AIM:To investigate aberrant DNA methylation of CpG islands and subsequent low-or high-level DNA microsatellite instability(MSI)which is assumed to drive colon carcinogenesis. METHODS:DNA of healthy individuals,adenoma...AIM:To investigate aberrant DNA methylation of CpG islands and subsequent low-or high-level DNA microsatellite instability(MSI)which is assumed to drive colon carcinogenesis. METHODS:DNA of healthy individuals,adenoma(tu-bular or villous/tubulovillous)patients,and colorectal carcinoma patients who underwent colonoscopy was used for assessing the prevalence of aberrant DNA methylation of human DNA mismatch repair gene mutator L homologue 1(hMLH1),Cyclin-dependent kinase inhibitor 2A(CDKN2A/p16),and O-6-methylguanine DNA methyltransferase(MGMT),as well as their rela- tion to MSI. RESULTS:The frequency of promoter methylation for each locus increased in the sequence healthy tissue/adenoma/carcinoma.MGMT showed the highest frequency in each group.MGMT and CDKN2A/p16 presented a statistically significant increase in promoter methylation between the less and more tumorigenic forms of colorectal adenomas(tubular vs tubullovillous and villous adenomas).All patients with tubulovillous/villous adenomas,as well as all colorectal cancer patients,showed promoter methylation in at least one of the examined loci.These findings suggest a potentially crucial role for methylation in the polyp/adenoma to cancer progres- sion in colorectal carcinogenesis.MSI and methylation seem to be interdependent,as simultaneous hMLH1, CDKN2A/p16,and MGMT promoter methylation was present in 8/9 colorectal cancer patients showing the MSI phenotype. CONCLUSION:Methylation analysis of hMLH1,CD- KN2A/p16,and MGMT revealed specific methylation profiles for tubular adenomas,tubulovillous/villous adenomas,and colorectal cancers,supporting the use of these alterations in assessment of colorectal tumorigenesis.展开更多
Poly(ADP-ribose)polymerase(PARP)inhibitor(PARPi),as a novel endocrine therapy,has been investigated in patients with metastatic castration-resistant prostate cancer(mCRPC)in recent years.Multiple large-scale clinical ...Poly(ADP-ribose)polymerase(PARP)inhibitor(PARPi),as a novel endocrine therapy,has been investigated in patients with metastatic castration-resistant prostate cancer(mCRPC)in recent years.Multiple large-scale clinical trials have consistently demonstrated that various PARP inhibitors,including olaparib,rucaparib,niraparib,and talazoparib,con-fer longer radiographic progression-free survival(rPFS)compared to new hormonal agents(NHA)in mCRPC patients with homologous recombination deficiency(HRD).Moreover,the incidence of grade 3 and above adverse events did not significantly increase.Additionally,when combined with androgen receptor signaling inhibitors(ARSI),olapa-rib,niraparib,and talazoparib have shown significant extension of rPFS but also an increased occurrence of serious adverse events in HRD-positive patients.Only PROpel yielded positive results among the homologous recombination repair(HRR)mutation negative population.Therefore,it remains uncertain whether ARSI-PARPi combination therapy should be considered as first-line treatment for mCRPC patients without HRR mutations.In this review article,we aim to elucidate the necessity and feasibility of combination therapy versus monotherapy specifically within the HRR mutant population while exploring its potential applicability to other non-HRR mutant subtypes.Furthermore,we conducted a comprehensive search on registered clinical trials at present to summarize the research progress of PARP inhibitors in prostate cancer patients at different disease stages.展开更多
Background Hereditary nonpolyposis colorectal cancer (HNPPC) is one of the most common genetic syndrome related with mutation of human mismatch repair genes. This study was to evaluate the clinical significance of su...Background Hereditary nonpolyposis colorectal cancer (HNPPC) is one of the most common genetic syndrome related with mutation of human mismatch repair genes. This study was to evaluate the clinical significance of suspected hereditary nonpolyposis colorectal cancer (sHNPCC) criteria I and the clinical and genetic features of International Collaborative Group-HNPCC (ICG-HNPCC) and sHNPCC families Methods Twenty-nine ICG-HNPCC families fulfilling the Amsterdam criteria and 34 sHNPCC families fulfilling the sHNPCC criteria I were collected PCR-SSCP and DNA sequencing analysis were employed to screen the germline mutations of the hMLH1 and hMSH2 genes in these families Results The ICG group had more colorectal cancer (CRC) patients per family than did the suspected group ( P <0 05) No statistical difference was observed in Lynch classification and familial tumor spectrum In both groups of families, colorectal cancer was the most frequent malignancy, and carcinomas of the stomach, pancreas and uterus were the three most common extracolonic malignancies Mutation screening showed that ICG-HNPCC and sHNPCC families had a similar mutation rate (31 0% vs 29 4%, P >0 05), mutation type, and mutation distribution Comparison of the families with and without mutation showed no significant difference in CRC patients per family, Lynch classification, and tumor spectrum Conclusions ICG-HNPCC and sHNPCC families that have similar clinical manifestations and genetic basis indicate a similar nature for cancer development The application of sHNPCC criteria I will facilitate clinical diagnosis and treatment of small families展开更多
