DCC Gene Research Articles

Prenatal Diagnosed Agenesis of the Corpus Callosum: Identifying the Underlying Genetic Etiologies.

To assess the genetic etiologies underlying agenesis of the corpus callosum (ACC) and its pregnancy outcomes in the era of next-generation sequencing. A retrospective analysis was conducted on prospectively collected prenatal ACC cases in which amniocentesis was performed between January 2016 and December 2022. ACC was divided into non-isolated and isolated according to the presence or absence of ultrasound abnormalities. Chromosomal microarray analysis (CMA), karyotyping and exome sequencing (ES) were performed after genetic counseling. Pregnancy outcomes were assessed by pediatric neurosurgeons and were followed up by telephone through their parents. Sixty-eight fetuses with ACC were enrolled in this study. CMA detected eight cases with pathogenic copy number variants (CNVs) and all were non-isolated ACC, with a detection rate of 11.8% (8/68). Among the CMA abnormalities, the majority (6/8) were detectable by karyotyping. ES was performed in 26 cases with normal CMA, revealing pathogenic or likely pathogenic gene variations in 12 cases (46.2%, 12/26), involving L1CMA, SMARCB1, PPP2R1A, ARID1B, USP34, CDC42, NFIA and DCC genes. The detection rates of ES in isolated and non-isolated ACC were 40% (6/15) and 54.5% (6/11), respectively. After excluding cases where pregnancy was terminated (56 cases), there were 12 live births, ranging in age from 15months to 7years. Of these, 91.7% (11 out of 12) demonstrated normal neurodevelopmental outcomes. Specifically, all five cases with isolated ACC and negative ES results exhibited normal neurodevelopment. The remaining six cases with favorable outcomes were all isolated ACC, among which ES identified variants of DCC and USP34 gene in one each case. The other four cases were CMA-negative and declined ES. We highlight the efficacy of prenatal ES in determining the genetic etiology of ACC, whether isolated or not. Favorable neurodevelopmental outcomes were observed when ACC was isolated and with normal ES results.

Adult-Onset Case of Female Idiopathic Hypogonadotropic Hypogonadism and Ataxia: Genetic Background

Adult-onset cases of idiopathic hypogonadotropic hypogonadism (IHH) are characterized by partial or normal puberty development until adolescence and by the impairment of the hypothalamic–pituitary–gonadal (HPG) axis in adulthood. WDR11 and DCC genes are known to be involved in axonal development, particularly of hypothalamic GnRH neurons, and ciliogenesis. We report a female case of adult-onset hypogonadism and cerebellar ataxia, in which we identified two gene mutations. A panel of 48 genes was set up to search for variants in the causative genes of CHH. The variants found were analyzed following the American College of Medical Genetics and Genomics (ACMG) criteria to define their pathogenicity. We identified a missense heterozygous variant in the WDR11 gene NM_018117.12:c.2306T>G (p.Met769Arg) and a mutation in a second gene DCC resulting in amino acid substitutions NM_005215.4:c.3533C>T (p.Ser1178Phe). These variants were classified as being of uncertain clinical significance. We assume that there is a link between the variants found and the impairment of the gonadotrophic and neurological phenotype of the patient. Therefore, we propose the genetic test to identify the best therapeutic approach to identify infertility in female patients with IHH; we believe it is necessary to test WDR11 and DCC genes in larger populations with the same condition to introduce it in future protocols of assessment.

Polymorphisms of the OPRM1, OPRK1, and DCC Genes and Non-Suicidal Self-Harming in Adults

Polymorphisms of the OPRM1, OPRK1, and DCC Genes and Non-Suicidal Self-Harming in Adults

Methylation analysis of DCC gene in saliva samples is an efficient method for non-invasive detection of superficial hypopharyngeal cancer

