RESUMO
PURPOSE: To analyze the copy number variation (CNV) in the X-linked genes BCORL1, POF1B, and USP9X in idiopathic diminished ovarian reserve (DOR). METHODS: This case-control study included 47 women, 26 with DOR and 21 in the control group. Age, weight, height, BMI, and FSH level were evaluated, as well as antral follicle count (AFC), oocyte retrieval after controlled ovarian stimulation, and metaphase II (MII) oocytes. The CNVs of BCORL1, USP9X, and POF1B genes were measured by quantitative real time PCR (qPCR) using two reference genes, the HPRT1 (X-linked) and MFN2 (autosomal). Protein-protein interaction network and functional enrichment analysis were performed using the STRING database. RESULTS: The mean age was 36.52 ± 4.75 in DOR women and 35.38 ± 4.14 in control. Anthropometric measures did not differ between the DOR and control groups. DOR women presented higher FSH (p = 0.0025) and lower AFC (p < .0001), oocyte retrieval after COS (p = 0.0004), and MII oocytes (p < .0001) when compared to the control group. BCORL1 and POF1B did not differ in copy number between DOR and control. However, DOR women had more copies of USP9X than the control group (p = 0.028). CONCLUSION: The increase in the number of copies of the USP9X gene may lead to overexpression in idiopathic DOR and contribute to altered folliculogenesis and oocyte retrieval.
Assuntos
Variações do Número de Cópias de DNA , Reserva Ovariana , Ubiquitina Tiolesterase , Humanos , Feminino , Reserva Ovariana/genética , Adulto , Variações do Número de Cópias de DNA/genética , Ubiquitina Tiolesterase/genética , Estudos de Casos e Controles , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/patologia , Recuperação de Oócitos , Proteínas Repressoras/genética , Oócitos/crescimento & desenvolvimento , Oócitos/metabolismo , Oócitos/patologiaRESUMO
SMYD4 is a member of the SMYD family that has lysine methyltransferase function. Little is known about the roles of SMYD4 in cancer. The aim of this study is to investigate genetic alterations in the SMYD4 gene across the most prevalent solid tumors and determine its potential as a biomarker. We performed an integrative multi-platform analysis of the most common mutations, copy number alterations (CNAs), and mRNA expression levels of the SMYD family genes using cohorts available at the Cancer Genome Atlas (TCGA), cBioPortal, and the Catalogue of Somatic Mutations in Cancer (COSMIC). SMYD genes displayed a lower frequency of mutations across the studied tumors, with none of the SMYD4 mutations detected demonstrating sufficient discriminatory power to serve as a biomarker. In terms of CNAs, SMYD4 consistently exhibited heterozygous loss and downregulation across all tumors evaluated. Moreover, SMYD4 showed low expression in tumor samples compared to normal samples, except for stomach adenocarcinoma. SMYD4 demonstrated a frequent negative correlation with other members of the SMYD family and a positive correlation between CNAs and mRNA expression. Additionally, patients with low SMYD4 expression in STAD and LUAD tumors exhibited significantly poorer overall survival. SMYD4 demonstrated its role as a tumor suppressor in the majority of tumors evaluated. The consistent downregulation of SMYD4, coupled with its association with cancer progression, underscores its potential usefulness as a biomarker.
Assuntos
Mutação , Neoplasias , Humanos , Neoplasias/genética , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Variações do Número de Cópias de DNA , Histona-Lisina N-Metiltransferase/genéticaRESUMO
Breast cancer (BRCA) is a prevalent malignancy with the highest incidence among females. BRCA can be categorized into five intrinsic molecular subtypes (LumA, LumB, HER2, Basal, and Normal), each characterized by varying molecular and clinical features determined by the expression of intrinsic genes (PAM50). The Heat Shock Protein (HSP) family is composed of 95 genes evolutionary conservated, they have critical roles in proteostasis in both normal and cancerous processes. Many studies have linked HSP to the development and spread of cancer. They modulate the activity of multiple proteins expressed by oncogenes and anti-oncogenes through a range of interactions. In this study, we evaluate the mutational changes that HSP undergoes in BRCA mainly from the TCGA database. We observe that Copy Number Variations (CNV) are the more frequent events analyzed surpassing the occurrence of point mutations, indels, and translation start site mutations. The Basal subtype showcased the highest count of amplified CNV, including subtype-specific changes, whereas the Luminals tumors accumulated the greatest number of deletion CNV. Meanwhile, the HER2 subtype exhibited a comparatively lower frequency of CNV alterations when compared to the other subtypes. This study integrates CNV and expression data, finding associations between these two variables and the influence of CNV on the deregulation of HSP expression. To enhance the role of HSP as a risk predictor in BRCA, we succeeded in identifying CNV profiles as a prognostic marker. We included Artificial Intelligence to improve the clustering of patients, and we achieved a molecular CNV signature as a significant risk factor independent of known classic markers, including molecular subtypes PAM50. This research enhances the comprehension of HSP DNA alterations in BRCA and its relation with predicting the risk of affected individuals providing insights to develop guide personalized treatment strategies.
