The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Colorectal carcinogenesis represents a heterogeneous process with a differing set of somatic molecular alte...The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Colorectal carcinogenesis represents a heterogeneous process with a differing set of somatic molecular alterations, influenced by diet, environmental and microbial exposures, and host immunity. Fusobacterium species are part of the human oral and intestinal microbiota. Metagenomic analyses have shown an enrichment of Fusobacterium nucleatum(F. nucleatum) in colorectal carcinoma tissue. Using 511 colorectal carcinomas from Japanese patients, we assessed the presence of F. nucleatum. Our results showed that the frequency of F. nucleatum positivity in the Japanese colorectal cancer was 8.6%(44/511), which was lower than that in United States cohort studies(13%). Similar to the United States studies, F. nucleatum positivityin Japanese colorectal cancers was significantly associated with microsatellite instability(MSI)-high status. Regarding the immune response in colorectal cancer, high levels of infiltrating T-cell subsets(i.e., CD3+, CD8+, CD45RO+, and FOXP3+ cells) have been associated with better patient prognosis. There is also evidence to indicate that molecular features of colorectal cancer, especially MSI, influence T-cell-mediated adaptive immunity. Concerning the association between the gut microbiome and immunity, F. nucleatum has been shown to expand myeloid-derived immune cells, which inhibit T-cell proliferation and induce T-cell apoptosis in colorectal cancer. This finding indicates that F. nucleatum possesses immunosuppressive activities by inhibiting human T-cell responses. Certain micro RNAs are induced during the macrophage inflammatory response and have the ability to regulate host-cell responses to pathogens. Micro RNA-21 increases the levels of IL-10 and prostaglandin E2, which suppress antitumor T-cell-mediated adaptive immunity through the inhibition of the antigen-presenting capacities of dendritic cells and T-cell proliferation in colorectal cancer cells. Thus, emerging evidence may provide insights for strategies to target microbiota, immune cells and tumor molecular alterations for colorectal cancer prevention and treatment. Further investigation is needed to clarify the association of Fusobacterium with T-cells and micro RNA expressions in colorectal cancer.展开更多
AIM:To investigate human epidermal growth factor receptor 2(HER2)-phosphatidylinositol 3-kinase(PI3K)-vAkt murine thymoma viral oncogene homolog signaling pathway.METHODS:We analyzed 231 formalin-fixed,paraffinembedde...AIM:To investigate human epidermal growth factor receptor 2(HER2)-phosphatidylinositol 3-kinase(PI3K)-vAkt murine thymoma viral oncogene homolog signaling pathway.METHODS:We analyzed 231 formalin-fixed,paraffinembedded gastric cancer tissue specimens from Japanese patients who had undergone surgical treatment.The patients' age,sex,tumor location,depth of invasion,pathological type,lymph node metastasis,and pathological stage were determined by a review of the medical records.Expression of HER2 was analyzed by immunohistochemistry(IHC) using the HercepTest TM kit.Standard criteria for HER2 positivity(0,1+,2+,and 3+) were used.Tumors that scored 3+ were considered HER2-positive.Expression of phospho Akt(pAkt) was also analyzed by IHC.Tumors were considered pAkt-positive when the percentage of positive tumor cells was 10% or more.PI3K,catalytic,alpha polypeptide(PIK3CA) mutations in exons 1,9 and 20 were analyzed by pyrosequencing.Epstein-Barr virus(EBV) infection was analyzed by in situ hybridization targeting EBV-encoded small RNA(EBER) with an EBER-RNA probe.Microsatellite instability(MSI) was analyzed by polymerase chain reaction using the mononucleotide markers BAT25 and BAT26.RESULTS:HER2 expression levels of 0,1+,2+ and 3+ were found in 167(72%),32(14%),12(5%) and 20(8.7%) samples,respectively.HER2 overexpression(IHC 3+) significantly correlated with intestinal histological type(15/20 vs 98 /205,P = 0.05).PIK3CA mutations were present in 20 cases(8.7%) and