BackgroundAdvances in upper gastrointestinal endoscopic technology have enabled early detection and treatment of hypopharyngeal cancer. However, in-depth pharyngeal observations require sedation and are invasive. It is important to establish a minimally invasive and simple evaluation method to identify high-risk patients.MethodsEighty-seven patients with superficial hypopharyngeal cancer and 51 healthy controls were recruited. We assessed the methylation status of DCC, PTGDR1, EDNRB, and ECAD, in tissue and saliva samples and verified the diagnostic accuracy by methylation analyses of their promoter regions using quantitative methylation-specific PCR.ResultsSignificant differences between cancer and their surrounding non-cancerous tissues were observed in the methylation values of DCC (p = 0.003), EDNRB (p = 0.001), and ECAD (p = 0.043). Using receiver operating characteristic analyses of the methylation values in saliva samples, DCC showed the highest area under the curve values for the detection of superficial hypopharyngeal cancer (0.917, 95% confidence interval = 0.864–0.970), compared with those for EDNRB (0.680) and ECAD (0.639). When the cutoff for the methylation values of DCC was set at ≥0.163, the sensitivity to detect hypopharyngeal cancer was 82.8% and the specificity was 90.2%.ConclusionsDCC methylation in saliva samples could be a non-invasive and efficient tool for early detection of hypopharyngeal cancer in high-risk patients.

Paroxysmal Dystonic Posturing Mimicking Nocturnal Leg Cramps as a Presenting Sign in an Infant with DCC Mutation, Callosal Agenesis and Mirror Movements.

Background/Objectives: Pathogenic variants in the deleted in colorectal cancer gene (DCC), encoding the Netrin-1 receptor, may lead to mirror movements (MMs) associated with agenesis/dysgenesis of the corpus callosum (ACC) and cognitive and/or neuropsychiatric issues. The clinical phenotype is related to the biological function of DCC in the corpus callosum and corticospinal tract development as Netrin-1 is implicated in the guidance of developing axons toward the midline. We report on a child with a novel inherited, monoallelic, pathogenic variant in the DCC gene. Methods: Standardized measures and clinical scales were used to assess psychomotor development, communication and social skills, emotional and behavioural difficulties. MMs were measured via the Woods and Teuber classification. Exome sequencing was performed on affected and healthy family members. Results: The patient's clinical presentation during infancy consisted of paroxysmal dystonic posturing when asleep, mimicking nocturnal leg cramps. A brain magnetic resonance imaging (MRI) showed complete ACC. He developed typical upper limb MMs during childhood and a progressively evolving neuro-phenotype with global development delay and behavioural problems. We found an intrafamilial clinical variability associated with DCC mutations: the proband's father and uncle shared the same DCC variant, with a milder clinical phenotype. The atypical early clinical presentation of the present patient expands the clinical spectrum associated with DCC variants, especially those in the paediatric age. Conclusions: This study underlines the importance of in-depth genetic investigations in young children with ACC and highlights the need for further detailed analyses of early motor symptoms in infants with DCC mutations.

Identification of specific codon 201 mutation of the DCC Gene in the colonoscopic specimen of colorectal cancer.

To identify the mutation in codon 201 of the deleted in colorectal cancer gene in colorectal cancer, and to correlate that mutation to the histopathological grading of colorectal cancer. The cross-sectional study was conducted from February 2019 to February 2021 after approval from the ethics review board of the Dow University of Health Sciences, Karachi, and comprised biopsy-proven colorectal cancer patients regardless of age and gender. After histopathological reporting, formalin-fixed paraffin-embedded tissue blocks of colorectal cancer were used for deoxyribonucleic acid extraction, followed by polymerase chain reaction optimisation and deoxyribonucleic acid Sanger sequencing for mutational analysis. Data was analysed using SPSS 25. Of the 100 biopsy specimens assessed, 45(45%) were selected. Of them, 13(29%) samples failed to show any band on gel electrophoresis. The remaining 32(71%) samples were used for Sanger sequencing. Of these, 1(3%) sample did not sequence, while 31(97%) showed sequencing. All the sequenced samples identified a mutation in codon 201 of exon 3 in the deleted in colorectal cancer gene; 30(97%) showed homozygosity, and 1(3%) showed heterozygosity. No significant association of point mutation was noted with various demographic and clinicopathological parameters (p>0.05). The deleted in colorectal cancer gene's missense mutation in codon 201 was frequently observed in colorectal cancer patients.