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Neoplasias da Mama , Variações do Número de Cópias de DNA , Proteínas de Choque Térmico , Mutação , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Proteínas de Choque Térmico/genética , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/genéticaRESUMO
BACKGROUND: Exploring the expression of X linked disorders like haemophilia A (HA) in females involves understanding the balance achieved through X chromosome inactivation (XCI). Skewed XCI (SXCI) may be involved in symptomatic HA carriers. We aimed to develop an approach for dissecting the specific cause of SXCI and verify its value in HA. METHODS: A family involving three females (two symptomatic with severe/moderate HA: I.2, the mother, and II.1, the daughter; one asymptomatic: II.2) and two related affected males (I.1, the father and I.3, the maternal uncle) was studied. The genetic analysis included F8 mutational screening, multiplex ligation-dependent probe amplification, SNP microarray, whole exome sequencing (WES) and Sanger sequencing. XCI patterns were assessed in ectoderm/endoderm and mesoderm-derived tissues using AR-based and RP2-based systems. RESULTS: The comprehensive family analysis identifies I.2 female patient as a heterozygous carrier of F8:p.(Ser1414Ter) excluding copy number variations. A consistent XCI pattern of 99.5% across various tissues was observed. A comprehensive filtering algorithm for WES data was designed, developed and applied to I.2. A Gly58Arg missense variant in VMA21 was revealed as the cause for SXCI.Each step of the variant filtering system takes advantage of publicly available genomic databases, non-SXCI controls and case-specific molecular data, and aligns with established concepts in the theoretical background of SXCI. CONCLUSION: This study acts as a proof of concept for our genomic filtering algorithm's clinical utility in analysing X linked disorders. Our findings clarify the molecular aspects of SXCI and improve genetic diagnostics and counselling for families with X linked diseases like HA.
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Hemofilia A , Linhagem , Inativação do Cromossomo X , Humanos , Inativação do Cromossomo X/genética , Feminino , Hemofilia A/genética , Masculino , Algoritmos , Sequenciamento do Exoma/métodos , Fator VIII/genética , Cromossomos Humanos X/genética , Genômica/métodos , Variações do Número de Cópias de DNA/genética , Mutação/genética , AdultoRESUMO
Endometriosis is a complex disease that affects 10-15% of women of reproductive age. Familial studies show that relatives of affected patients have a higher risk of developing the disease, implicating a genetic role for this disorder. Little is known about the impact of germline genomic copy number variant (CNV) polymorphisms on the heredity of the disease. In this study, we describe a rare CNV identified in two sisters with familial endometriosis, which contain genes that may increase the susceptibility and progression of this disease. We investigated the presence of CNVs from the endometrium and blood of the sisters with endometriosis and normal endometrium of five women as controls without the disease using array-CGH through the Agilent 2x400K platform. We excluded common CNVs that were present in the database of genomic variation. We identified, in both sisters, a rare CNV gain affecting 113kb at band 3q12.2 involving two candidate genes: ADGRG7 and TFG. The CNV gain was validated by qPCR. ADGRG7 is located at 3q12.2 and encodes a G protein-coupled receptor influencing the NF-kappaß pathway. TFG participates in chromosomal translocations associated with hematologic tumor and soft tissue sarcomas, and is also involved in the NF-kappa B pathway. The CNV gain in this family provides a new candidate genetic marker for future familial endometriosis studies. Additional longitudinal studies of affected families must confirm any associations between this rare CNV gain and genes involved in the NF-kappaß pathway in predisposition to endometriosis.