significantly correlated with MSI(10/20 vs 9/211,P < 0.01).The mutation frequency was high(21%) in T4 cancers and very low(6%) in T2 cancers.Mutations in exons 1,9 and 20 were detected in 5(2%),9(4%) and 7(3%) cases,respectively.Two new types of PIK3CA mutation,R88Q and R108H,were found in exon1.All PIK3CA mutations were heterozygous missense singlebase substitutions,the most common being H1047R(6/20,30%) in exon20.Eighteen cancers(8%) were EBV-positive and this positivity significantly correlated with a diffuse histological type(13/18 vs 93/198,P = 0.04).There were 7 cases of lymphoepithelioma-like carcinomas(LELC) and 6 of those cases were EBV-positive(percent/EBV:6/18,33%;percent/all LELC:6/7,86%).pAkt expression was positive in 119(53%) cases but showed no correlation with clinicopathological characteristics.pAkt expression was significantly correlated with HER2 overexpression(16/20 vs 103/211,P < 0.01) but not with PIK3CA mutations(12/20 vs 107/211,P = 0.37) or EBV infection(8/18 vs 103/211,P = 0.69).The frequency of pAkt expression was higher in cancers with exon20 mutations(100%) than in those with exon1(40%) or exon9(56%) mutations.One case showed both HER2 overexpression and EBV infection and 3 cases showed both PIK3CA mutations and EBV infection.However,no cases showed both PIK3CA mutations and HER2 overexpression.One EBVpositive cancer with PIK3CA mutation(H1047R) was MSI-positive.Three of these 4 cases were positive for pAkt expression.In survival analysis,pAkt expression significantly correlated with a poor prognosis(hazard ratio 1.75;95%CI:1.12-2.80,P = 0.02).CONCLUSION:HER2 expression,PIK3CA mutations and EBV infection in gastric cancer were characterized.pAkt expression significantly correlates with HER2 expression and with a poor prognosis.展开更多
AIM： To clarify alterations of Dickkopfs （Dkks） and Kremen2 （Krm2） in gastrointestinal cancer. METHODS： We investigated the expression profiles and epigenetic alterations of Dkks and Krm2 genes in gastrointestin...AIM： To clarify alterations of Dickkopfs （Dkks） and Kremen2 （Krm2） in gastrointestinal cancer. METHODS： We investigated the expression profiles and epigenetic alterations of Dkks and Krm2 genes in gastrointestinal cancer using RT-PCR, tissue microarray analysis, and methylation specific PCR （MSP）. Cancer cells were treated with the demethylating agent and/or histone deacetylase inhibitor. WST-8 assays and/n y/tro invasion assays after treatment with specific siRNA for those genes were performed. RESULTS： Dkks and Krm2 expression levels were reduced in a certain subset of the gastrointestinal cancer cell lines and cancer tissues. This was correlated with promoter hypermethylation. There were significant correlations between Dkks over-expression levels and beta-catenin over-expression in colorectal cancer. In colorectal cancers with beta-catenin over-expression, Dkk-1 expression levels were significantly lower in those with lymph node metastases than in those without. Down-regulation of Dkks expression by siRNA resulted in a significant increase in cancer cell growth and invasiveness in vitro.CONCLUSION： Down-regulation of the Dkks associated to promoter hypermethylation appears to be frequently involved in gastrointestinal tumorigenesis.展开更多
There is an increasing understanding of the roles that microsatellite instability （MSI） plays in Lynch syndrome （by mutations） and sporadic （by mainly epigenetic changes） gastrointestinal （GI） and other cancer...There is an increasing understanding of the roles that microsatellite instability （MSI） plays in Lynch syndrome （by mutations） and sporadic （by mainly epigenetic changes） gastrointestinal （GI） and other cancers. Defi- cient DNA mismatch repair （MMR） results in the strong mutator phenotype known as MSI, which is the hall- mark of cancers arising within Lynch syndrome. MSI is characterized by length alterations within simple repeated sequences called microsatellites. Lynch syn- drome occurs primarily because of germline mutations in one of the MMR genes, mainly MLH1 or MSH2, less frequently MSH6, and rarely PMS2. MSI is also observed in about 15% of