<i>In silico</i> prediction of the transcription factor-enhancer interaction as a first stage of axonal growth regulation

The development of neurodegenerative diseases is associated with proper neuronal circuit formation, axonal guidance. The DCC receptor (deleted in colorectal cancer / colorectal cancer suppressor) and SHH (sonic hedgehog protein) are among the key regulators of axonal guidance.Aim. Interaction prediction of specific enhancer regions of DCC and SHH genes with respectively annotated transcription factors.Materials and methods. An in silico study was performed. The iEnhancer-2L and ES-ARCNN algorithms were selected to estimate enhancer sequence strength. The interaction between transcription factor and enhancer sequence was assessed using the molecular docking method. The enhancer sequence of DCC and SHH protein genes were taken from the NCBI open-source database in FASTA format. Ensembl database was used for enhancer mapping, GeneCards was used for screening and selection of potentially appropriate enhancers and transcription factors associated with these enhancers. The structures of transcription factors as well as their DNA-binding domains were taken from the UniProtKB/Swiss-prot database. An HDOCK scoring function was used as a metric for assessing the possibility of interaction of the target gene transcription factor with associated enhancer sequence.Results. The results showed that the interactions of transcription factor NANOG with the DCC gene enhancer sequence and the interaction of transcription factor CEBPA with the SHH gene enhancer sequence predicted by molecular docking method are potentially possible. The iEnhancer-2L and ES-ARCNN algorithms predicted the enhancer sequence of the SHH gene as strong one. The enhancer sequence of the DCC gene was estimated as strong in the iEnhancer-2L algorithm and as weak in ES-ARCNN. Binding of the DCC gene enhancer sequence to the transcription factor NANOG at 1–206 bp and 686–885 bp sites is the most probable, binding of the SHH gene enhancer sequence to the transcription factor CEBPA at 1–500 bp (HDOCK limitation of 500 bp) is possible.Conclusion. In silico techniques applied in this study demonstrated satisfactory results of predicting the interaction of the transcription factor with the enhancer sequence. Limitations of the current techniques is the lack of consideration of specific transcription factor binding sites. This drawback can be eliminated by implementing an ab initio molecular dynamics simulations into the present pipeline.

Relationship between insulin and Netrin-1/DCC guidance cue pathway regulation in the prefrontal cortex of rodents exposed to prenatal dietary restriction.

Fetal restriction (FR) alters insulin sensitivity, but it is unknown how the metabolic profile associated with restriction affects development of the dopamine (DA) system and DA-related behaviors. The Netrin-1/DCC guidance cue system participates in maturation of the mesocorticolimbic DA circuitry. Therefore, our objective was to identify if FR modifies Netrin-1/DCC receptor protein expression in the prefrontal cortex (PFC) at birth and mRNA in adulthood in rodent males. We used cultured HEK293 cells to assess if levels of miR-218, microRNA regulator of DCC, are sensitive to insulin. To assess this, pregnant dams were subjected to a 50% FR diet from gestational day 10 until birth. Medial PFC (mPFC) DCC/Netrin-1 protein expression was measured at P0 at baseline and Dcc/Netrin-1 mRNA levels were quantified in adults 15 min after a saline/insulin injection. miR-218 levels in HEK-293 cells were measured in response to insulin exposure. At P0, Netrin-1 levels are downregulated in FR animals in comparison to controls. In adult rodents, insulin administration results in an increase in Dcc mRNA levels in control but not FR rats. In HEK293 cells, there is a positive correlation between insulin concentration and miR-218 levels. Since miR-218 is a Dcc gene expression regulator and our in vitro results show that insulin regulates miR-218 levels, we suggest that FR-induced changes in insulin sensitivity could be affecting Dcc expression via miR-218, impacting DA system maturation and organization. As fetal adversity is linked to nonadaptive behaviors later in life, this may contribute to early identification of vulnerability to chronic diseases associated with fetal adversity.

The impact of the OPRM1, OPRK1, DCC genes polymorphisms on the motivation for non-suicidal self-injury in young adults: a pilot study

