AIM: To investigate the significance of p16 and O6- methylguanine-DNA methyltransferase (MGMT) genes promoter hypermethylation and K-ras mutations on colorectal tumorigenesis and progression. METHODS: p16 and MGMT met...AIM: To investigate the significance of p16 and O6- methylguanine-DNA methyltransferase (MGMT) genes promoter hypermethylation and K-ras mutations on colorectal tumorigenesis and progression. METHODS: p16 and MGMT methylation status was examined on 47 tumor samples, and K-ras mutational status was examined on 85 tumor samples. For methylation analysis, a methylation specific PCR (MS-PCR) method was used. RESULTS: p16 and MGMT promoter methylation was found in 51% (24/47) and 43% (20/47) of CRCs, respectively, and the K-ras mutation was found in 44% (37/85) of CRCs. Comethylation of p16 and MGMT genes was significantly associated with lower aggressiveness of the disease within a two-year period of observation. Only 27% of patients with simultaneous p 16 and MGMT methylation showed the detectible occurrence of metastasis and/or death, compared to 67% of patients without double methylation or with no methylation (3/11 vs 22/33, P < 0.05, χ2-test). In addition, p16 and MGMT comethylation showed a trend toward an association with longer survival in patients with CRCs (35.5 ± 6.0 mo vs 23.1 ± 3.2 mo, P = 0.072, Log-rank test). Progression of the disease within a two-year period was observed in 66% of patients carrying the K-ras mutation, compared to only 19% of patients with wild type K-ras (29/44 vs 7/37, P < 0.001, χ2-test). The presence of the K-ras mutation significantly correlated to shortened overall survival (20.0 ± 1.9 mo vs 37.0 ± 1.8 mo, P < 0.001, Log-rank test). The comethylation of p16 and MGMT genes was significantly associated with lower aggressiveness of the disease even when K-ras mutations were included in the analysis as an independent variable. CONCLUSION: Our data suggest that comethylation of promoters of p 16 and MGMT genes could have a prognostic value in patients with CRC. Specifically, concurrent methylation of both genes correlates with better prognosis.展开更多
Peripheral T-cell lymphoma, not otherwise specified （PTCL-NOS） is a heterogeneous group of aggressive T-ce lymphomas with no treatment consensus and poor prognosis. We herein described an extraordinary refractory ca...Peripheral T-cell lymphoma, not otherwise specified （PTCL-NOS） is a heterogeneous group of aggressive T-ce lymphomas with no treatment consensus and poor prognosis. We herein described an extraordinary refractory case of PTCL-NOS with widely involvement of subcutaneous tissue, which showed an excellent response to Semustine personal- ized chemotherapy based on the detection finding of positive O6-methylguanine-DNA methyltransferase （MGMT） promoter methylation. This is the first english report to indicate that single nitrosourea agent such as Semustine may have good efficacy and safety for widespread subcutaneous involvement of PTCL-NOS with positive MGMT promoter methylation.展开更多
Objective:This phase II study aimed at investigating the correlation between O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and protein expression,together with Ki-67 labeling index (LI),to respons...Objective:This phase II study aimed at investigating the correlation between O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and protein expression,together with Ki-67 labeling index (LI),to response,time to progression (TTP),and overall survival (OS) in newly diagnosed glioblastoma multiforme (GBM) patients treated with temozolomide (TMZ) concomitant with and adjuvant to radiotherapy (RT).Methods:From June 2005 to August 2008,34 adult patients (18-65 years),PS ≥70,with newly diagnosed GBM received TMZ 75 mg/m2 plus RT up to 60 Gy,followed by TMZ 175 mg/m2 5 days every 4 weeks for 12 doses.MGMT Methylation-specific PCR assay,MGMT protein expression,and Ki-67 expression using immunohistochemistry (IHC) were performed on the tissue blocks.The patients were followed by MRI while MR spectroscopy (MRS) was performed for the stable cases or to confirm progression and accordingly Bevacizumab 10 mg/kg every 2 weeks was added to 7 patients till further progression was proved.Results:31 cases were evaluable,12 (38.7%) had unmethylated MGMT,while 19 (61.3%) were methylated.Seventeen cases (55%) were MGMT immunonegative while 14 cases (45%) were immunopositive.The cut off value of Ki-67 LI in relation to survival was 17%,where 15 were < 17% (48.4%),and 16 were ≥ 17% (51.6%).Response evaluation started after the second dose of the adjuvant TMZ and was repeated every 2 months.The overall disease control rate (ODC) was 74.2%,where 2 patients had complete response (CR),14 had partial response (PR),and 7 had stable disease (SD),while 8 (25.8%) had progressive disease (PD).The ODC was significantly higher among methylated patients and in those with Ki-67 < 17% (P=0.0003).The median overall TTP was 12 months and the median OS was 20 months for all the patients including those who received Bevacizumab