sporadic colorectal, gastric, and en-dometrial cancers and in lower frequencies in a minor- ity of other cancers where it is often associated with the hypermethylation of the IVlLH1 gene. miRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level and are critical in many biological processes and cellular pathways. There is accumulating evidence to support the notion that the interrelationship between MSI and miRNA plays a key role in the pathogenesis of GI cancer. As a possible new mechanism underlying MSI, overexpression of m/R-IEE has been shown to downregulate expression of MLH1, IVlSH2, and MSH6. Thus, a subset of MSI-positive （MSI＋） cancers without known MMR defects may result from m/R-1E5 overexpression. Target genes of frameshift mutation for MSI are involved in various cellular func- tions, such as DNA repair, cell signaling, and apoptosis. A novel class of target genes that included not only epi- genetic modifier genes, such as HDAC2, but also miRNA processing machinery genes, including TARBP2 and XPO5, were found to be mutated in MSI＋ GI cancers. Thus, a subset of MSI＋ colorectal cancers （CRCs） has been proposed to exhibit a mutated miRNA machinery phenotype. Genetic, epigenetic, and transcriptomic dif- ferences exist between MSI＋ and MSI- cancers. Mo- lecular signatures of miRNA expression apparently have the potential to distinguish between MSI＋ and MSI- CRCs. In this review, we summarize recent advances in the MSI pathogenesis of GI cancer, with the focus on its relationship with miRNA as well as on the potential to use MSI and related alterations as biomarkers and novel therapeutic targets.展开更多
Gastric cancer(GC)is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide.There is an increasing understanding of the roles that genetic and epigenetic alterations...Gastric cancer(GC)is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide.There is an increasing understanding of the roles that genetic and epigenetic alterations play in GCs.Recent studies using nextgeneration sequencing(NGS)have revealed a number of potential cancer-driving genes in GC.Whole-exome sequencing of GC has identified recurrent somatic mutations in the chromatin remodeling gene ARID1A and alterations in the cell adhesion gene FAT4,a member of the cadherin gene family.Mutations in chromatin remodeling genes(ARID1A,MLL3 and MLL)have been found in 47%of GCs.Whole-genome sequencing and whole-transcriptome sequencing analyses have also discovered novel alterations in GC.Recent studies of cancer epigenetics have revealed widespread alterations in genes involved in the epigenetic machinery,such as DNA methylation,histone modifications,nucleosome positioning,noncoding RNAs and microRNAs.Recent advances in molecular research on GC have resulted in the introduction of new diagnostic and therapeutic strategies into clinical settings.The antihuman epidermal growth receptor 2(HER2)antibody trastuzumab has led to an era of personalized therapy in GC.In addition,ramucirumab,a monoclonal antibody targeting vascular endothelial growth factor receptor(VEGFR)-2,is the first biological treatment that showed survival benefits as a single-agent therapy in patients with advanced GC who progressed after firstline chemotherapy.Using NGS to systematically identify gene alterations in GC is a promising approach with remarkable potential for investigating the pathogenesis of GC and identifying novel therapeutic targets,as well as useful biomarkers.In this review,we will summarize the recent advances in the understanding of the molecular pathogenesis of GC,focusing on the potential use of these genetic and epigenetic alterations as diagnostic biomarkers and novel therapeutic targets.展开更多
