RESUMO
Fusion genes resulting from chromosomal rearrangements represent a hallmark of childhood acute lymphoblastic leukemia (ALL). Unlike more common fusion genes generated via simple reciprocal chromosomal translocations, formation of the ETV6-ABL1 fusion gene requires 3 DNA breaks and usually results from an interchromosomal insertion. We report a child with ALL in which a single interchromosomal insertion led to the formation of ETV6-ABL1 and 2 novel fusion genes: AIF1L-ETV6 and ABL1-AIF1L. We demonstrate the prenatal origin of this complex chromosomal rearrangement, which apparently initiated the leukemogenic process, by successful backtracking of the ETV6-ABL1 fusion into the patient's archived neonatal blood. We cloned coding sequences of AIF1L-ETV6 and ABL1-AIF1L in-frame fusion transcripts from the patient's leukemic blasts and we show that the chimeric protein containing the DNA binding domain of ETV6 is expressed from the AIF1L-ETV6 transcript and localized in both the cytoplasm and nucleus of transfected HEK293T cells. Transcriptomic and genomic profiling of the diagnostic bone marrow sample revealed Ph-like gene expression signature and loss of the IKZF1 and CDKN2A/B genes, the typical genetic lesions accompanying ETV6-ABL1-positive ALL. The prenatal origin of the rearrangement confirms that ETV6-ABL1 is not sufficient to cause overt leukemia, even when combined with the 2 novel fusions. We did not find the AIF1L-ETV6 and ABL1-AIF1L fusions in other ETV6-ABL1-positive ALL. Nevertheless, functional studies would be needed to establish the biological role of AIF1L-ETV6 and ABL1-AIF1L and to determine whether they contribute to leukemogenesis and/or to the final leukemia phenotype.
Assuntos
Proteínas de Ligação a DNA/genética , Proteínas Oncogênicas v-abl/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Proteínas de Ligação ao Cálcio , Aberrações Cromossômicas , Proteínas de Ligação a DNA/sangue , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células HEK293 , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Cariotipagem , Masculino , Proteínas dos Microfilamentos , Proteínas Oncogênicas v-abl/sangue , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Proteínas Proto-Oncogênicas c-ets/sangue , Proteínas Repressoras/sangue , Transcriptoma/genética , Translocação Genética/genética , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
Circulating tumor cells (CTCs) have been implicated in tumor progression and prognosis. Techniques detecting CTCs in the peripheral blood of patients with non-small cell lung carcinoma (NSCLC) may help to identify individuals likely to benefit from early systemic treatment. However, the detection of CTCs with a single marker is challenging, owing to low specificity and sensitivity and due to the heterogeneity and rareness of CTCs. Herein, the probability of cell-free RNA content in the peripheral blood as a potential biomarker for detecting CTCs in cancer patients was investigated. An immunomagnetic enrichment of real-time reverse-transcription PCR (RT-PCR) technology for analysis of CTCs in NSCLC patients was also developed. The mRNA levels of four candidate genes, cytokeratin 7 (CK7), E74-like factor 3 (ELF3), epidermal growth factor receptor (EGFR), and erythropoietin-producing hepatocellular carcinoma receptor B4 (EphB4) that were significantly elevated in tumor tissues and peripheral blood mononuclear cells (PBMCs) were determined. The expression of CK7 and ELF3 in tumor tissues and EGFR in PBMCs was associated with lymph node metastasis (all p < 0.05). The expression of CK7 in PBMCs was correlated with age and EphB4 in PBMCs correlated with histopathological type, respectively (all p < 0.05). The expression of all four genes in tumor tissues and PBMCs was significantly correlated with the clinical stage (all p < 0.01). Survival analysis showed that the patients with enhanced expression of CK7, ELF3, EGFR, and EphB4 mRNA in PBMCs had poorer disease-free survival (DFS) and overall survival (OS) than those without (all p < 0.0001). The present study showed that this alteration of cell-free RNA content in peripheral blood might have clinical ramifications in the diagnosis and treatment of NSCLC patients.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Proteínas de Ligação a DNA/genética , Receptores ErbB/genética , Queratina-7/genética , Neoplasias Pulmonares/diagnóstico , Proteínas Proto-Oncogênicas c-ets/genética , RNA Neoplásico/genética , Receptor EphB4/genética , Fatores de Transcrição/genética , Adulto , Idoso , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Proteínas de Ligação a DNA/sangue , Receptores ErbB/sangue , Feminino , Humanos , Separação Imunomagnética/métodos , Queratina-7/sangue , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Prognóstico , Proteínas Proto-Oncogênicas c-ets/sangue , RNA Mensageiro/sangue , RNA Mensageiro/genética , RNA Neoplásico/sangue , Reação em Cadeia da Polimerase em Tempo Real/métodos , Receptor EphB4/sangue , Análise de Sobrevida , Fatores de Transcrição/sangueRESUMO
The introduction and widespread adoption of prostate-specific antigen (PSA) has revolutionized the way prostate cancer is diagnosed and treated. However, the use of PSA has also led to overdiagnosis and overtreatment of prostate cancer resulting in controversy about its use for screening. PSA also has limited predictive accuracy for predicting outcomes after treatment and for making clinical decisions about adjuvant and salvage therapies. Hence, there is an urgent need for novel biomarkers to supplement PSA for detection and management of prostate cancer. A plethora of promising blood- and urine-based biomarkers have shown promise in early studies and are at various stages of development (Human kallikrein 2, Early Prostate Cancer Antigen, Transforming Growth Factor-Beta 1 and Interleukin-6, Endoglin, PCA3, AMACR and ETS Gene Fusions). In this article, we review those biomarkers and then discuss the challenges a biomarker has to undergo before it is approved in a clinical use.