using an in silico panel of candidate genes. However, identified variants emerging from both approaches were considered unlikely to be causative of MBS, mainly due to the lack of clinical overlap. In conclusion, despite this large cohort, WES failed to identify mutations possibly associated with MBS, further supporting the heterogeneity of this syndrome, and suggesting the need for integrated omics approaches to identify the molecular causes underlying MBS development.

The "extreme phenotype approach" applied to male breast cancer allows the identification of rare variants of ATR as potential breast cancer susceptibility alleles.

In oncogenetics, some patients could be considered as "extreme phenotypes", such as those with very early onset presentation or multiple primary malignancies, unusually high numbers of cancers of the same spectrum or rare cancer types in the same parental branch. For these cases, a genetic predisposition is very likely, but classical candidate gene panel analyses often and frustratingly remains negative. In the framework of the EX2TRICAN project, exploring unresolved extreme cancer phenotypes, we applied exome sequencing on rare familial cases with male breast cancer, identifying a novel pathogenic variant of ATR (p.Leu1808*). ATR has already been suspected as being a predisposing gene to breast cancer in women. We next identified 3 additional ATR variants in a cohort of both male and female with early onset and familial breast cancers (c.7762-2A>C; c.2078+1G>A; c.1A>G). Further molecular and cellular investigations showed impacts on transcripts for variants affecting splicing sites and reduction of ATR expression and phosphorylation of the ATR substrate CHEK1. This work further demonstrates the interest of an extended genetic analysis such as exome sequencing to identify very rare variants that can play a role in cancer predisposition in extreme phenotype cancer cases unexplained by classical cancer gene panels testing.

Dementia-related genetic variants in an Italian population of early-onset Alzheimer's disease.

Early-onset Alzheimer’s disease (EOAD) is the most common form of early-onset dementia. Although three major genes have been identified as causative, the genetic contribution to the disease remains unsolved in many patients. Recent studies have identified pathogenic variants in genes representing a risk factor for developing Alzheimer’s disease (AD) and in causative genes for other degenerative dementias as responsible for EOAD. To study them further, we investigated a panel of candidate genes in 102 Italian EOAD patients, 45.10% of whom had a positive family history and 21.74% with a strong family history of dementia. We found that 10.78% of patients carried pathogenic or likely pathogenic variants, including a novel variant, in PSEN1, PSEN2, or APP, and 7.84% showed homozygosity for the ε4 APOE allele. Additionally, 7.84% of patients had a moderate risk allele in PSEN1, PSEN2, or TREM2 genes. Besides, we observed that 12.75% of our patients carried only a variant in genes associated with other neurodegenerative diseases. The combination of these variants contributes to explain 46% of cases with a definite familiarity and 32% of sporadic forms. Our results confirm the importance of extensive genetic screening in EOAD for clinical purposes, to select patients for future treatments and to contribute to the definition of overlapping pathogenic mechanisms between AD and other forms of dementia.

TBIO-01. Mutation Profiling of Paediatric Solid Tumours in a Cohort of South African Patients

BACKGROUND: The incidence of childhood cancer incidence is increasing gradually in low-middle income countries, such as South Africa. Globally, there is an extensive range of familial- and hereditary-cancer syndromes, where underlying germline variants increase the likelihood of developing cancer in childhood. Next-Generation Sequencing (NGS) technologies have been key in determining the occurrence and genetic contribution of germline variants to paediatric cancer development. We aimed to design and evaluate a candidate gene panel, specific to inherited cancer-predisposing genes to provide a comprehensive insight into the contribution of germline variants to childhood cancer. METHODS: 32 paediatric patients (aged 0-18 years) diagnosed with a malignant tumour were recruited and biological samples were obtained. After quality control, DNA was sequenced using an ion Ampliseq 50 candidate gene panel design and Ion Torrent S5 technologies. Sequencing variants were called using Ion Torrent Suite software and were subsequently annotated using Ion Reporter and Ensembl's VEP. High priority variants were manually analysed using tools such as MutationTaster, SIFT-INDEL and VarSome. Putative identified candidates were validated via Sanger Sequencing. RESULTS: The patients studied had a variety of cancers, the most common being nephroblastoma (13), followed by osteosarcoma (4) and astrocytoma (3). We identified 10 pathogenic / likely pathogenic variants in 10 patients, most of which were novel. CONCLUSIONS: According to literature, we expected ~10% of our patient population to harbour pathogenic or likely pathogenic germline variants, however we reported about 3 times (~30%) more than we expected. Majority of the identified variants are novel; this may be because this is the first study of its kind in an understudied South African population