MicroRNAs have been increasingly recognized as useful biomarkers for colorectal cancers(CRC).We have recently observed that microRNA-31(miR-31)expression is associated with BRAF mutation and prognosis in CRC.Moreover,...MicroRNAs have been increasingly recognized as useful biomarkers for colorectal cancers(CRC).We have recently observed that microRNA-31(miR-31)expression is associated with BRAF mutation and prognosis in CRC.Moreover,high miR-31 expression is frequently detected in sessile serrated adenomas compared with hyperplastic polyps(HPs).These results suggest that miR-31 may contribute to the progression of serrated lesions.At a follow-up colonoscopy,we observed the case of a 75-year-old man with a 7-mm flat-elevated lesion in the cecum and diagnosed the lesion as an early invasive carcinoma with serrated features.Tissue specimens were obtained from the representative areas to compare the molecular alterations in the carcinoma component with those in the HP component.Higher miR-31 expression was observed in the carcinoma component(57-fold increase)and the HP component(8-fold increase)compared with the paired normal mucosa,suggesting that miR-31 may be one of the key molecules in serrated pathway progression.展开更多
AIM： To clarify the significance of JC virus （JCV） T-antigen （T-Ag） expression in human gastric cancer. METHODS： We investigated the relationship between TAg detected by immunohistochemistry and Epstein- Barr vi...AIM： To clarify the significance of JC virus （JCV） T-antigen （T-Ag） expression in human gastric cancer. METHODS： We investigated the relationship between TAg detected by immunohistochemistry and Epstein- Barr virus （EBV） infection, microsatellite instability （MSI）, and genetic and epigenetic alterations in gastric cancers. Mutations in the p53,β-catenin, K/MS, BRAF, PIK3CA genes were analyzed by PCR- single strand conformation polymorphism and DNA sequencing. Allelic losses were determined by PCR at 7 microsatellite loci. Aberrant DNA methylation was analyzed by MethyLight assay. RESULTS： JCV T-Ag protein expression was found in 49% of 90 gastric cancer tissues. TAg positivity was not correlated with clinicopathological characteristics. TAg expression was detected in a similar percentage of EBV positive cancers （4 of 9, 44%） and EBV negative cancers （35 of 73, 48%）. TAg expression was detected in a significantly lower percentage of MSI-H cancers （14%） than in non MSI-H cancers （55%, P = 0.005）. TAg expression was detected in a significantly higher percentage of cancers with nuclear/cytoplasmic localization of β-catenin （15 of 21, 71%） than in cancers without （42%, P = 0.018）. p53 mutations were detected in a significantly lower percentage of T-Ag positive cancers （32%） than in TAg negative cancers （57%, P = 0.018）. TAg positive gastric cancers showed a significant increase in the allelic losses and aberrant methylation compared with T-Ag negative gastric cancers （P = 0.008 and P = 0.003）. CONCLUSION： The results suggest that JCV T-Ag is involved in gastric carcinogenesis through multiple mechanisms of genetic and epigenetic alterations.展开更多
The clinical and endoscopic features of amyloid lightchain(AL) amyloidosis are diverse and mimic various other diseases.Endoscopically,few reports on submucosal hematomas of the gastrointestinal(GI) tract are availabl...The clinical and endoscopic features of amyloid lightchain(AL) amyloidosis are diverse and mimic various other diseases.Endoscopically,few reports on submucosal hematomas of the gastrointestinal(GI) tract are available in the literature.Here,we report two cases of AL amyloidosis presenting as submucosal hematomas in the absence of clinical disease elsewhere in the body.The 2 cases were referred to our hospital because of hematochezia.The endoscopic findings in both cases were similar in submucosal hematoma formation.However,the clinical courses differed.In the first case,there was no evidence of systemic amyloidosis and the disease was conservatively managed.In the second case,the disease progressed to systemic amyloidosis and the patient died within a short time.We conclude that the endoscopic detection of a submucosal hematoma in the setting of GI bleeding should raise suspicion of AL amyloidosis.Referral to a hematologist should be done immediately for treatment while the involvement is limited to the GI tract.展开更多
AIM: To investigate insulin-like growth factor 2 (IGF2) differentially methylated region (DMR)0 hypomethylation in relation to clinicopathological and molecular features in colorectal serrated lesions.