基金Supported by A 2-year grant of the Greek Ministry of Health and Welfare,No.111K/56
文摘AIM:To investigate aberrant DNA methylation of CpG islands and subsequent low-or high-level DNA microsatellite instability(MSI)which is assumed to drive colon carcinogenesis. METHODS:DNA of healthy individuals,adenoma(tu-bular or villous/tubulovillous)patients,and colorectal carcinoma patients who underwent colonoscopy was used for assessing the prevalence of aberrant DNA methylation of human DNA mismatch repair gene mutator L homologue 1(hMLH1),Cyclin-dependent kinase inhibitor 2A(CDKN2A/p16),and O-6-methylguanine DNA methyltransferase(MGMT),as well as their rela- tion to MSI. RESULTS:The frequency of promoter methylation for each locus increased in the sequence healthy tissue/adenoma/carcinoma.MGMT showed the highest frequency in each group.MGMT and CDKN2A/p16 presented a statistically significant increase in promoter methylation between the less and more tumorigenic forms of colorectal adenomas(tubular vs tubullovillous and villous adenomas).All patients with tubulovillous/villous adenomas,as well as all colorectal cancer patients,showed promoter methylation in at least one of the examined loci.These findings suggest a potentially crucial role for methylation in the polyp/adenoma to cancer progres- sion in colorectal carcinogenesis.MSI and methylation seem to be interdependent,as simultaneous hMLH1, CDKN2A/p16,and MGMT promoter methylation was present in 8/9 colorectal cancer patients showing the MSI phenotype. CONCLUSION:Methylation analysis of hMLH1,CD- KN2A/p16,and MGMT revealed specific methylation profiles for tubular adenomas,tubulovillous/villous adenomas,and colorectal cancers,supporting the use of these alterations in assessment of colorectal tumorigenesis.
文摘Poly(ADP-ribose)polymerase(PARP)inhibitor(PARPi),as a novel endocrine therapy,has been investigated in patients with metastatic castration-resistant prostate cancer(mCRPC)in recent years.Multiple large-scale clinical trials have consistently demonstrated that various PARP inhibitors,including olaparib,rucaparib,niraparib,and talazoparib,con-fer longer radiographic progression-free survival(rPFS)compared to new hormonal agents(NHA)in mCRPC patients with homologous recombination deficiency(HRD).Moreover,the incidence of grade 3 and above adverse events did not significantly increase.Additionally,when combined with androgen receptor signaling inhibitors(ARSI),olapa-rib,niraparib,and talazoparib have shown significant extension of rPFS but also an increased occurrence of serious adverse events in HRD-positive patients.Only PROpel yielded positive results among the homologous recombination repair(HRR)mutation negative population.Therefore,it remains uncertain whether ARSI-PARPi combination therapy should be considered as first-line treatment for mCRPC patients without HRR mutations.In this review article,we aim to elucidate the necessity and feasibility of combination therapy versus monotherapy specifically within the HRR mutant population while exploring its potential applicability to other non-HRR mutant subtypes.Furthermore,we conducted a comprehensive search on registered clinical trials at present to summarize the research progress of PARP inhibitors in prostate cancer patients at different disease stages.
文摘Background Hereditary nonpolyposis colorectal cancer (HNPPC) is one of the most common genetic syndrome related with mutation of human mismatch repair genes. This study was to evaluate the clinical significance of suspected hereditary nonpolyposis colorectal cancer (sHNPCC) criteria I and the clinical and genetic features of International Collaborative Group-HNPCC (ICG-HNPCC) and sHNPCC families Methods Twenty-nine ICG-HNPCC families fulfilling the Amsterdam criteria and 34 sHNPCC families fulfilling the sHNPCC criteria I were collected PCR-SSCP and DNA sequencing analysis were employed to screen the germline mutations of the hMLH1 and hMSH2 genes in these families Results The ICG group had more colorectal cancer (CRC) patients per family than did the suspected group ( P <0 05) No statistical difference was observed in Lynch classification and familial tumor spectrum In both groups of families, colorectal cancer was the most frequent malignancy, and carcinomas of the stomach, pancreas and uterus were the three most common extracolonic malignancies Mutation screening showed that ICG-HNPCC and sHNPCC families had a similar mutation rate (31 0% vs 29 4%, P >0 05), mutation type, and mutation distribution Comparison of the families with and without mutation showed no significant difference in CRC patients per family, Lynch classification, and tumor spectrum Conclusions ICG-HNPCC and sHNPCC families that have similar clinical manifestations and genetic basis indicate a similar nature for cancer development The application of sHNPCC criteria I will facilitate clinical diagnosis and treatment of small families