Panel of Candidate Genes to Predict the Survival of Patients with Clear Cell Renal Cancer on the Basis of Gene Expression Regulated by HIF1α/HIF2α.

The detection of genes related to the lifetime of patients with clear cell renal cancer provides information on the mechanisms of the tumor development and can be the basis for creating approaches to predict patient survival. In this paper, the expression of genes regulated by the HIF2α transcriptional factor was studied. Based on the results obtained here and previously identified genes regulated by the transcriptional factor HIF1α, a new panel of 6 genes, including the BAP1 gene, was proposed. Expression of genes of this panel allows predicting the survival of patients with clear cell renal cancer with high sensitivity (93%), specificity (96%), and relative risk (21.5). After verification, the application of this panel can be useful for personalized treatment of patients with clear cell renal cancer, which will increase the effectiveness of therapy.

Bioinformatics screening the novel and promising targets of curcumin in hepatocellular carcinoma chemotherapy and prognosis

BackgroundThe aim of present study was to screen the novel and promising targets of curcumin in hepatocellular carcinoma diagnosis and chemotherapy.MethodsPotential targets of curcumin were screened from SwissTargetPrediction, ParmMapper and drugbank databases. Potential aberrant genes of hepatocellular carcinoma were screened from Genecards databases. Fifty paired hepatocellular carcinoma patients’ gene expression profiles from the GEO database were used to test potential targets of curcumin. Besides, GO analysis, KEGG pathway enrichment analysis and PPI network construction were used to explore the underlying mechanism of candidate hub genes. ROC analysis and Kaplan-Meier analysis were used to evaluate the diagnostic and prognostic value of candidate hub genes, respectively. Real-time PCR was used to verify the results of bioinformatics analysis.ResultsBioinformatics analysis results suggested that AURKA, CDK1, CCNB1, TOP2A, CYP2B6, CYP2C9, and CYP3A4 genes served as candidate hub genes. AURKA, CDK1, CCNB1 and TOP2A were significantly upregulated and correlated with poor prognosis in hepatocellular carcinoma, AUC values of which were 95.7, 96.9, 98.1 and 96.1% respectively. There was not significant correlation between the expression of CYP2B6 and prognosis of hepatocellular carcinoma, while CYP2C9 and CYP3A4 genes were significantly downregulated and correlated with poor prognosis in hepatocellular carcinoma. AUC values of CYP2B6, CYP2C9, and CYP3A4 were 96.0, 97.0 and 88.0% respectively. In vitro, we further confirmed that curcumin significantly downregulated the expression of AURKA, CDK1, and TOP2A genes, while significantly upregulated the expression of CYP2B6, CYP2C9, and CYP3A4 genes.ConclusionsOur results provided a novel panel of AURKA, CDK1, TOP2A, CYP2C9, and CYP3A4 candidate genes for curcumin related chemotherapy of hepatocellular carcinoma.

Tissue sensitivity to thyroid hormones may change over time.