基金Supported by Japanese Society of Gastroenterology Research Foundation(to Nosho K)Pancreas Research Foundation of Japan(to Nosho K)+4 种基金Medical Research Encouragement Prize of The Japan Medical Association(to Nosho K)The Japan Society for the Promotion of Science Challenging Exploratory Researchgrant No.25670371(to Shinomura Y)Ono Cancer Research Foundation(to Ito M)
文摘The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Colorectal carcinogenesis represents a heterogeneous process with a differing set of somatic molecular alterations, influenced by diet, environmental and microbial exposures, and host immunity. Fusobacterium species are part of the human oral and intestinal microbiota. Metagenomic analyses have shown an enrichment of Fusobacterium nucleatum(F. nucleatum) in colorectal carcinoma tissue. Using 511 colorectal carcinomas from Japanese patients, we assessed the presence of F. nucleatum. Our results showed that the frequency of F. nucleatum positivity in the Japanese colorectal cancer was 8.6%(44/511), which was lower than that in United States cohort studies(13%). Similar to the United States studies, F. nucleatum positivityin Japanese colorectal cancers was significantly associated with microsatellite instability(MSI)-high status. Regarding the immune response in colorectal cancer, high levels of infiltrating T-cell subsets(i.e., CD3+, CD8+, CD45RO+, and FOXP3+ cells) have been associated with better patient prognosis. There is also evidence to indicate that molecular features of colorectal cancer, especially MSI, influence T-cell-mediated adaptive immunity. Concerning the association between the gut microbiome and immunity, F. nucleatum has been shown to expand myeloid-derived immune cells, which inhibit T-cell proliferation and induce T-cell apoptosis in colorectal cancer. This finding indicates that F. nucleatum possesses immunosuppressive activities by inhibiting human T-cell responses. Certain micro RNAs are induced during the macrophage inflammatory response and have the ability to regulate host-cell responses to pathogens. Micro RNA-21 increases the levels of IL-10 and prostaglandin E2, which suppress antitumor T-cell-mediated adaptive immunity through the inhibition of the antigen-presenting capacities of dendritic cells and T-cell proliferation in colorectal cancer cells. Thus, emerging evidence may provide insights for strategies to target microbiota, immune cells and tumor molecular alterations for colorectal cancer prevention and treatment. Further investigation is needed to clarify the association of Fusobacterium with T-cells and micro RNA expressions in colorectal cancer.
基金Supported by Grants-in-Aid for Scientific Research from the Ministry of Education,Culture,Sports,Science and Technology of Japan,to Yamamoto H and Shinomura Y
文摘AIM:To investigate human epidermal growth factor receptor 2(HER2)-phosphatidylinositol 3-kinase(PI3K)-vAkt murine thymoma viral oncogene homolog signaling pathway.METHODS:We analyzed 231 formalin-fixed,paraffinembedded gastric cancer tissue specimens from Japanese patients who had undergone surgical treatment.The patients' age,sex,tumor location,depth of invasion,pathological type,lymph node metastasis,and pathological stage were determined by a review of the medical records.Expression of HER2 was analyzed by immunohistochemistry(IHC) using the HercepTest TM kit.Standard criteria for HER2 positivity(0,1+,2+,and 3+) were used.Tumors that scored 3+ were considered HER2-positive.Expression of phospho Akt(pAkt) was also analyzed by IHC.Tumors were considered pAkt-positive when the percentage of positive tumor cells was 10% or more.PI3K,catalytic,alpha polypeptide(PIK3CA) mutations in exons 1,9 and 20 were analyzed by