RESUMO
Association of gene alterations and prognosis has not fully been elucidated in hepatocellular carcinoma (HCC). To clarify the relationship between p53 and hMSH2 mutations and prognosis, we analysed these mutations in 83 HCC cases and assessed their association with various clinicopathological factors. The 3-year disease-free survival (DFS) or overall survival (OS) rates in HCC patients with p53 mutation and p53 wild/hMSH2 mutation significantly decreased compared with those without these mutations (14.3% and 37.5% versus 67.5% for DFS; 35.7% and 50.0% versus 96.4% for OS, respectively). In the multivariate analysis, categories by p53 and hMSH2 mutation status, and liver cirrhosis demonstrated statistical significances for DFS and OS. Moreover, the frequency of patients with p53 and/or hMSH2 mutations in intrahepatic metastasis (75.0%) was significantly higher than that in multicentric occurrence (14.3%). Thus, p53 and hMSH2 mutations will be useful for identifying subsets of HCC patients with poor prognosis.
Assuntos
Carcinoma Hepatocelular/genética , Genes p53 , Neoplasias Hepáticas/genética , Proteína 2 Homóloga a MutS/genética , Mutação/genética , Idoso , Análise de Variância , Carcinoma Hepatocelular/mortalidade , Intervalo Livre de Doença , Éxons/genética , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo Conformacional de Fita Simples , PrognósticoRESUMO
The risk for hepatocellular carcinoma (HCC) development is significantly heightened in the atomic bomb survivors, but the mechanism is unclear. We have previously reported finding a radiation dose-dependent increase in HCCs with TP53 mutations from the survivors. We now show that, in the same HCC samples, the frequency of 3'-untranslated region (3'UTR) mutations in M6P/IGF2R, a candidate HCC tumor suppressor gene, decreases with dose (P = 0.0091), implying a radiation dose-dependent negative selection of cells harboring such mutations. The fact that they were in the 3'UTR implicates changes in transcript stability rather than in protein function as the mechanism. Moreover, these M6P/IGF2R 3'UTR mutations and the TP53 mutations detected previously were mutually exclusive in most of the tumors, suggesting two independent pathways to HCC development, with the TP53 pathway being more favored with increasing radiation dose than the M6P/IGF2R pathway. These results suggest that tumors attributable to radiation may be genotypically different from tumors of other etiologies and hence may provide a way of distinguishing radiation-induced cancers from "background" cancers--a shift from the current paradigm.
Assuntos
Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/genética , Neoplasias Induzidas por Radiação/epidemiologia , Neoplasias Induzidas por Radiação/genética , Guerra Nuclear/estatística & dados numéricos , Receptor IGF Tipo 2/genética , Carga Corporal (Radioterapia) , Análise Mutacional de DNA , Relação Dose-Resposta à Radiação , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Incidência , Japão/epidemiologia , Masculino , Manosefosfatos/genética , Mutação , Doses de Radiação , Medição de Risco/métodos , Fatores de Risco , Sobreviventes/estatística & dados numéricosRESUMO
Individuals who are homozygotes for mutations in DNA repair genes are at high risk for cancer. It is not well documented, however, if the heterozygous carriers of the mutation are also predisposed to cancer. To address the issue, xeroderma pigmentosum (XP) in Japan is an interesting candidate because of three major reasons: XP is an autosomal recessive disorder with an enormously elevated risk of skin cancer, the frequency of XP patients is higher in Japan than in other parts of the world, and more than half of Japanese XP patients are homozygous for the same founder mutation in the XPA gene. We screened archival blood samples from Japanese individuals who resided in Hiroshima or Nagasaki. A simple PCR-RFLP method was developed that is highly specific for detection of XPA heterozygotes carrying the founder mutation. We identified nine XPA heterozygotes among 1,020 individuals screened for a prevalence of 0.88%. This rate, if representative, implies that there are about 1 million carriers of the XPA founder mutation in the Japanese population. Thus, investigation of their cancer risk may be warranted.