IntroductionPatients with congenital hypothyroidism (CH) may transiently show a certain degree of pituitary resistance to levothyroxine (LT4) which, however, normalizes subsequently. However, in some individuals, thyroid-stimulating hormone (TSH) fails to normalize despite adequate LT4 treatment.MethodsNine patients with CH followed in three Academic Centre who developed over time resistance to thyroid hormones underwent extensive biochemical and genetic analyses. These latter were performed by Sanger sequence or targeted next-generation sequencing technique including a panel of candidate genes involved in thyroid hormone actions and congenital hypothyroidism (CH): THRA, THRB, DIO1, DIO2, SLC16A2, SECISBP2, DUOX2, DUOXA2, FOXE1, GLIS3, IYD, JAG1, NKX2-1, NKX2- 5, PAX8, SLC26A4, SLC5A5, TG, TPO, TSHR.ResultsAll patients displayed a normal sensitivity to thyroid hormone (TH) in the first years of life but developed variable degrees of resistance to LT4 treatment at later stages. In all cases, TSH normalized only in the presence of high free thyroxine levels. Tri-iodothyronine suppression test followed by thyrotrophin-releasing hormone stimulation was performed in two cases and was compatible with central resistance to THs. This biochemical feature was present independently on the cause of CH, being observed either in patients with an ectopic (n = 2) or eutopic gland (n = 3) or in case of athyreosis (n = 1). None of the patients had genetic variants in genes involved in the regulation of TH actions, while in two cases, we found two double heterozygous missense variants in TSHR and GLIS3 or in DUOX2 and SLC26A4 genes, respectively.ConclusionsWe report CH patients who showed an acquired and unexplainable pituitary refractoriness to TH action.

Comparative proteomic analysis of nuclear and cytoplasmic compartments in human cardiac progenitor cells

Clinical trials evaluating cardiac progenitor cells (CPC) demonstrated feasibility and safety, but no clear functional benefits. Therefore a deeper understanding of CPC biology is warranted to inform strategies capable to enhance their therapeutic potential. Here we have defined, using a label-free proteomic approach, the differential cytoplasmic and nuclear compartments of human CPC (hCPC). Global analysis of cytoplasmic repertoire in hCPC suggested an important hypoxia response capacity and active collagen metabolism. In addition, comparative analysis of the nuclear protein compartment identified a significant regulation of a small number of proteins in hCPC versus human mesenchymal stem cells (hMSC). Two proteins significantly upregulated in the hCPC nuclear compartment, IL1A and IMP3, showed also a parallel increase in mRNA expression in hCPC versus hMSC, and were studied further. IL1A, subjected to an important post-transcriptional regulation, was demonstrated to act as a dual-function cytokine with a plausible role in apoptosis regulation. The knockdown of the mRNA binding protein (IMP3) did not negatively impact hCPC viability, but reduced their proliferation and migration capacity. Analysis of a panel of putative candidate genes identified HMGA2 and PTPRF as IMP3 targets in hCPC. Therefore, they are potentially involved in hCPC proliferation/migration regulation.

High Level of Staufen1 Expression Confers Longer Recurrence Free Survival to Non-Small Cell Lung Cancer Patients by Promoting THBS1 mRNA Degradation.

Stau1 is a pluripotent RNA-binding protein that is responsible for the post-transcriptional regulation of a multitude of transcripts. Here, we observed that lung cancer patients with a high Stau1 expression have a longer recurrence free survival. Strikingly, Stau1 did not impair cell proliferation in vitro, but rather cell migration and cell adhesion. In vivo, Stau1 depletion favored tumor progression and metastases development. In addition, Stau1 depletion strongly impaired vessel maturation. Among a panel of candidate genes, we specifically identified the mRNA encoding the cell adhesion molecule Thrombospondin 1 (THBS1) as a new target for Staufen-mediated mRNA decay. Altogether, our results suggest that regulation of THBS1 expression by Stau1 may be a key process involved in lung cancer progression.

Genome-wide selection signatures detection in Shanghai Holstein cattle population identified genes related to adaption, health and reproduction traits