IntroductionNon-suicidal self-injury (NSSI) – the deliberate, self-directed damage of body tissue without suicidal intent and for purposes not socially or culturally sanctioned – is a highly prevalent phenomenon in adolescents and young adults. Motivation for the NSSI is known to be heterogenous in different patients. However, biological and especially genetic markers associated with different motivation for the NSSI have not been studied to date. One of the possible candidates are mu- (OPRM1) and kappa-opioid receptor (OPRK1) genes, since opioid system is known to be involved in the NSSI. Another perspective candidate is the DCC gene, encoding the netrin 1 receptor, which plays vital part in the formation of the prefrontal cortex.ObjectivesWe conducted a pilot cross-sectional study to test the impact of the rs1779971 OPRM1, rs6473797 OPRK1 and rs8084280 DCC gene polymorphisms on the characteristics and motivations for the NSSI in young adults.Methods28 patients of European ancestry with NSSI (89,3%; n=25) women, median age (Q1-Q3) – 23 (21,25-25) years) were included in the pilot sample. The majority of the sample had a diagnosis of bipolar disorder (78,6%; n=20). Characteristics and motivation for the NSSI were measured by the Inventory of Statements about Self-Injury (ISAS). The Childhood Trauma Questionnaire (CTQ) was used to control for adverse childhood experiences, a potent environmental factor, associated with NSSI. Genotyping was performed using RT-PCR. The genetic effect was evaluated using the dominant model. For statistical analysis multiple linear regression with the presence of minor alleles, different types of childhood trauma, diagnosis, age and sex as factors and ISAS scores as dependent variables were used.ResultsMultiple linear regression showed that minor C allele of rs6473796 OPRK1 gene polymorphism was associated with an increase of the “Affect regulation” (B=2,23; CI95% [0,39–4,06]; p=0,022), “Anti-dissociation” (B=3,31; CI95% [0,18–6,44]; p=0,039) subscales of ISAS scores. Moreover, the minor T allele of the rs8082480 DCC gene polymorphism was associated with a decrease of the “Affect regulation” subscale score (B=-1,74; CI95% [-3,30 – -0,18]; p=0,032).ConclusionsTo our knowledge, this is the first study on the genetic markers of motivations for NSSI. Our pilot results showed that, controlling for diagnosis, age, sex and childhood trauma, OPRK1 and DCC gene polymorphisms may be associated with the heterogeneity of motivations for NSSI. However, these results require confirmation on the larger samples.Disclosure of InterestNone Declared

Inhibition of MicroRNA-182/183 Cluster Ameliorates Schizophrenia by Activating the Axon Guidance Pathway and Upregulating DCC

Schizophrenia (SZ) is a complex disorder caused by a variety of genetic and environmental factors. Mounting evidence suggests the involvement of microRNAs (miRNAs) in the pathology of SZ. Accordingly, the current study set out to investigate the possible implication of the miR-182/183 cluster, as well as its associated mechanism in the progression of SZ. Firstly, rat models of SZ were established by intraperitoneal injection of MK-801. Moreover, rat primary hippocampal neurons were exposed to MK-801 to simulate injury of hippocampal neurons. The expression of miR-182/183 or its putative target gene DCC was manipulated to examine their effects on SZ in vitro and in vivo. It was found that miR-182 and miR-183 were both highly expressed in peripheral blood of SZ patients and hippocampal tissues of SZ rats. In addition, the miR-182/183 cluster could target DDC and downregulate the expression of DDC. On the other hand, inhibition of the miR-182/183 cluster ameliorated SZ, as evidenced by elevated serum levels of NGF and BDNF, along with reductions in spontaneous activity, serum GFAP levels, and hippocampal neuronal apoptosis. Additionally, DCC was found to activate the axon guiding pathway and influence synaptic activity in hippocampal neurons. Collectively, our findings highlighted that inhibition of the miR-182/183 cluster could potentially attenuate SZ through DCC-dependent activation of the axon guidance pathway. Furthermore, inhibition of the miR-182/183 cluster may represent a potential target for the SZ treatment.

Computational prediction of potential drug-like compounds from Cannabis sativa leaf extracts targeted towards Alzheimer therapy

• Phytochemicals isolated from Cannabis sativa can improve behavioral symptoms associated with neurological diseases including AD. • Morphinan-6-one demonstrated inhibitory actions against AChE and DDC, suggesting that it might have dual functions in AD. • Morphinan-6-one is hypothesized to be a modulatory molecule for acetylcholinesterase. This study was aimed at evaluating the inhibitory effects of the phytochemicals from the Cannabis sativa (Cannabis) leaf extracts against Alzheimer’s disease (AD) protein targets. Twelve compounds derived from the Cannabis sativa leaf extracts were evaluated as potential inhibitors of acetylcholinesterase (AChE), dopa decarboxylase (DDC), serotonin receptor 2C (HTR2C) and monoamine oxidase (MAO). Ligand-based and receptor-ligand complex were used to derive the pharmacophore hypothesis. In silico study through molecular docking simulation method was adopted to analyze the inhibitory activity of the compounds in question. Molecular dynamic simulation (MDs) was performed to assess the stability of the top-ranked phytochemicals. The binding energies of these compounds to the four targets were investigated by the Molecular Mechanics for the Generalized Born Model and Solvent Accessibility method (MM-GBSA). The binding-free energy suggests that cannabinol, cannabichromene, linoelaidic acid and morphinan-6-one can be utilized as lead compounds in drug discovery and development of AD to inhibit activity of AChE, DCC gene, MAO and HTR2C. The MDs indicated that AChE-Cannabinol, DCC-Cannabicoumaronone, MAO-Linoelaidic acid, and HTR2C-morphinan-6-one were stable over the entire course of 100 ns suggesting their role in the regulation of the diseases in which their respective receptors are implicated.