for some stable cases or as a salvage treatment in patients with good PS,the MGMT-methylated patients had a higher median TTP of 13 months (range 8 to 18 months,95% CI of 9.36 to 12.9),and OS of 24 months (range 12 to 31 months,95% CI of 16.1 to 21.32),while the unmethylated patients had a median TTP of 6.5 months and a median OS of 12 months,such correlations were highly significant (P=0.0001).MGMT immunoexpression failed to show significant correlation with MGMT promotor methylation or the outcome of the patients.Patients with Ki-67 < 17% had a median TTP of 16 months and median OS of 24 months compared to 7 and 12.5 months respectively for the patients with Ki-67 ≥17%.Significant correlation was found between the ODC,TTP,and OS with age < 52,near total excision,and TMZ doses received ≥ 10.The commonest grade 3 and 4 toxicities was neutropenia recorded in 3 patients (9.67%),thrombocytopenia in 4 patients (12.9%),and one patient with G3 nausea,vomiting,and constipations (3%),all were medically manageable.Conclusion:MGMT promotor methylation status and Ki-67 LI (but not the MGMT protein expression),could serve as prognostic markers for survival,also MGMT could identify the newly diagnosed GBM patients who will have better response to TMZ.展开更多
OBJECTIVE This study is to investigate the prevalence ofpromoter CpG island methylation of O^6-methylguananine-DNAmethyltransferase (MGMT), mismatch repair genes (hMLH1 andhMSH2) in both tumor and serum samples of gli...OBJECTIVE This study is to investigate the prevalence ofpromoter CpG island methylation of O^6-methylguananine-DNAmethyltransferase (MGMT), mismatch repair genes (hMLH1 andhMSH2) in both tumor and serum samples of gliomas.METHODS Methylation-specific PCR (MSP) was employed todetect promoter CpG island methylation of the MGMT, hMLH1and hMSH2 genes in 39 samples taken from surgery and 32samples of pretreatment serum all from the patients with gliomas.RESULTS Promoter CpG island methylation of MGMT, hMLH1and hMSH2 was detected and the results were 46.2%, 10.3% and20.5%, respectively in tumor DNA of the cases with gliomas,and 40.6%, 9.4% and 18.8%, respectively in serum DNA of thecases. The methylation pattern in primary tumor and serum wasfound to be concordant in matched tissue and serum samplesof 21 patients. In the cases with positive result of methylationfor MGMT, hMLH1 and hMSH2 in tumor tissues, the results ofdetection for those in the paired serum sample were 77.8% (7/9),66.7% (2/3) and 75.0 % (3/4), respectively. False positive resultswere not obtained in any of the patients who did not exhibitmethylation. No association was found between the promotermethylation of MGMT, hMLH1, and hMSH2 genes in primarygliomas and gender, age, localization, grade of malignant or tumorstage.CONCLUSION Promoter CpG island methylation is a frequentevent in gliomagenesis. Methylation analysis appears to bea promising predictive factor of the prognosis for the gliomapatients treated with alkylating drugs and a noninvasive tumormarker in serum DNA.展开更多
基金Supported by the grant 143010 from the Ministry of Science and Environment Protection of the Republic of Serbia
文摘AIM: To investigate the significance of p16 and O6- methylguanine-DNA methyltransferase (MGMT) genes promoter hypermethylation and K-ras mutations on colorectal tumorigenesis and progression. METHODS: p16 and MGMT methylation status was examined on 47 tumor samples, and K-ras mutational status was examined on 85 tumor samples. For methylation analysis, a methylation specific PCR (MS-PCR) method was used. RESULTS: p16 and MGMT promoter methylation was found in 51% (24/47) and 43% (20/47) of CRCs, respectively, and the K-ras mutation was found in 44% (37/85) of CRCs. Comethylation of p16 and MGMT genes was significantly associated with lower aggressiveness of the disease within a two-year period of observation. Only 27% of patients with simultaneous p 16 and MGMT methylation showed the detectible occurrence of metastasis and/or death, compared to 67% of patients without double methylation or with no methylation (3/11 vs 22/33, P < 0.05, χ2-test). In addition, p16 and MGMT comethylation showed a trend toward an association with longer survival in patients with CRCs (35.5 ± 6.0 mo vs 23.1 ± 3.2 mo, P = 0.072, Log-rank test). Progression of the disease within a two-year period was observed in 66% of patients carrying the K-ras mutation, compared to only 19% of patients with wild type K-ras (29/44 vs 7/37, P < 0.001, χ2-test). The presence of the K-ras mutation significantly correlated to shortened overall survival (20.0 ± 1.9 mo vs 37.0 ± 1.8 mo, P < 0.001, Log-rank test). The comethylation of p16 and MGMT genes was significantly associated with lower aggressiveness of the disease even when K-ras mutations were included in the analysis as an independent variable. CONCLUSION: Our data suggest that comethylation of promoters of p 16 and MGMT genes could have a prognostic value in patients with CRC. Specifically, concurrent methylation of both genes correlates with better prognosis.