BackgroundOver several decades, a wide range of natural and artificial selection events in response to subtropical environments, intensive pasture and intensive feedlot systems have greatly changed the customary behaviour, appearance, and important economic traits of Shanghai Holstein cattle. In particular, the longevity of the Shanghai Holstein cattle population is generally short, approximately the 2nd to 3rd lactation. In this study, two complementary approaches, integrated haplotype score (iHS) and runs of homozygosity (ROH), were applied for the detection of selection signatures within the genome using genotyping by genome-reduced sequence data from 1092 cows.ResultsIn total, 101 significant iHS genomic regions containing selection signatures encompassing a total of 256 candidate genes were detected. There were 27 significant |iHS| genomic regions with a mean |iHS| score > 2. The average number of ROH per individual was 42.15 ± 25.47, with an average size of 2.95 Mb. The length of 78 % of the detected ROH was within the range of 1–2 MB and 2–4 MB, and 99 % were shorter than 8 Mb. A total of 168 genes were detected in 18 ROH islands (top 1 %) across 16 autosomes, in which each SNP showed a percentage of occurrence > 30 %. There were 160 and 167 genes associated with the 52 candidate regions within health-related QTL intervals and 59 candidate regions within reproduction-related QTL intervals, respectively. Annotation of the regions harbouring clustered |iHS| signals and candidate regions for ROH revealed a panel of interesting candidate genes associated with adaptation and economic traits, such as IL22RA1, CALHM3, ITGA9, NDUFB3, RGS3, SOD2, SNRPA1, ST3GAL4, ALAD, EXOSC10, and MASP2. In a further step, a total of 1472 SNPs in 256 genes were matched with 352 cis-eQTLs in 21 tissues and 27 trans-eQTLs in 6 tissues. For SNPs located in candidate regions for ROH, a total of 108 cis-eQTLs in 13 tissues and 4 trans-eQTLs were found for 1092 SNPs. Eighty-one eGenes were significantly expressed in at least one tissue relevant to a trait (P value < 0.05) and matched the 256 genes detected by iHS. For the 168 significant genes detected by ROH, 47 gene-tissue pairs were significantly associated with at least one of the 37 traits.ConclusionsWe provide a comprehensive overview of selection signatures in Shanghai Holstein cattle genomes by combining iHS and ROH. Our study provides a list of genes associated with immunity, reproduction and adaptation. For functional annotation, the cGTEx resource was used to interpret SNP-trait associations. The results may facilitate the identification of genes relevant to important economic traits and can help us better understand the biological processes and mechanisms affected by strong ongoing natural or artificial selection in livestock populations.

A kaleidoscopic view of ovarian genes associated with premature ovarian insufficiency and senescence.

Ovarian infertility and subfertility presenting with premature ovarian insufficiency (POI) and diminished ovarian reserve are major issues facing the developed world due to the trend of delaying childbirth. Ovarian senescence and POI represent a continuum of physiological/pathophysiological changes in ovarian follicle functions. Based on advances in whole exome sequencing, evaluation of gene copy variants, together with family-based and genome-wide association studies, we discussed genes responsible for POI and ovarian senescence. We used a gene-centric approach to sort out literature deposited in the Ovarian Kaleidoscope database (http://okdb.appliedbioinfo.net) by sub-categorizing candidate genes as ligand-receptor signaling, meiosis and DNA repair, transcriptional factors, RNA metabolism, enzymes, and others. We discussed individual gene mutations found in POI patients and verification of gene functions in gene-deleted model organisms. Decreased expression of some of the POI genes could be responsible for ovarian senescence, especially those essential for DNA repair, meiosis and mitochondrial functions. We propose to set up a candidate gene panel for targeted sequencing in POI patients together with studies on mitochondria-associated genes in middle-aged subfertile patients.

Screening by single-molecule molecular inversion probes targeted sequencing panel of candidate genes of infertility in azoospermic infertile Jordanian males

Infertility is a common health problem that affects around 1 in 6 couples in the United States, where half of these cases are attributed to male factors. Genetics play an important role in infertility and it is estimated that up to 50% of cases are due to genetic factors. Despite this, many male infertility cases are still idiopathic. This study aimed to identify the presence of possibly pathogenic rare variants in a set of candidate genes related to azoospermia in 69 Jordanian men using a next-generation sequencing-based panel covering more than a hundred male infertility related genes. A total of 9 variants were found and validated. Among them, two variants included reported pathogenic variants in CFTR and one novel pathogenic variant in the USP9Y gene. We also report the detection of 6 other variants with uncertain significance in other genes. Interestingly, male cases with CFTR variants did not show the expected cystic fibrosis phenotypes except for infertility. This work helps to uncover the contribution of additional genetic factors to the aetiology of male infertility and highlights the importance to obtain more reliable information about the presence of genetic variation in the Jordanian population.