pyrosequencing.Epstein-Barr virus(EBV) infection was analyzed by in situ hybridization targeting EBV-encoded small RNA(EBER) with an EBER-RNA probe.Microsatellite instability(MSI) was analyzed by polymerase chain reaction using the mononucleotide markers BAT25 and BAT26.RESULTS:HER2 expression levels of 0,1+,2+ and 3+ were found in 167(72%),32(14%),12(5%) and 20(8.7%) samples,respectively.HER2 overexpression(IHC 3+) significantly correlated with intestinal histological type(15/20 vs 98 /205,P = 0.05).PIK3CA mutations were present in 20 cases(8.7%) and significantly correlated with MSI(10/20 vs 9/211,P < 0.01).The mutation frequency was high(21%) in T4 cancers and very low(6%) in T2 cancers.Mutations in exons 1,9 and 20 were detected in 5(2%),9(4%) and 7(3%) cases,respectively.Two new types of PIK3CA mutation,R88Q and R108H,were found in exon1.All PIK3CA mutations were heterozygous missense singlebase substitutions,the most common being H1047R(6/20,30%) in exon20.Eighteen cancers(8%) were EBV-positive and this positivity significantly correlated with a diffuse histological type(13/18 vs 93/198,P = 0.04).There were 7 cases of lymphoepithelioma-like carcinomas(LELC) and 6 of those cases were EBV-positive(percent/EBV:6/18,33%;percent/all LELC:6/7,86%).pAkt expression was positive in 119(53%) cases but showed no correlation with clinicopathological characteristics.pAkt expression was significantly correlated with HER2 overexpression(16/20 vs 103/211,P < 0.01) but not with PIK3CA mutations(12/20 vs 107/211,P = 0.37) or EBV infection(8/18 vs 103/211,P = 0.69).The frequency of pAkt expression was higher in cancers with exon20 mutations(100%) than in those with exon1(40%) or exon9(56%) mutations.One case showed both HER2 overexpression and EBV infection and 3 cases showed both PIK3CA mutations and EBV infection.However,no cases showed both PIK3CA mutations and HER2 overexpression.One EBVpositive cancer with PIK3CA mutation(H1047R) was MSI-positive.Three of these 4 cases were positive for pAkt expression.In survival analysis,pAkt expression significantly correlated with a poor prognosis(hazard ratio 1.75;95%CI:1.12-2.80,P = 0.02).CONCLUSION:HER2 expression,PIK3CA mutations and EBV infection in gastric cancer were characterized.pAkt expression significantly correlates with HER2 expression and with a poor prognosis.
基金Supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (H.Y. and F.I.)Grants-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan (H.Y. and F.I.)
文摘AIM： To clarify alterations of Dickkopfs （Dkks） and Kremen2 （Krm2） in gastrointestinal cancer. METHODS： We investigated the expression profiles and epigenetic alterations of Dkks and Krm2 genes in gastrointestinal cancer using RT-PCR, tissue microarray analysis, and methylation specific PCR （MSP）. Cancer cells were treated with the demethylating agent and/or histone deacetylase inhibitor. WST-8 assays and/n y/tro invasion assays after treatment with specific siRNA for those genes were performed. RESULTS： Dkks and Krm2 expression levels were reduced in a certain subset of the gastrointestinal cancer cell lines and cancer tissues. This was correlated with promoter hypermethylation. There were significant correlations between Dkks over-expression levels and beta-catenin over-expression in colorectal cancer. In colorectal cancers with beta-catenin over-expression, Dkk-1 expression levels were significantly lower in those with lymph node metastases than in those without. Down-regulation of Dkks expression by siRNA resulted in a significant increase in cancer cell growth and invasiveness in vitro.CONCLUSION： Down-regulation of the Dkks associated to promoter hypermethylation appears to be frequently involved in gastrointestinal tumorigenesis.