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Variações do Número de Cópias de DNA , Endometriose , Humanos , Endometriose/genética , Feminino , Adulto , Cromossomos Humanos Par 3/genética , Predisposição Genética para Doença , Polimorfismo GenéticoRESUMO
Copy number variation is a common contributor to phenotypic diversity, yet its involvement in ecological adaptation is not easily discerned. Instances of parallelly evolving populations of the same species in a similar environment marked by strong selective pressures present opportunities to study the role of copy number variants (CNVs) in adaptation. By identifying CNVs that repeatedly occur in multiple populations of the derived ecotype and are not (or are rarely) present in the populations of the ancestral ecotype, the association of such CNVs with adaptation to the novel environment can be inferred. We used this paradigm to identify CNVs associated with recurrent adaptation of the Mexican tetra (Astyanax mexicanus) to cave environment. Using a read-depth approach, we detected CNVs from previously re-sequenced genomes of 44 individuals belonging to two ancestral surfaces and three derived cave populations. We identified 102 genes and 292 genomic regions that repeatedly diverge in copy number between the two ecotypes and occupy 0.8% of the reference genome. Functional analysis revealed their association with processes previously recognized to be relevant for adaptation, such as vision, immunity, oxygen consumption, metabolism, and neural function and we propose that these variants have been selected for in the cave or surface waters. The majority of the ecotype-divergent CNVs are multiallelic and display copy number increases in cavefish compared to surface fish. Our findings suggest that multiallelic CNVs - including gene duplications - and divergence in copy number provide a fast route to produce novel phenotypes associated with adaptation to subterranean life.
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Cavernas , Characidae , Variações do Número de Cópias de DNA , Variações do Número de Cópias de DNA/genética , Animais , Characidae/genética , Genética Populacional , Adaptação Fisiológica/genética , Ecótipo , MéxicoRESUMO
PURPOSE: Managing high-grade endometrial cancer in Martinique poses significant challenges. The diversity of copy number alterations in high-grade endometrial tumors, often associated with a TP53 mutation, is a key factor complicating treatment. Due to the high incidence of high-grade tumors with poor prognosis, our study aimed to characterize the molecular signature of these tumors within a cohort of 25 high-grade endometrial cases. METHODS: We conducted a comprehensive pangenomic analysis to categorize the copy number alterations involved in these tumors. Whole-Exome Sequencing (WES) and Homologous Recombination (HR) analysis were performed. The alterations obtained from the WES were classified into various signatures using the Copy Number Signatures tool available in COSMIC. RESULTS: We identified several signatures that correlated with tumor stage and disctinct prognoses. These signatures all seem to be linked to replication stress, with CCNE1 amplification identified as the primary driver of oncogenesis in over 70% of tumors analyzed. CONCLUSION: The identification of CCNE1 amplification, which is currently being explored as a therapeutic target in clinical trials, suggests new treatment strategies for high-grade endometrial cancer. This finding holds particular significance for Martinique, where access to care is challenging.
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Ciclina E , Variações do Número de Cópias de DNA , Neoplasias do Endométrio , Amplificação de Genes , Gradação de Tumores , Proteínas Oncogênicas , Feminino , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Humanos , Ciclina E/genética , Proteínas Oncogênicas/genética , Variações do Número de Cópias de DNA/genética , Carcinogênese/genética , Pessoa de Meia-Idade , Sequenciamento do Exoma , Replicação do DNA/genética , Prognóstico , IdosoRESUMO
BACKGROUND: Transmembrane protein 92 (TMEM92) has been implicated in the facilitation of tumor progression. Nevertheless, comprehensive analyses concerning the prognostic significance of TMEM92, as well as its role in immunological responses across diverse cancer types, remain to be elucidated. METHODS: In this study, data was sourced from a range of publicly accessible online platforms and databases, including TCGA, GTEx, UCSC Xena, CCLE, cBioPortal, HPA, TIMER2.0, GEPIA, CancerSEA, GDSC, exoRBase, and ImmuCellAI. We systematically analyzed the expression patterns of TMEM92 at both mRNA and protein levels across diverse human organs, tissues, extracellular vesicles (EVs), and cell lines associated with multiple cancer types. Subsequently, analyses were conducted to determine the relationship between TMEM92 and various parameters such as prognosis, DNA methylation, copy number variation (CNV), the tumor microenvironment (TME), immune cell infiltration, genes with immunological relevance, tumor mutational burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and half-maximal inhibitory concentration (IC50) values. RESULTS: In the present study, we observed a pronounced overexpression of TMEM92 across a majority of cancer types, which was concomitantly associated with a less favorable prognosis. A notable association emerged between TMEM92 expression and both DNA methylation and CNV. Furthermore, a pronounced relationship was discerned between TMEM92 expression, the TME, and the degree of immune cell infiltration. Intriguingly, while TMEM92 expression displayed a positive correlation with macrophage presence, it inversely correlated with the infiltration level of CD8 + T cells. Concurrently, significant associations were identified between TMEM92 and the major histocompatibility complex, TMB, MSI, and MMR. Results derived from Gene Set Enrichment Analysis and Gene Set Variation Analysis further substantiated the nexus of TMEM92 with both immune and metabolic pathways within the oncogenic context. CONCLUSIONS: These findings expanded the understanding of the roles of TMEM92 in tumorigenesis and progression and suggest that TMEM92 may have an immunoregulatory role in several malignancies.