The Population Diversity of Candidate Genes for Resistance/Susceptibility to Coronavirus Infection in Domestic Cats: An Inter-Breed Comparison.

Feline coronavirus (FCoV) is a complex pathogen causing feline infectious peritonitis (FIP). Host genetics represents a factor contributing to the pathogenesis of the disease. Differential susceptibility of various breeds to FIP was reported with controversial results. The objective of this study was to compare the genetic diversity of different breeds on a panel of candidate genes potentially affecting FCoV infection. One hundred thirteen cats of six breeds were genotyped on a panel of sixteen candidate genes. SNP allelic/haplotype frequencies were calculated; pairwise FST and molecular variance analyses were performed. Principal coordinate (PCoA) and STRUCTURE analyses were used to infer population structure. Interbreed differences in allele frequencies were observed. PCoA analysis performed for all genes of the panel indicated no population substructure. In contrast to the full marker set, PCoA of SNP markers associated with FCoV shedding (NCR1 and SLX4IP) showed three clusters containing only alleles associated with susceptibility to FCoV shedding, homozygotes and heterozygotes for the susceptibility alleles, and all three genotypes, respectively. Each cluster contained cats of multiple breeds. Three clusters of haplotypes were identified by PCoA, two clusters by STRUCTURE. Haplotypes of a single gene (SNX5) differed significantly between the PCoA clusters.

Prevalence of hereditary factors in different age groups in patients with acute coronary syndrome

BACKGROUND: Genetic factors are essential for the pathogenesis of coronary heart disease (CHD). This study presents the role of genetic factors in a prematurely developing disease in males under 55 years old and females under 60 years old. Additionally, genetic risk factors may also be significant for CHD development in other age groups although specific genetic factors may differ.&#x0D; AIM: The work aimed to analyze the prevalence of hereditary genetic factors in different age groups in patients with coronary heart disease.&#x0D; MATERIALS AND METHODS: The study was conducted as part of the analysis of data from two observational multicenter Russian studies of acute coronary syndrome (ACS) ORACUL I (1193 patients) and ORACUL II (1803 patients) (the study was registered on ClinicalTrials.gov with an ID number NCT04068909). The average age of patients was 63.512.45 years (1875 men and 1121 women). The study of a panel of candidate genes was performed using the polymerase chain reaction method.&#x0D; RESULTS: In order to analyze the significance of hereditary factors in patients of different ages, groups of patients with early development of CHD (men under 55 years old, women under 60 years old) were formed (n=828). The middle-aged group included men aged 5574 years and women aged 6074 years (n=1410). The older age group consisted of patients aged 75 years and older (n=602). In the group of patients with early onset coronary heart disease, the proportion of patients with aggravated heredity was higher. In the older age group, the proportion of patients with non-burdened or unknown heredity was higher. Significant differences in the frequencies of alleles and genotypes of the polymorphic variants studied by us were revealed only for the G-2667C variant of the CRP gene (the frequency of the GG genotype was 87.3% in young patients and 77.2% in the elderly and old patients (p=0.007) and for the C804A variant of the LTA gene (frequency of the CC genotype was 52 0% in young patients, 49.4% in middle-aged patients, and 34.2% in elderly and old patients, p=0.026).&#x0D; CONCLUSIONS: A burdened family history is more common among patients with early onset coronary artery disease. The differences revealed in the frequencies of genetic variants of genes encoding anti-inflammatory cytokines may indicate their role in the pathogenesis of coronary heart disease in older individuals.