基金Supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan
文摘There is an increasing understanding of the roles that microsatellite instability （MSI） plays in Lynch syndrome （by mutations） and sporadic （by mainly epigenetic changes） gastrointestinal （GI） and other cancers. Defi- cient DNA mismatch repair （MMR） results in the strong mutator phenotype known as MSI, which is the hall- mark of cancers arising within Lynch syndrome. MSI is characterized by length alterations within simple repeated sequences called microsatellites. Lynch syn- drome occurs primarily because of germline mutations in one of the MMR genes, mainly MLH1 or MSH2, less frequently MSH6, and rarely PMS2. MSI is also observed in about 15% of sporadic colorectal, gastric, and en-dometrial cancers and in lower frequencies in a minor- ity of other cancers where it is often associated with the hypermethylation of the IVlLH1 gene. miRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level and are critical in many biological processes and cellular pathways. There is accumulating evidence to support the notion that the interrelationship between MSI and miRNA plays a key role in the pathogenesis of GI cancer. As a possible new mechanism underlying MSI, overexpression of m/R-IEE has been shown to downregulate expression of MLH1, IVlSH2, and MSH6. Thus, a subset of MSI-positive （MSI＋） cancers without known MMR defects may result from m/R-1E5 overexpression. Target genes of frameshift mutation for MSI are involved in various cellular func- tions, such as DNA repair, cell signaling, and apoptosis. A novel class of target genes that included not only epi- genetic modifier genes, such as HDAC2, but also miRNA processing machinery genes, including TARBP2 and XPO5, were found to be mutated in MSI＋ GI cancers. Thus, a subset of MSI＋ colorectal cancers （CRCs） has been proposed to exhibit a mutated miRNA machinery phenotype. Genetic, epigenetic, and transcriptomic dif- ferences exist between MSI＋ and MSI- cancers. Mo- lecular signatures of miRNA expression apparently have the potential to distinguish between MSI＋ and MSI- CRCs. In this review, we summarize recent advances in the MSI pathogenesis of GI cancer, with the focus on its relationship with miRNA as well as on the potential to use MSI and related alterations as biomarkers and novel therapeutic targets.
基金Supported by Grants-in-Aid for Scientific Research from the Ministry of Education,Culture,Sports,Science and Technology of Japan
文摘Gastric cancer(GC)is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide.There is an increasing understanding of the roles that genetic and epigenetic alterations play in GCs.Recent studies using nextgeneration sequencing(NGS)have revealed a number of potential cancer-driving genes in GC.Whole-exome sequencing of GC has identified recurrent somatic mutations in the chromatin remodeling gene ARID1A and alterations in the cell adhesion gene FAT4,a member of the cadherin gene family.Mutations in chromatin remodeling genes(ARID1A,MLL3 and MLL)have been found in 47%of GCs.Whole-genome sequencing and whole-transcriptome sequencing analyses have also discovered novel alterations in GC.Recent studies of cancer epigenetics have revealed widespread alterations in genes involved in the epigenetic machinery,such as DNA methylation,histone modifications,nucleosome positioning,noncoding RNAs and microRNAs.Recent advances in molecular research on GC have resulted in the introduction of new diagnostic and therapeutic strategies into clinical settings.The antihuman epidermal growth receptor 2(HER2)antibody trastuzumab has led to an era of personalized therapy in GC.In addition,ramucirumab,a monoclonal antibody targeting vascular endothelial growth factor receptor(VEGFR)-2,is the first biological treatment that showed survival benefits as a single-agent therapy in patients with advanced GC who progressed after firstline chemotherapy.Using NGS to systematically identify gene alterations in GC is a promising approach with remarkable potential for investigating the pathogenesis of GC and identifying novel therapeutic targets,as well as useful biomarkers.In this review,we will summarize the recent advances in the understanding of the molecular pathogenesis of GC,focusing on the potential use of these genetic and epigenetic alterations as diagnostic biomarkers and novel therapeutic targets.
基金Supported by Japan Society for the Promotion of Science(JSPS)Grant-in-Aid for Scientific Research,grant No.23790800(to Nosho K)A-STEP(Adaptable and Seamless Technology Transfer Program through Target-driven R and D)(to Nosho K)
文摘MicroRNAs have been increasingly recognized as useful biomarkers for colorectal cancers(CRC).We have recently observed that microRNA-31(miR-31)expression is associated with BRAF mutation and prognosis in CRC.Moreover,high miR-31 expression is frequently detected in sessile serrated adenomas compared with hyperplastic polyps(HPs).These results suggest that miR-31 may contribute to the progression of serrated lesions.At a follow-up colonoscopy,we observed the case of a 75-year-old man with a 7-mm flat-elevated lesion in the cecum and diagnosed the lesion as an early invasive carcinoma with serrated features.Tissue specimens were obtained from the representative areas to compare the molecular alterations in the carcinoma component with those in the HP component.Higher miR-31 expression was observed in the carcinoma component(57-fold increase)and the HP component(8-fold increase)compared with the paired normal mucosa,suggesting that miR-31 may be one of the key molecules in serrated pathway progression.
