RESUMEN
Approximately 5%-10% of all breast cancers are inherited as the result of germline mutations in the BRCAl gene. Large genomic rearrangements (LGRs) in BRCA1 have not been well-researched in the Egyptian population. Using multiplex ligation-dependent probe amplification, we showed BRCA1 rearrangements in 4/22 cases (18.2%) of familial breast cancer. No influence of having multiple breast cancer cases within the family was observed in patients diagnosed at
Asunto(s)
Neoplasias de la Mama/genética , Salud de la Familia/estadística & datos numéricos , Genes BRCA1 , Pruebas Genéticas/métodos , Adulto , Edad de Inicio , Anciano , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/epidemiología , Egipto/epidemiología , Femenino , Pruebas Genéticas/estadística & datos numéricos , Humanos , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa Multiplex/métodos , Reacción en Cadena de la Polimerasa Multiplex/estadística & datos numéricosRESUMEN
Approximately 5%-10% of all breast cancers are inherited as the result of germline mutations in the BRCA1 gene. Large genomic rearrangements [LGRs] in BRCA1 have not been well-researched in the Egyptian population. Using multiplex ligation-dependent probe amplification, we showed BRCA1 rearrangements in 4/22 cases [18.2%] of familial breast cancer. No influence of having multiple breast cancer cases within the family was observed in patients diagnosed at < or >/= 45 years and having BRCA1-positive LGRs. However, focusing on cases with first- and second-degree relatives affected, we observed a significant difference between the percentage of patients with BRCA1-positive versus BRCA1-negative LGRs. Our results provide the first evidence that LGRs in BRCA1 exist in the Egyptian population. Screening for these alterations may be desirable when breast cancer patients are diagnosed at an early age, especially if these cases have first- and second-degree of relatives with breast cancer
Asunto(s)
Neoplasias de la Mama , Genómica , Reacción en Cadena de la Polimerasa Multiplex , Mutación , Genes BRCA1RESUMEN
Genome-wide microarray-based comparative genomic hybridization (array CGH) was used to identify common chromosomal alterations involved in cervical carcinogenesis as a first step towards the discovery of novel biomarkers. The genomic profiles of nine squamous cell carcinomas (SCCs) and seven adenocarcinomas (AdCAs), as well as four human papillomavirus (HPV)-immortalized keratinocyte cell lines, were assessed. On a genome-wide scale, SCCs showed significantly more gains than AdCAs. More specifically, there was a striking and highly significant difference between the two histological types for gain at 3q12.1-28, which was predominantly observed in SCC. Other frequent alterations included gains of 1q21.1-31.1 and 20q11.21-13.33, and losses of 11q22.3-25 and 13q14.3-21.33. Subsequent FISH analysis for hTR, located at 3q26, confirmed the presence of 3q gain in SCCs and HPV-immortalized cell lines. Fine mapping of chromosome 20q using multiplex ligation-dependent probe amplification (MLPA) showed copy number increases for a number of genes located at 20q11-q12, including DNMT3B and TOP1. For DNMT3B, this correlated with elevated mRNA expression in 79% of cases. In conclusion, the assessment of frequent genomic alterations resulted in the identification of potential novel biomarkers, which may ultimately enable a better risk stratification of high-risk (hr)-HPV-positive women.