文摘Peripheral T-cell lymphoma, not otherwise specified （PTCL-NOS） is a heterogeneous group of aggressive T-ce lymphomas with no treatment consensus and poor prognosis. We herein described an extraordinary refractory case of PTCL-NOS with widely involvement of subcutaneous tissue, which showed an excellent response to Semustine personal- ized chemotherapy based on the detection finding of positive O6-methylguanine-DNA methyltransferase （MGMT） promoter methylation. This is the first english report to indicate that single nitrosourea agent such as Semustine may have good efficacy and safety for widespread subcutaneous involvement of PTCL-NOS with positive MGMT promoter methylation.
文摘Objective:This phase II study aimed at investigating the correlation between O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and protein expression,together with Ki-67 labeling index (LI),to response,time to progression (TTP),and overall survival (OS) in newly diagnosed glioblastoma multiforme (GBM) patients treated with temozolomide (TMZ) concomitant with and adjuvant to radiotherapy (RT).Methods:From June 2005 to August 2008,34 adult patients (18-65 years),PS ≥70,with newly diagnosed GBM received TMZ 75 mg/m2 plus RT up to 60 Gy,followed by TMZ 175 mg/m2 5 days every 4 weeks for 12 doses.MGMT Methylation-specific PCR assay,MGMT protein expression,and Ki-67 expression using immunohistochemistry (IHC) were performed on the tissue blocks.The patients were followed by MRI while MR spectroscopy (MRS) was performed for the stable cases or to confirm progression and accordingly Bevacizumab 10 mg/kg every 2 weeks was added to 7 patients till further progression was proved.Results:31 cases were evaluable,12 (38.7%) had unmethylated MGMT,while 19 (61.3%) were methylated.Seventeen cases (55%) were MGMT immunonegative while 14 cases (45%) were immunopositive.The cut off value of Ki-67 LI in relation to survival was 17%,where 15 were < 17% (48.4%),and 16 were ≥ 17% (51.6%).Response evaluation started after the second dose of the adjuvant TMZ and was repeated every 2 months.The overall disease control rate (ODC) was 74.2%,where 2 patients had complete response (CR),14 had partial response (PR),and 7 had stable disease (SD),while 8 (25.8%) had progressive disease (PD).The ODC was significantly higher among methylated patients and in those with Ki-67 < 17% (P=0.0003).The median overall TTP was 12 months and the median OS was 20 months for all the patients including those who received Bevacizumab for some stable cases or as a salvage treatment in patients with good PS,the MGMT-methylated patients had a higher median TTP of 13 months (range 8 to 18 months,95% CI of 9.36 to 12.9),and OS of 24 months (range 12 to 31 months,95% CI of 16.1 to 21.32),while the unmethylated patients had a median TTP of 6.5 months and a median OS of 12 months,such correlations were highly significant (P=0.0001).MGMT immunoexpression failed to show significant correlation with MGMT promotor methylation or the outcome of the patients.Patients with Ki-67 < 17% had a median TTP of 16 months and median OS of 24 months compared to 7 and 12.5 months respectively for the patients with Ki-67 ≥17%.Significant correlation was found between the ODC,TTP,and OS with age < 52,near total excision,and TMZ doses received ≥ 10.The commonest grade 3 and 4 toxicities was neutropenia recorded in 3 patients (9.67%),thrombocytopenia in 4 patients (12.9%),and one patient with G3 nausea,vomiting,and constipations (3%),all were medically manageable.Conclusion:MGMT promotor methylation status and Ki-67 LI (but not the MGMT protein expression),could serve as prognostic markers for survival,also MGMT could identify the newly diagnosed GBM patients who will have better response to TMZ.
基金supported by a grant from National Natural Science Foundation of China(No.30671995).
文摘OBJECTIVE This study is to investigate the prevalence ofpromoter CpG island methylation of O^6-methylguananine-DNAmethyltransferase (MGMT), mismatch repair genes (hMLH1 andhMSH2) in both tumor and serum samples of gliomas.METHODS Methylation-specific PCR (MSP) was employed todetect promoter CpG island methylation of the MGMT, hMLH1and hMSH2 genes in 39 samples taken from surgery and 32samples of pretreatment serum all from the patients with gliomas.RESULTS Promoter CpG island methylation of MGMT, hMLH1and hMSH2 was detected and the results were 46.2%, 10.3% and20.5%, respectively in tumor DNA of the cases with gliomas,and 40.6%, 9.4% and 18.8%, respectively in serum DNA of thecases. The methylation pattern in primary tumor and serum wasfound to be concordant in matched tissue and serum samplesof 21 patients. In the cases with positive result of methylationfor MGMT, hMLH1 and hMSH2 in tumor tissues, the results ofdetection for those in the paired serum sample were 77.8% (7/9),66.7% (2/3) and 75.0 % (3/4), respectively. False positive resultswere not obtained in any of the patients who did not exhibitmethylation. No association was found between the promotermethylation of MGMT, hMLH1, and hMSH2 genes in primarygliomas and gender, age, localization, grade of malignant or tumorstage.CONCLUSION Promoter CpG island methylation is a frequentevent in gliomagenesis. Methylation analysis appears to bea promising predictive factor of the prognosis for the gliomapatients treated with alkylating drugs and a noninvasive tumormarker in serum DNA.