基金Supported by Grants-in-Aid for Scientific Research from the Ministry of Education,Culture,Sports,Science and Technology of Japan(Yamamoto H,Imai K and Shinomura Y)Grants-in-Aid for Cancer Research from the Ministry of Health,Laborand Welfare of Japan(Yamamoto H)
文摘AIM： To clarify the significance of JC virus （JCV） T-antigen （T-Ag） expression in human gastric cancer. METHODS： We investigated the relationship between TAg detected by immunohistochemistry and Epstein- Barr virus （EBV） infection, microsatellite instability （MSI）, and genetic and epigenetic alterations in gastric cancers. Mutations in the p53,β-catenin, K/MS, BRAF, PIK3CA genes were analyzed by PCR- single strand conformation polymorphism and DNA sequencing. Allelic losses were determined by PCR at 7 microsatellite loci. Aberrant DNA methylation was analyzed by MethyLight assay. RESULTS： JCV T-Ag protein expression was found in 49% of 90 gastric cancer tissues. TAg positivity was not correlated with clinicopathological characteristics. TAg expression was detected in a similar percentage of EBV positive cancers （4 of 9, 44%） and EBV negative cancers （35 of 73, 48%）. TAg expression was detected in a significantly lower percentage of MSI-H cancers （14%） than in non MSI-H cancers （55%, P = 0.005）. TAg expression was detected in a significantly higher percentage of cancers with nuclear/cytoplasmic localization of β-catenin （15 of 21, 71%） than in cancers without （42%, P = 0.018）. p53 mutations were detected in a significantly lower percentage of T-Ag positive cancers （32%） than in TAg negative cancers （57%, P = 0.018）. TAg positive gastric cancers showed a significant increase in the allelic losses and aberrant methylation compared with T-Ag negative gastric cancers （P = 0.008 and P = 0.003）. CONCLUSION： The results suggest that JCV T-Ag is involved in gastric carcinogenesis through multiple mechanisms of genetic and epigenetic alterations.
文摘The clinical and endoscopic features of amyloid lightchain(AL) amyloidosis are diverse and mimic various other diseases.Endoscopically,few reports on submucosal hematomas of the gastrointestinal(GI) tract are available in the literature.Here,we report two cases of AL amyloidosis presenting as submucosal hematomas in the absence of clinical disease elsewhere in the body.The 2 cases were referred to our hospital because of hematochezia.The endoscopic findings in both cases were similar in submucosal hematoma formation.However,the clinical courses differed.In the first case,there was no evidence of systemic amyloidosis and the disease was conservatively managed.In the second case,the disease progressed to systemic amyloidosis and the patient died within a short time.We conclude that the endoscopic detection of a submucosal hematoma in the setting of GI bleeding should raise suspicion of AL amyloidosis.Referral to a hematologist should be done immediately for treatment while the involvement is limited to the GI tract.
基金Supported by The Japan Society for the Promotion of Science(JSPS)Grant-in-Aid for Scientific Research,grant No.23790800(to Nosho K)and 23390200(to Shinomura Y)A-STEP(Adaptable and Seamless Technology Transfer Program through Targetdriven R and D)(to Nosho K)+4 种基金Daiwa Securities Health Foundation(to Nosho K)Kobayashi Foundation for Cancer Research(to Nosho K)Sagawa Foundation for Promotion of Cancer Research(to Nosho K)Suzuken Memorial Foundation(to Nosho K),and Takeda Science Foundation(to Nosho K)USA National Institute of Health,grant number R01 CA151993(to Ogino S)
文摘AIM: To investigate insulin-like growth factor 2 (IGF2) differentially methylated region (DMR)0 hypomethylation in relation to clinicopathological and molecular features in colorectal serrated lesions.