Asunto(s)
Adenocarcinoma/genética , Carcinoma de Células Escamosas/genética , Cromosomas Humanos Par 20/genética , Neoplasias del Cuello Uterino/genética , Adulto , Anciano , Línea Celular Tumoral , Aberraciones Cromosómicas , Mapeo Cromosómico/métodos , Cromosomas Humanos/genética , ADN (Citosina-5-)-Metiltransferasas/genética , Femenino , Genoma Humano/genética , Humanos , Hibridación Fluorescente in Situ/métodos , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Papillomaviridae , ARN Mensajero/análisis , ARN Neoplásico/análisis , ADN Metiltransferasa 3BRESUMEN
BACKGROUND: C-Myc, a well-known oncogene located on 8q24.12-q24.23, is often amplified and over-expressed in both primary and metastasizing colorectal cancer. In addition, PRL-3 (also known as PTP4A3), a tyrosine phosphatase located on 8q24.3, is amplified in colorectal cancer metastasis. Beside PRL-3 and c-myc, other oncogenes located on the 8q23-24 region might be involved in this process. Therefore, the present study aims to correlate DNA copy number status of a series of genes at 8q23-24 in colorectal cancer at high resolution in correlation to metastatic disease. MATERIALS AND METHODS: Thirty-two cases of colorectal cancer, 10 stage B1, 10 B2 and 12 D (Astler-Coller) with their corresponding liver metastasis and one colorectal cell line (colo205, previously analyzed by array-CGH), were included in this study. A chromosome 8 specific MLPA probe mixture was used to analyze the presence of DNA copy number changes. The probe mixture contained 29 probes covering 25 genes on chromosome 8, as well as 6 control probes on other chromosomes. RESULTS AND DISCUSSION: MLPA results obtained of the colo205 colorectal cell line were comparable with previous array-CGH results, thus validating the MLPA probe mixture. Astler-Coller B1 and B2 colorectal cancers differed significantly in DNA copy number of the genes, MOS (p=0.04), MYC (p=0.007), DDEF1 (p=0.004), PTK2 (p=0.02) and PTP4A3 (p=0.04). When comparing these with Astler-Coller D primary tumors, significant differences were seen for several genes as well (MYC (p<0.000), DDEF1 (p<0.000), SLA (p<0.000), PTK2 (p<0.000), PTP4A3 (p=0.002), and RECQL4 (p=0.01)). When comparing primary Astler-Coller D tumors and their corresponding liver metastases, a similar pattern of gains and losses was observed. Most of the liver metastases showed higher DNA copy number ratios than the corresponding primary tumors, but this difference was only significant for TPD52 (p=0.02) and EIF3S6 (p=0.007). CONCLUSION: In addition to c-myc, multiple genes on chromosome 8 differed significantly between primary colorectal cancers with and without liver metastases. This observation is consistent with the concept that clinical behaviour, like risk of liver metastasis, is determined by the genomic profile that is already present in the primary tumor.
Asunto(s)
Cromosomas Humanos Par 8 , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Secuencia de Bases , Línea Celular Tumoral , Neoplasias Colorrectales/metabolismo , ADN/genética , ADN/metabolismo , Cartilla de ADN/química , Genes myc/genética , Humanos , Proteínas Inmediatas-Precoces/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Datos de Secuencia Molecular , Metástasis de la Neoplasia , Proteínas de Neoplasias , Hibridación de Ácido Nucleico , Análisis de Secuencia por Matrices de Oligonucleótidos , Oligonucleótidos/química , Proteínas Tirosina Fosfatasas/genética , Proteínas Tirosina Fosfatasas/metabolismoRESUMEN
Flat adenomas are flat or slightly elevated dysplastic lesions of the colorectal mucosa, mostly with a tubular architecture. Compared with polypoid adenomas of similar size, flat adenomas show a higher frequency of high-grade dysplasia and rapid submucosal invasion. The aim of this study was to survey whether flat colorectal lesions differ in their pattern of chromosomal aberrations from their polypoid counterparts. Six flat adenomas and 12 flat carcinomas were analysed by comparative genomic hybridization (CGH) and the pattern of chromosomal aberrations was compared with a previously published series of 112 polypoid adenomas and 82 polypoid carcinomas. In addition, multiplex ligation-dependent probe amplification (MLPA) for identifying DNA copy number changes of 25 individual genes on chromosome 20 was performed on 14 flat and 15 polypoid tumours. With CGH, flat adenomas showed on average 1.8 gains (range 1-4) and 3.2 losses (range 0-4), and the flat carcinomas 4.5 gains (range 0-8) and 3.5 losses (range 1-6). In both adenomas and carcinomas, high frequencies of 20q gain (83% and 92%, respectively) and 18q loss (83% and 92%, respectively) were found. This correlation between 20q gain and 18q loss had previously been observed in a subgroup of polypoid colorectal tumours. Both flat and polypoid colorectal tumours with 20q gains by CGH showed similar patterns of copy number ratios for the individual genes tested. TOP1, BCL2L1, and E2F1 had median copy number ratios of 2 or higher, while ZNF217 had a ratio around 3. In conclusion, flat adenomas and carcinomas of the large intestine show a similar pattern of chromosomal aberrations to that observed in a specific subgroup of polypoid lesions. The transcription factor ZNF217 is an important candidate for driving the 20q gain.