Assuntos
Proteínas de Membrana , Neoplasias , Microambiente Tumoral , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Variações do Número de Cópias de DNA , Metilação de DNA , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Regulação Neoplásica da Expressão Gênica , Linfócitos do Interstício Tumoral/imunologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Instabilidade de Microssatélites , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/metabolismo , Prognóstico , Microambiente Tumoral/imunologiaRESUMO
OBJECTIVE: The objective of this study was to examine associations between umbilical cord mitochondrial DNA copy number (mtDNAcn) and adiposity across childhood. METHODS: In a prospective birth cohort of Dominican and African American children from New York City, New York (1998-2006), mtDNAcn was measured in cord blood. Children (N = 336) were evaluated for their height, weight, and bioimpedance at age 5, 7, 9, and 11 years. We used linear mixed-effects models to assess associations of mtDNAcn tertiles in cord blood with child BMI, BMI z scores, fat mass index, and body fat percentage. Latent class growth models and interactions between mtDNAcn and child age or child age2 were used to assess associations between age and adiposity trajectories. RESULTS: BMI was, on average, 1.5 kg/m2 higher (95% CI: 0.58, 2.5) in individuals with mtDNAcn in the low- compared with the middle-mtDNAcn tertile. Results were similar for BMI z score, fat mass index, and body fat percentage. Moreover, children in the low-mtDNAcn group had increased odds of being in an "increasing" or "high-stable" adiposity class. CONCLUSIONS: Lower mtDNAcn at birth may predict greater childhood adiposity, highlighting the potential key role of perinatal mitochondrial function in adiposity during development.
Assuntos
Adiposidade , Índice de Massa Corporal , Variações do Número de Cópias de DNA , DNA Mitocondrial , Sangue Fetal , Obesidade Infantil , Humanos , DNA Mitocondrial/sangue , DNA Mitocondrial/genética , Sangue Fetal/metabolismo , Sangue Fetal/química , Adiposidade/genética , Feminino , Masculino , Criança , Pré-Escolar , Estudos Prospectivos , Obesidade Infantil/genética , Obesidade Infantil/sangue , Cidade de Nova Iorque , Negro ou Afro-Americano/genética , Coorte de Nascimento , República DominicanaRESUMO
OBJECTIVE: This study used array comparative genomic hybridization to assess copy number alterations (CNAs) involving miRNA genes in pleomorphic adenoma (PA), recurrent pleomorphic adenoma (RPA), residual PA, and carcinoma ex pleomorphic adenoma (CXPA). MATERIALS AND METHODS: We analyzed 13 PA, 4 RPA, 29 CXPA, and 14 residual PA using Nexus Copy Number Discovery software. The miRNAs genes affected by CNAs were evaluated based on their expression patterns and subjected to pathway enrichment analysis. RESULTS: Across the groups, we found 216 CNAs affecting 2261 miRNA genes, with 117 in PA, 59 in RPA, 846 in residual PA, and 2555 in CXPA. The chromosome 8 showed higher involvement in altered miRNAs in PAs and CXPA patients. Six miRNA genes were shared among all groups. Additionally, miR-21, miR-455-3p, miR-140, miR-320a, miR-383, miR-598, and miR-486 were prominent CNAs found and is implicated in carcinogenesis of several malignant tumors. These miRNAs regulate critical signaling pathways such as aerobic glycolysis, fatty acid biosynthesis, and cancer-related pathways. CONCLUSION: This study was the first to explore CNAs in miRNA-encoding genes in the PA-CXPA sequence. The findings suggest the involvement of numerous miRNA genes in CXPA development and progression by regulating oncogenic signaling pathways.