RESUMO
BACKGROUND: Testicular germ cell tumors (TGCTs) account for 1-2% of all tumors in young and middle aged men. A 75-fold increase in TCGT development has been reported for monozygotic (MZ) twins. Therefore, the occurrence of simultaneous tumors in MZ twins emphasizes the importance of genetic factors that influence the risk of developing these tumors. Genomic screening was performed for one family containing MZ twins with testicular germ cell tumors, in order to define alterations associated with risk of tumor development. METHODS: Copy number alterations were evaluated using array-CGH (4x44K, Agilent Technologies) in one seminoma and one embryonal carcinoma (EC) from MZ twins. In addition, genomic alterations from the tumors and peripheral blood cells of the twins were compared to the parental genomes via their peripheral blood cells. RESULTS: Embryonal carcinoma (Twin-1 t) presented a lower frequency of genomic alterations compared to the seminoma (Twin-2 t). One minimal common region of loss was observed in 9p13.1-p12 in the comparison between DNA from blood samples for Twin-1 and Twin-2. In this region is mapped the CNTNAP3 gene which was confirmed as involved in losses by qPCR. Comparative analysis of novel CNVs between the Twin-1 t and Twin-2 t showed five minimal common regions involving gain at chromosomes 12 (12p12.3-p11.1 and 12p13.33-p12.3), while losses were observed at 10p15.3-p15.2, 13q21.1-q21.2 and 15q11.1-q11.2. In addition, one exclusive rare copy number alteration was detected in Twin-1 t and Twin-2 t, and 19 novel alterations were identified in the Twin-2 t. CONCLUSION: Distinct genomic profiles for MZ twins with phenotypically different TGCT were described. Of particular interest, 12p gains were detected exclusively in tumor samples. In peripheral blood samples, loss of 9p13.1-p12 was the unique novel CNV shared by the twins, confirming the involvement of CNTNAP3 gene in TGCTs development. Although similar CNV profiles were shared by both the peripheral blood and tumor samples of the twins, tumor-specific CNV loci were identified for seminoma and non-seminomatous tumors. These findings suggest the presence of de novo germline structural alterations and TGCT predisposition.
Assuntos
Testes Genéticos/métodos , Genômica , Proteínas de Membrana/genética , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/genética , Proteínas do Tecido Nervoso/genética , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/genética , Gêmeos Monozigóticos/genética , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Adulto JovemRESUMO
Undifferentiated high-grade pleomorphic sarcomas (UPSs) display aggressive clinical behavior and frequently develop local recurrence and distant metastasis. Because these sarcomas often share similar morphological patterns with other tumors, particularly leiomyosarcomas (LMSs), classification by exclusion is frequently used. In this study, array-based comparative genomic hybridization (array CGH) was used to analyze 20 UPS and 17 LMS samples from untreated patients. The LMS samples presented a lower frequency of genomic alterations compared with the UPS samples. The most frequently altered UPS regions involved gains at 20q13.33 and 7q22.1 and losses at 3p26.3. Gains at 8q24.3 and 19q13.12 and losses at 9p21.3 were frequently detected in the LMS samples. Of these regions, gains at 1q21.3, 11q12.2-q12.3, 16p11.2, and 19q13.12 were significantly associated with reduced overall survival times in LMS patients. A multivariate analysis revealed that gains at 1q21.3 were an independent prognostic marker of shorter survival times in LMS patients (HRâ=â13.76; Pâ=â0.019). Although the copy number profiles of the UPS and LMS samples could not be distinguished using unsupervised hierarchical clustering analysis, one of the three clusters presented cases associated with poor prognostic outcome (Pâ=â0.022). A relative copy number analysis for the ARNT, SLC27A3, and PBXIP1 genes was performed using quantitative real-time PCR in 11 LMS and 16 UPS samples. Gains at 1q21-q22 were observed in both tumor types, particularly in the UPS samples. These findings provide strong evidence for the existence of a genomic signature to predict poor outcome in a subset of UPS and LMS patients.