Outcomes of post mortem genetic diagnosis in SCD victims and primary prevention of cardiac arrest in relatives: a nationwide multidisciplinary and multicentric collaboration in the Czechia

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Supported by Ministry of Health of the Czech Republic Introduction Post mortem genetic analysis in sudden cardiac death (SCD) represents an important diagnostic tool for the primary prevention of cardiac arrest in victim´s relatives. Purpose To assess the underlying molecular pathogenesis of SCD in a representative Czech cohort and to evaluate the effects of primary prevention of SCD in genetic relatives. Patients and Methods Between 2016 and 2020 we have ascertained 100 SCD cases (29 females/71 males; age range 0-52 years). According to autopsy protocols, cases with SCD were divided into categories of sudden arrhythmic death (SADS), sudden unexplained death (in infants; SUD/SUDI), thoracic aortic aneurysm/dissection and cardiomyopathy hypertrophic, arrhythmic, dilated (HCM, ACM, DCM) and sudden infant death syndrome (SIDS). DNA was isolated from post mortem biopsies / relatives blood and subjected to massively parallel sequencing (Illumina, USA) comprising custom-made candidate gene panel (100 genes). Genetic counselling and cardiological examinations were carried out in 245 family members. Results According to post mortem-established diagnosis, we identified 20 victims with SADS and SUD/SUDI, 11 with HCM and DCM, 19 with ACMG, 8 SIDS cases and 9 acute dissection cases. Most of victims died at sleep or at rest, while only 10/100 victims died during strenuous sport activities. About 50% of SCD victims did not report any apparent cardiac complaints. Highly likely or certain molecular etiology (i.e. based on presence of ACMG.net Class 4 to 5 variants) was disclosed in 19/100 (19%) in RYR2, KCNH2, SCN5A, FLNC (stop), TTN, RBM 20, LMNA/C, PRKAG2, MYBPC3, DSC2, FHL1, TGFBR1 and Col3A1 genes (see Tab). Finally, we identified 52/241 phenotype/genotype positive family members who are at risk of cardiac arrest and were offered corresponding cardiological care. Conclusion Multidisciplinary cooperation, together with centralized and standardized molecular genetic testing, enables the primary prevention of cardiac arrest in relatives of SCD victims. Results of post mortem genetic analysis Post mortem diagnosis Nr. Gender Age (years) Nr. of positive cases (DNA variant class IV or V) Gene Nr. examined relatives/phenotype or genotype positive cases SADS 20 8 females12 males 3-52 5/20 (25%) KCNH2 3x RYR2RANGFR 56/11 SUD/SUDI 20 5 females, 15 males 0-50 1/18 (5%, 2 non informative cases) RYR2 45/9 HCM 11 0 females11 males 14-52 3/11 (27%) MYBPC3FHL1PRKAG2 26/9 DCM 11 3 females8 males 8-48 4/11 (36%) TTN (3x)RBM 20FLNC (stop) 24/7 ACM 19 9 females10 males 17 - 49 4/19 (21%) SCN5AFLNC (stop)DSC2LMNA/C 58/9 SIDS 8 3 females5 males &amp;lt; 1 0/8 - 12/0 Acute dissection 9 1 female8 males 16-49 2/9 (22%) TGFBR1Col3A1 24/7

Whole-exome sequencing identifies two novel ALMS1 mutations in Indian patients with Leber congenital amaurosis

Leber congenital amaurosis (LCA) is a severe autosomal recessive retinal degenerative disease. The current study describes exome sequencing results for two unrelated Indian LCA patients carrying novel nonsense p.(Glu636*) and frameshift p.(Pro2281Leufs*63) mutations in the ALMS1 gene. Although ALMS1 gene mutations are associated with Alstrom syndrome (AS), the current patients did not exhibit typical syndromic features of AS. These data suggest that ALMS1 should be included in the candidate gene panel for LCA to improve diagnostic efficiency.

An integrated approach for identification of a panel of candidate genes arbitrated for invasion and metastasis in oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is known for its aggressiveness associated with poor prognosis. The molecular mechanisms underlying the invasion and metastasis are still poorly understood. An improved understanding of these mechanisms shall precede the development of new diagnostic tools and targeted therapies. We report an integrated approach using bioinformatics to predict candidate genes, coupled with proteomics and immunohistochemistry for validating their presence and involvement in OSCC pathways heralding invasion and metastasis. Four genes POSTN, TNC, CAV1 and FSCN1 were identified. A protein–protein interaction network analysis teamed with pathway analysis led us to propose the role of the identified genes in invasion and metastasis in OSCC. Further analyses of archived FFPE blocks of various grades of oral cancer was carried out using TMT-based mass spectrometry and immunohistochemistry. Results of this study expressed a strong communiqué and interrelationship between these candidate genes. This study emphasizes the significance of a molecular biomarker panel as a diagnostic tool and its correlation with the invasion and metastatic pathway of OSCC. An insight into the probable association of CAF's and these biomarkers in the evolution and malignant transformation of OSCC further magnifies the molecular-biological spectrum of OSCC tumour microenvironment.