Omics approaches to discover pathophysiological pathways contributing to human pain.

Omics approaches to discover pathophysiological pathways contributing to human pain.

KARDIOMIOPATIA ROZSTRZENIOWA U PSA DOMOWEGO – ANALIZA IN SILICO WYBRANYCH GENÓW

Dilated cardiomyopathy (DCM) is a progressive loss of contractility of the heart muscle as the disease progresses. It causes a decrease in the heart’s minute capacity, i.e. the volume of blood pumped by the heart into the blood vessels in one minute. DCM leads to congestive heart failure and sudden death. The aim of this study was to identify in silico genes within which mutations have occurred that may cause DCM in the domestic dog (Canis lupus familiaris), to identify dog breeds at risk, and to propose breed-specific diagnostic molecular tests. For bioinformatic analyses of sequences retrieved from GenBank (NC_006587.3 – FGGY, NC_006583.3 – DCC and CM023383.1 – PDE3B) and from scientific publications (PDK4 – from patent publication number US 2011/0307965 A1 and STRN – Meurs et al. 2010), the following programs were used: Primer3 v. 0.4.0, NEBcutter v. 2.0 and BLAST. Based on literature data, domestic dog breeds such as Doberman Pinscher, Boxer, Portuguese Water Dog, Newfoundland, Irish Wolfhound and Great Dane were found to be among the breeds with the highest risk of DCM. In order to identify relevant mutations in the genes studied (FGGY, DCC, PDE3B, PDK4 and STRN) that may cause the occurrence of dilated cardiomyopathy, the use of specific restriction enzymes has been proposed in molecular diagnostic tests: BmiI for mutations in the PDK4 gene and Tth111I for SNPs in the FGGY gene (Doberman Pinscher) and TaqI for SNPs in the DCC gene and HinfI for SNPs in the PDE3B gene (Irish Wolfhound). This work, may serve as a prelude to analysis for targeted genetic testing to enable correct diagnosis of DCM in asymptomatic dogs

Corticolimbic DCC gene co-expression networks as predictors of impulsivity in children

Inhibitory control deficits are prevalent in multiple neuropsychiatric conditions. The communication- as well as the connectivity- between corticolimbic regions of the brain are fundamental for eliciting inhibitory control behaviors, but early markers of vulnerability to this behavioral trait are yet to be discovered. The gradual maturation of the prefrontal cortex (PFC), in particular of the mesocortical dopamine innervation, mirrors the protracted development of inhibitory control; both are present early in life, but reach full maturation by early adulthood. Evidence suggests the involvement of the Netrin-1/DCC signaling pathway and its associated gene networks in corticolimbic development. Here we investigated whether an expression-based polygenic score (ePRS) based on corticolimbic-specific DCC gene co-expression networks associates with impulsivity-related phenotypes in community samples of children. We found that lower ePRS scores associate with higher measurements of impulsive choice in 6-year-old children tested in the Information Sampling Task and with impulsive action in 6- and 10-year-old children tested in the Stop Signal Task. We also found the ePRS to be a better overall predictor of impulsivity when compared to a conventional PRS score comparable in size to the ePRS (4515 SNPs in our discovery cohort) and derived from the latest GWAS for ADHD. We propose that the corticolimbic DCC-ePRS can serve as a novel type of marker for impulsivity-related phenotypes in children. By adopting a systems biology approach based on gene co-expression networks and genotype-gene expression (rather than genotype-disease) associations, these results further validate our methodology to construct polygenic scores linked to the overall biological function of tissue-specific gene networks.

Oncogenic and tumor suppressor genes expression in myeloproliferative neoplasms: The hidden side of a complex pathology.

