RESUMO
OBJECTIVES: Prior studies have shown that allelic loss on chromosome 1p36 occurs frequently in ovarian as well as several other types of cancer. This suggests that inactivation of gene(s) in this region may play a role in the pathogenesis of these cancers. The aim of this study was to further delineate the region of loss on chromosome 1p36 in ovarian cancers and to identify associated patient or tumor characteristics. METHODS: Paired normal/cancer DNA samples from 75 ovarian cancers (21 early stage I/II and 54 advanced stage III/IV) were analyzed using microsatellite markers. RESULTS: Forty-nine of 75 (65%) ovarian cancers had loss of at least one marker. The marker demonstrating the most frequent loss was D1S1597, which was lost in 29/57 (51%) informative cases. Allele loss on 1p36 was significantly more common in poorly differentiated ovarian cancers (73%) relative to well or moderately differentiated cases (48%) (P = 0.03). Evidence was obtained for two common regions of deletion: one flanked by D1S1646/D1S244 and another more proximally by D1S244/D1S228. CONCLUSION: These findings further delineate regions on chromosome 1p36 proposed to contain tumor suppressor gene(s) that may play a role in the development and/or progression of epithelial ovarian carcinoma. Allele loss on 1p36 is associated with poor histologic grade.
Assuntos
Alelos , Cromossomos Humanos Par 1/genética , Neoplasias Ovarianas/genética , DNA de Neoplasias/análise , Feminino , Genes Supressores de Tumor/genética , Humanos , Perda de Heterozigosidade , Repetições de Microssatélites , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Reação em Cadeia da PolimeraseRESUMO
Expression of 14-3-3 final sigma (final sigma) is induced in response to DNA damage, and causes cells to arrest in G(2). By SAGE (serial analysis of gene expression) analysis, we identified final sigma as a gene whose expression is 7-fold lower in breast carcinoma cells than in normal breast epithelium. We verified this finding by Northern blot analysis. Remarkably, final sigma mRNA was undetectable in 45 of 48 primary breast carcinomas. Genetic alterations at final sigma such as loss of heterozygosity were rare (1/20 informative cases), and no mutations were detected (0/34). On the other hand, hypermethylation of CpG islands in the final sigma gene was detected in 91% (75/82) of breast tumors and was associated with lack of gene expression. Hypermethylation of final sigma is functionally important, because treatment of final sigma-non-expressing breast cancer cell lines with the drug 5-aza-2'-deoxycytidine resulted in demethylation of the gene and synthesis of final sigma mRNA. Breast cancer cells lacking final sigma expression showed increased number of chromosomal breaks and gaps when exposed to gamma-irradiation. Therefore, it is possible that loss of final sigma expression contributes to malignant transformation by impairing the G(2) cell cycle checkpoint function, thus allowing an accumulation of genetic defects. Hypermethylation and loss of final sigma expression are the most consistent molecular alterations in breast cancer identified so far.
Assuntos
Neoplasias da Mama/genética , Proteínas de Ciclo Celular/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Proteínas/genética , Tirosina 3-Mono-Oxigenase , Proteínas 14-3-3 , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Mama/citologia , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular/biossíntese , Proteínas de Ciclo Celular/fisiologia , Linhagem Celular/efeitos dos fármacos , Linhagem Celular Transformada/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Ilhas de CpG , Metilação de DNA/efeitos dos fármacos , Reparo do DNA/genética , Decitabina , Células Epiteliais/metabolismo , Feminino , Fase G2/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiologia , Biossíntese de Proteínas , Proteínas/fisiologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Tolerância a Radiação/genética , Proteínas Recombinantes de Fusão/fisiologia , Transcrição Gênica , Transfecção , Células Tumorais Cultivadas/metabolismoRESUMO
The recently described Bcl10 gene has been suggested to be a major target gene for inactivation in a variety of human cancers. In order to further evaluate the role of this gene in human adult malignancies, we have analysed a series of carcinomas for mutations in the Bcl10 gene. We have screened a panel of 174 carcinoma samples in total, comprised of 47 breast, 36 epithelial ovarian, 36 endometrial, 12 cervical, 23 colorectal and 20 head/neck carcinomas, all unselected for grade or stage. This panel reflects, in part, tumours reported to have involvement of the 1p22 region of chromosome 1, the region harbouring the Bcl10 gene. No deleterious mutations were detected in any of the samples analysed, strongly suggesting that Bcl10 is not a common target for inactivation in adult malignancies and that BCL10 is not the gene targeted for frequent inactivation at 1p22.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Neoplasias Colorretais/genética , Neoplasias dos Genitais Femininos/genética , Neoplasias de Cabeça e Pescoço/genética , Mutação , Proteínas de Neoplasias/genética , Adulto , Proteína 10 de Linfoma CCL de Células B , Feminino , Humanos , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita SimplesRESUMO
Endometrial carcinoma is the second most common tumor type in women with hereditary nonpolyposis colorectal carcinoma. Microsatellite instability (MI) has been observed in the inherited (hereditary nonpolyposis colorectal carcinoma-associated) form of endometrial carcinoma as well as in approximately 20% of presumably sporadic cases. Recent studies suggest that MI in many cell lines or xenografts derived from sporadic colorectal carcinomas is not attributable to mutations in four known human DNA mismatch repair (MMR) genes (hMSH2, hMLH1, hPMS1, and hPMS2). Mutational analyses of these four MMR genes in endometrial carcinomas have not been previously reported. We analyzed nine sporadic MI-positive primary endometrial carcinomas for mutations in the above four MMR genes. Mutations were detected in two tumors (in hMSH2), and both of the mutations were acquired somatically. Immunohistochemical staining revealed a lack of expression of hMSH2 protein in the two tumors containing hMSH2 mutations. Our data suggest that mutations in these four known DNA MMR genes are not responsible for MI in the majority of sporadic endometrial carcinomas displaying this phenotype.