Increased Expression of VANGL1 is Predictive of Lymph Node Metastasis in Colorectal Cancer: Results from a 20-Gene Expression Signature.

This study aimed at building a prognostic signature based on a candidate gene panel whose expression may be associated with lymph node metastasis (LNM), thus potentially able to predict colorectal cancer (CRC) progression and patient survival. The mRNA expression levels of 20 candidate genes were evaluated by RT-qPCR in cancer and normal mucosa formalin-fixed paraffin-embedded (FFPE) tissues of CRC patients. Receiver operating characteristic curves were used to evaluate the prognosis performance of our model by calculating the area under the curve (AUC) values corresponding to stage and metastasis. A total of 100 FFPE primary tumor tissues from stage I–IV CRC patients were collected and analyzed. Among the 20 candidate genes we studied, only the expression levels of VANGL1 significantly varied between patients with and without LNMs (p = 0.02). Additionally, the AUC value of the 20-gene panel was found to have the highest predictive performance (i.e., AUC = 79.84%) for LNMs compared with that of two subpanels including 5 and 10 genes. According to our results, VANGL1 gene expression levels are able to estimate LNMs in different stages of CRC. After a proper validation in a wider case series, the evaluation of VANGL1 gene expression and that of the 20-gene panel signature could help in the future in the prediction of CRC progression.

Identification of key genes involved in post-traumatic stress disorder: Evidence from bioinformatics analysis.

BACKGROUNDPost-traumatic stress disorder (PTSD) is a serious stress-related disorder.AIMTo identify the key genes and pathways to uncover the potential mechanisms of PTSD using bioinformatics methods.METHODSGene expression profiles were obtained from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified by using GEO2R. Gene functional annotation and pathway enrichment were then conducted. The gene-pathway network was constructed with Cytoscape software. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was applied for validation, and text mining by Coremine Medical was used to confirm the connections among genes and pathways.RESULTSWe identified 973 DEGs including 358 upregulated genes and 615 downregulated genes in PTSD. A group of centrality hub genes and significantly enriched pathways (MAPK, Ras, and ErbB signaling pathways) were identified by using gene functional assignment and enrichment analyses. Six genes (KRAS, EGFR, NFKB1, FGF12, PRKCA, and RAF1) were selected to validate using qRT-PCR. The results of text mining further confirmed the correlation among hub genes and the enriched pathways. It indicated that these altered genes displayed functional roles in PTSD via these pathways, which might serve as key signatures in the pathogenesis of PTSD.CONCLUSIONThe current study identified a panel of candidate genes and important pathways, which might help us deepen our understanding of the underlying mechanism of PTSD at the molecular level. However, further studies are warranted to discover the critical regulatory mechanism of these genes via relevant pathways in PTSD.

Laboratory quality assessment of candidate gene panel testing for acute myeloid leukaemia: a joint ALLG / RCPAQAP initiative

Accurate classification of acute myeloid leukaemia (AML) has become increasingly reliant on molecular characterisation of this blood cancer. Throughout Australia and New Zealand massively parallel sequencing (MPS) is being adopted by diagnostic laboratories for the routine evaluation of patients with AML. This technology enables the surveying of many genes simultaneously, with many technical advantages over single gene testing approaches. However, there are many variations in wet and dry lab MPS procedures, which raises the prospect of discordant results between laboratories. This study compared the results obtained from MPS testing of ten diagnostic AML bone marrow aspirate samples sent to eight participating laboratories across Australasia. A reassuringly high concordance of 94% was observed with regard to variant detection and characterisation of pathogenicity. The level of discordance observed, although low, demonstrates the need for ongoing assessment of concordance between diagnostic testing laboratories through quality assurance programs.