BackgroundThe present study aimed to explore the changes in the expressions of six tumor‐related genes in myeloproliferative neoplasms (MPNs). The study population included 130 patients with MPNs (52 with chronic myeloid leukemia (CML), 49 with essential thrombocythemia (ET), 20 with polycythemia vera (PV), and 9 with primary myelofibrosis (PMF)) and 51 healthy individuals.MethodsThe expression profiling of six genes (ADAMTS18, CMTM5, CDKN2B, DCC, FHIT, and WNT5B) in the peripheral blood granulocyte cells was explored by real‐time quantitative reverse transcription polymerase chain reaction.ResultsThe patients with MPNs showed significant downregulation of CMTM5 (EFC = 0.66) and DCC (EFC = 0.65) genes in contrast to a non‐significant upregulation of ADAMTS18, CDKN2B, FHIT, and WNT5B genes. Downregulation of DCC was consistent in all subtypes of MPN (EFC range: 0.591–0.860). However, CMTM5 had a 1.22‐fold upregulation in PMF in contrast to downregulation in other MPN subtypes (EFC range: 0.599–0.775). The results revealed a significant downregulation in CMTM5 and DCC at below 60‐years of age. Furthermore, female patients showed a clear‐cut downregulation in both CMTM5 and DCC (EFC DCC: 0.436 and CMTM5: 0.570), while male patients presented a less prominent downregulation with a borderline p‐value only in DCC (EFC: 0.69; p = 0.05).ConclusionsChronic myeloid leukemia cases showed a significant upregulation of WNT5B, as a known oncogenesis gene. Two tumor suppressor genes, namely DCC and CMTM5, were downregulated in the patients with MPNs, especially in females and patients below 60 years of age.

Low Back Pain With Persistent Radiculopathy; the Clinical Role of Genetic Variants in the Genes SOX5, CCDC26/GSDMC and DCC.

In a recently published genome-wide association study (GWAS) chronic back pain was associated with three loci; SOX5, CCDC26/GSDMC and DCC. This GWAS was based on a heterogeneous sample of back pain disorders, and it is unknown whether these loci are of clinical relevance for low back pain (LBP) with persistent radiculopathy. Thus, we examine if LBP with radiculopathy 12 months after an acute episode of LBP with radiculopathy is associated with the selected single nucleotide polymorphisms (SNPs); SOX5 rs34616559, CCDC26/GSDMC rs7833174 and DCC rs4384683. In this prospective cohort study, subjects admitted to a secondary health care institution due to an acute episode of LBP with radiculopathy, reported back pain, leg pain, and Oswestry Disability Index (ODI), were genotyped and followed up at 12 months (n = 338). Kruskal-Wallis H test showed no association between the SNPs and back pain, leg pain or ODI. In conclusion, LBP with radiculopathy 12 months after an acute episode of LBP with radiculopathy, is not associated with the selected SNPs; SOX5 rs34616559, CCDC26/GSDMC rs7833174 and DCC rs4384683. This absent or weak association suggests that the SNPs previously associated with chronic back pain are not useful as prognostic biomarkers for LBP with persistent radiculopathy.

Genome-wide association studies confirms role of DCC gene in depression without recent stress exposure

Genome-wide association studies confirms role of DCC gene in depression without recent stress exposure

Molecular and clinical analysis of genes involved in gastric cancer

Gastric cancer is the abnormal growth of stomach cells. The symptoms of this disease include difficulty in swallowing, heartburn, stomach pain, indigestion, nausea, vomiting, and blood in the stool. Gastric cancer is a multifactorial and genetic disease, and many genes and factors are involved in it. DCC and CDH1 are the genes silenced by hypermethylation in gastric cancer and play an influential role in suppressing gastric cancer tumors. The aim of this study was bioinformatics analysis at the genome and proteome level and evaluation and comparison of the expression of DCC and CDH1 genes in different human body tissues. The results of this study showed that the CDH1 gene is more expressed in the thyroid gland and Parathyroid gland and the DCC gene is more expressed in the testis, hippocampal formation, basal ganglia, midbrain, cerebral cortex, and hypothalamus. The expression analysis of these genes showed that both genes generally are more active in glands and have little expression in other body organs. Cellular analysis of DCC and CDH1 genes by antibodies that bind to the proteins of the target genes showed that both genes are active in the Golgi apparatus, with the difference that the DCC gene is more present in the nucleus and the CDH1 gene is more present in the plasma membrane. The expression level of the CDH1 gene is relatively higher than that of the DCC gene. Also, phenotypic studies of the DCC gene showed that this gene is related to colorectal cancer, and it was found that the CDH1 gene is effective in Blepharocheilodontic syndrome 1. Finally, considering the role of CDH1 and DCC genes as tumor suppressor genes, these items can be used for targeted treatments in gastric cancer.