Assuntos
Efeito Fundador , Heterozigoto , Mutação/genética , Proteína de Xeroderma Pigmentoso Grupo A/genética , Adolescente , Adulto , Povo Asiático/genética , Estudos de Coortes , Frequência do Gene , Predisposição Genética para Doença/genética , Humanos , Japão , Reação em Cadeia da Polimerase/métodos , Xeroderma Pigmentoso/genéticaRESUMO
PURPOSE: BRAF mutations are common in sporadic colorectal cancers (CRCs) with a DNA mismatch repair (MMR) deficiency that results from promoter methylation of hMLH1, whereas KRAS mutations are common in MMR proficient CRCs associated with promoter methylation of MGMT. The aim of this study was to further investigate the link between genetic alterations in the RAS/RAF/ERK pathway and an underlying epigenetic disorder. PATIENTS AND METHODS: Activating mutations of BRAF and KRAS were identified and correlated with promoter methylation of 11 loci, including MINT1, MINT2, MINT31, CACNA1G, p16(INK4a), p14(ARF), COX2, DAPK, MGMT, and the two regions in hMLH1 in 468 CRCs and matched normal mucosa. RESULTS: BRAF V599E mutations were identified in 21 (9%) of 234 CRCs, and KRAS mutations were identified in 72 (31%) of 234 CRCs. Mutations in BRAF and KRAS were never found in the same tumor. CRCs with BRAF mutations showed high-level promoter methylation in multiple loci, with a mean number of methylated loci of 7.2 (95% CI, 6.6 to 7.9) among 11 loci examined (P < .0001). Tumors with KRAS mutations showed low-level promoter methylation, and CRCs with neither mutation showed a weak association with promoter methylation, with an average number of methylated loci of 1.8 (95% CI, 1.5 to 2.1) and 1.0 (95% CI, 0.79 to 1.3), respectively. CONCLUSION: In CRC, the methylation status of multiple promoters can be predicted through knowledge of BRAF and, to a lesser extent, KRAS activating mutations, indicating that these mutations are closely associated with different patterns of DNA hypermethylation. These changes may be important events in colorectal tumorigenesis.
Assuntos
Neoplasias Colorretais/genética , Metilação de DNA , Genes ras/genética , Proteínas Proto-Oncogênicas B-raf/genética , Idoso , Estudos de Casos e Controles , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Reparo do DNA , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Regiões Promotoras GenéticasRESUMO
PURPOSE: Allelic loss involving chromosome arms 5q, 8p, 17p, and 18q is commonly detected in colorectal cancer (CRC). The short arm of chromosome 1 is also frequently affected in a whole range of cancer types, including CRC. Our aim in the present study was to determine whether allelic losses on 1p were likely to be of much value in predicting the prognosis of CRC cases. EXPERIMENTAL DESIGN: Genomic DNA was prepared from tumor and corresponding normal tissue specimens from 90 patients who had undergone curative resection for CRC. Loss of heterozygosity (LOH) on chromosome arms 1p, 2p, 5q, 7q, 8p, 17p, 17q, and 18q was examined using 14 microsatellite markers, and possible correlations between LOH and clinicopathological factors (including tumor recurrence and patient survival) were investigated. LOH at the MYCL1 microsatellite marker at 1p34 was detected in 12 of 74 (16.2%) patients who were informative for this marker. RESULTS: After controlling for tumor stage and gender and excluding findings for patients with remote metastasis, we found that patients who were positive for LOH at MYCL1 were 31 times more likely to experience recurrence than those who were negative for LOH at this locus (95% confidence intervals, 2.27- infinity; P = 0.04). There were indications of a similar tendency for LOH at the 14-3-3-sigma-TG microsatellite marker at 1p35, but we could find no evidence of a significant association between LOH at this site and tumor recurrence or patient survival. We were also unable to detect significant association between LOH at the various sites on 2p, 5q, 7q, 8p, 17p, 17q, and 18q and either tumor recurrence or patient survival. CONCLUSIONS: CRC patients whose tumors exhibited LOH at MYCL1 at chromosome 1p34 were likely to have a poor prognosis, suggesting that this marker may have clinical relevance.