Assuntos
Genômica , Leiomiossarcoma/diagnóstico , Leiomiossarcoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Pré-Escolar , Cromossomos Humanos/genética , Variações do Número de Cópias de DNA , Feminino , Humanos , Leiomiossarcoma/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , PrognósticoRESUMO
BACKGROUND: To better characterize the pathophysiology of juvenile nasopharyngeal angiofibroma (JNA), endothelial and stromal cells were evaluated by genomic imbalances in association with transcript expression levels of genes mapped on these altered regions. METHODS: High-resolution comparative genomic hybridization (HR-CGH) was used in laser-captured endothelial and stromal cells from 9 JNAs. Ten genes were evaluated by quantitative real-timereverse transcription polymerase chain reaction (qRT-PCR) in 15 cases. RESULTS: Although gains were more frequently detected in endothelial cells, 57% of chromosomal alterations were common by both components. Gene expression analyses revealed a positive correlation between endothelial and stromal components for ASPM, CDH1, CTNNB1, FGF18, and SUPT16H. A significant difference was found for FGF18 and AURKB overexpression in stromal cells and AR down-expression in endothelial cells. CONCLUSIONS: A similar pattern of gene expression and chromosomal imbalances in both exponents would suggest a common mechanism of functional regulation. AURKB, FGF18, and SUPT16H were identified as potential molecular markers in JNA.
Assuntos
Angiofibroma/genética , Aberrações Cromossômicas , Predisposição Genética para Doença , Neoplasias Nasofaríngeas/genética , Microambiente Tumoral/genética , Adolescente , Angiofibroma/patologia , Hibridização Genômica Comparativa/métodos , Intervalos de Confiança , Regulação Neoplásica da Expressão Gênica/genética , Instabilidade Genômica , Humanos , Masculino , Neoplasias Nasofaríngeas/patologia , Reação em Cadeia da Polimerase em Tempo Real/métodos , Estudos de Amostragem , Inclusão do Tecido , Adulto JovemRESUMO
O sarcoma pleomórfico indiferenciado (SPI) é uma lesão de alto grau que, em geral, exibe um comportamento clinicamente agressivo com o desenvolvimento frequente de metástases à distância e recidiva local. Estes tumores são caracterizados por alterações genômicas complexas e considerável heterogeneidade biológica intratumoral. A classificação dos SPI é uma questão controversa pelo fato destes tumores compartilharem um padrão morfológico similar com outros subtipos indiferenciados e pleomórficos de outras entidades definidas de sarcomas, particularmente leiomiossarcomas (LMS). O objetivo deste estudo foi caracterizar o perfil de alterações no número de cópias genômicas em SPI e LMS e correlacionar os resultados com os dados clínicos e histopatológicos. Foram avaliados 20 SPI e 17 LMS por CGH-array (Agilent Human 4x44K CGH Microarrays). Os dados foram extraídos usando o software Feature Extraction 10.1.1.1.1 e análise dos resultados foi realizada no programa Nexus 6.0 (Biodiscovery) com algoritmo estatístico FASST segmentation 2 e limiar de significância de 1,00E-5. Foram identificadas 31 alterações genômicas significativas associadas com características de pior prognóstico. Entre os SPI, os ganhos em 16q24.3 e perdas em 18p11.32 foram significativamente associados a pacientes sem sinais da doença (P = 0,043) e com a doença (P = 0,016), respectivamente. Entre os LMS, ganhos em 1q21.3, 11q12.2-q12.3 e 19q13.12 foram significativamente associados a pacientes que morreram pela doença (P = 0,001, P = 0,003 e P = 0,020, respectivamente). Ganhos em 1q21.3 foram também correlacionados com desenvolvimento de metástases a distância (P = 0,001). Em adição, os ganhos em 17q25.1 e 19q13.43, assim como as perdas em 16p11.2 foram associados significativamente com recorrência local em LMS (P = 0,041, P = 0,044 e P = 0,006, respectivamente)...