ETV4 plays a role on the primary events during the adenoma-adenocarcinoma progression in colorectal cancer

BackgroundColorectal cancer (CRC) is one of the most common cancers worldwide; it is the fourth leading cause of death in the world and the third in Brazil. Mutations in the APC, DCC, KRAS and TP53 genes have been associated with the progression of sporadic CRC, occurring at defined pathological stages of the tumor progression and consequently modulating several genes in the corresponding signaling pathways. Therefore, the identification of gene signatures that occur at each stage during the CRC progression is critical and can present an impact on the diagnosis and prognosis of the patient. In this study, our main goal was to determine these signatures, by evaluating the gene expression of paired colorectal adenoma and adenocarcinoma samples to identify novel genetic markers in association to the adenoma-adenocarcinoma stage transition.MethodsTen paired adenoma and adenocarcinoma colorectal samples were subjected to microarray gene expression analysis. In addition, mutations in APC, KRAS and TP53 genes were investigated by DNA sequencing in paired samples of adenoma, adenocarcinoma, normal tissue, and peripheral blood from ten patients.ResultsGene expression analysis revealed a signature of 689 differentially expressed genes (DEG) (fold-change> 2, p< 0.05), between the adenoma and adenocarcinoma paired samples analyzed. Gene pathway analysis using the 689 DEG identified important cancer pathways such as remodeling of the extracellular matrix and epithelial-mesenchymal transition. Among these DEG, the ETV4 stood out as one of the most expressed in the adenocarcinoma samples, further confirmed in the adenocarcinoma set of samples from the TCGA database. Subsequent in vitro siRNA assays against ETV4 resulted in the decrease of cell proliferation, colony formation and cell migration in the HT29 and SW480 colorectal cell lines. DNA sequencing analysis revealed KRAS and TP53 gene pathogenic mutations, exclusively in the adenocarcinomas samples.ConclusionOur study identified a set of genes with high potential to be used as biomarkers in CRC, with a special emphasis on the ETV4 gene, which demonstrated involvement in proliferation and migration.

DCC gene network in the prefrontal cortex is associated with total brain volume in childhood.

BackgroundGenetic variation in the guidance cue DCC gene is linked to psychopathologies involving dysfunction in the prefrontal cortex. We created an expression-based polygenic risk score (ePRS) based on the DCC coexpression gene network in the prefrontal cortex, hypothesizing that it would be associated with individual differences in total brain volume.MethodsWe filtered single nucleotide polymorphisms (SNPs) from genes coexpressed with DCC in the prefrontal cortex obtained from an adult postmortem donors database (BrainEAC) for genes enriched in children 1.5 to 11 years old (BrainSpan). The SNPs were weighted by their effect size in predicting gene expression in the prefrontal cortex, multiplied by their allele number based on an individual’s genotype data, and then summarized into an ePRS. We evaluated associations between the DCC ePRS and total brain volume in children in 2 community-based cohorts: the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) and University of California, Irvine (UCI) projects. For comparison, we calculated a conventional PRS based on a genome-wide association study of total brain volume.ResultsHigher ePRS was associated with higher total brain volume in children 8 to 10 years old (β = 0.212, p = 0.043; n = 88). The conventional PRS at several different thresholds did not predict total brain volume in this cohort. A replication analysis in an independent cohort of newborns from the UCI study showed an association between the ePRS and newborn total brain volume (β = 0.101, p = 0.048; n = 80). The genes included in the ePRS demonstrated high levels of coexpression throughout the lifespan and are primarily involved in regulating cellular function.LimitationsThe relatively small sample size and age differences between the main and replication cohorts were limitations.ConclusionOur findings suggest that the DCC coexpression network in the prefrontal cortex is critically involved in whole brain development during the first decade of life. Genes comprising the ePRS are involved in gene translation control and cell adhesion, and their expression in the prefrontal cortex at different stages of life provides a snapshot of their dynamic recruitment.