Assuntos
Cromossomos Humanos Par 1/genética , Neoplasias Colorretais/genética , Perda de Heterozigosidade , Repetições de Microssatélites/genética , Mapeamento Cromossômico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , DNA de Neoplasias/genética , DNA de Neoplasias/isolamento & purificação , Intervalo Livre de Doença , Humanos , Estadiamento de Neoplasias , Deleção de Sequência , Análise de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: Because O(6)-methylguanine-DNA methyltransferase (MGMT) plays an essential role in repairing DNA damage caused by environmental alkylating chemicals, we were interested in determining whether we could see any obvious changes in the properties of colorectal cancers (CRCs) in which the MGMT gene had been silenced by hypermethylation and hence in which very few MGMT protein molecules were being produced. EXPERIMENTAL DESIGN: We used a methylation-specific PCR assay to determine the methylation status of the MGMT promoter in the DNA molecules extracted from CRC and nontumor tissue samples from 116 patients who had undergone CRC surgery and for whom clinical outcome information was available on file. RESULTS: We found evidence of MGMT promoter hypermethylation in 26 of 90 CRC cases, and we noted that the later the stage at which a tumor was diagnosed, the less likely its MGMT promoter was to be methylated (P = 0.03, adjusting for chemotherapy), especially for stage D patients (P = 0.01). We also found that CRC patients with unmethylated MGMT promoters were much more likely to experience recurrence within 36 months than patients with hypermethylated MGMT promoters (crude odds ratio, 14.0; 95% confidence interval, 2.42-81.01). After adjustment for stage, CRC patients with unmethylated MGMT promoters who had been exposed to chemotherapy were found to have a 5.3-fold greater risk of recurrence than those who had no exposure to chemotherapy (95% confidence interval, 1.15-30.92). CONCLUSIONS: Hypermethylation of the MGMT promoter may be predictive of a low risk of recurrence in CRC patients receiving adjuvant chemotherapy.
Assuntos
Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Recidiva Local de Neoplasia/genética , O(6)-Metilguanina-DNA Metiltransferase/genética , Regiões Promotoras Genéticas , Idoso , Colo/enzimologia , Neoplasias Colorretais/tratamento farmacológico , Reparo do DNA , Feminino , Regulação Enzimológica da Expressão Gênica , Inativação Gênica , Humanos , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/enzimologia , Valor Preditivo dos Testes , Reto/enzimologiaRESUMO
To study the long-term effects of radiation-induced T-cell depletion on the T-cell receptor (TCR) Vbeta repertoires of human peripheral CD4 T-cell populations, we measured the percentages of CD4 T cells representing each of the full range of possible TCR Vbeta families in a cohort of atomic bomb survivors. We then estimated the extent to which the expression levels for individual TCR Vbeta families differed from the average expression level for that particular TCR Vbeta family across the entire cohort. We found no evidence of a systematic change in the TCR Vbeta repertoires of the naïve CD4 T-cell populations, but memory CD4 T-cell TCR Vbeta family expression levels diverged significantly from the population average for counterpart families, especially in individuals who had been exposed to higher doses and were at least 20 years of age at the time of the bombing. Comparisons of the TCR Vbeta family expression profiles in the naïve and memory CD4 T-cell pools of the same group of adult survivors revealed that differences in the TCR Vbeta repertoires of these two types of CD4 T-cell pool were larger in more heavily exposed survivors than in unexposed controls. These findings suggest that the memory CD4 T-cell pools of individuals who received significant radiation doses in adulthood may well have become (and could still be) dependent upon a much less diverse complement of TCR Vbeta families than would otherwise have been the case.