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Tislelizumab in previously treated,locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid tumors
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作者 Jian Li Ye Xu +22 位作者 Aimin Zang Yunong Gao Quanli Gao Yanqiao Zhang Dong Wang Jianming Xu Ying Yuan Haiping Jiang Jieer Ying Chunmei Shi Yanhong Deng Jing Wang Tianshu Liu Yi Huang Xiaoping Qian Yueyin Pan Ying Cheng Sheng Hu Jin Wang Mengyue Shi Ke Wang Han Hu Lin Shen 《Chinese Journal of Cancer Research》 SCIE CAS CSCD 2024年第3期257-269,共13页
Objective:The open-label,phase II RATIONALE-209 study evaluated tislelizumab(anti-programmed cell death protein 1 antibody)as a tissue-agnostic monotherapy for microsatellite instability-high(MSI-H)/mismatch repair-de... Objective:The open-label,phase II RATIONALE-209 study evaluated tislelizumab(anti-programmed cell death protein 1 antibody)as a tissue-agnostic monotherapy for microsatellite instability-high(MSI-H)/mismatch repair-deficient(dMMR)tumors.Methods:Adults with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled.Patients received tislelizumab 200 mg intravenously every 3 weeks.Objective response rate(ORR;primary endpoint),duration of response(DoR),and progression-free survival(PFS)were assessed by independent review committee(Response Evaluation Criteria in Solid Tumors v1.1).Results:Eighty patients were enrolled and treated;75(93.8%)patients had measurable disease at baseline.Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease(n=79;98.8%).At primary analysis(data cutoff July 8,2021;median follow-up 15.2 months),overall ORR[46.7%;95%confidence interval(95%CI),35.1−58.6;one-sided P<0.0001]and ORR across tumor-specific subgroups[colorectal(n=46):39.1%(95%CI,25.1–54.6);gastric/gastroesophageal junction(n=9):55.6%(95%CI,21.2−86.3);others(n=20):60.0%(95%CI,36.1−80.9)]were significantly greater with tislelizumab vs.a prespecified historical control ORR of 10%;five(6.7%)patients had complete responses.Median DoR,PFS,and overall survival were not reached with long-term follow-up(data cutoff December 5,2022;median follow-up 28.9 months).Tislelizumab was well tolerated with no unexpected safety signals.Treatment-related adverse events(TRAEs)of grade≥3 occurred in 53.8%of patients;7.5%of patients discontinued treatment due to TRAEs.Conclusions:Tislelizumab demonstrated a significant ORR improvement in patients with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated. 展开更多
关键词 Biomarkers DNA mismatch repair immune checkpoint inhibitors microsatellite instability phase II clinical trials programmed cell death 1 receptor
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Application of immune checkpoint inhibitors and microsatellite instability in gastric cancer
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作者 Shi-Yan Yan Jian-Gao Fan 《World Journal of Gastroenterology》 SCIE CAS 2024年第21期2734-2739,共6页
In this editorial we comment on the article by Li published in the recent issue of the World Journal of Gastroenterology.We focus specifically on the application of immune checkpoint inhibitors(ICIs)and microsatellite... In this editorial we comment on the article by Li published in the recent issue of the World Journal of Gastroenterology.We focus specifically on the application of immune checkpoint inhibitors(ICIs)and microsatellite instability(MSI)in gastric cancer(GC).The four pillars of GC management have long been considered,including surgery,chemotherapy,radiotherapy and targeted therapy.However,immunotherapy has recently emerged as a“fifth pillar”,and its use is rapidly expanding.There are four principal strategies for tumor immunotherapy:ICIs,tumor vaccines,adoptive immunotherapy and nonspecific immunomodulators.Of them,ICIs are the most advanced and widespread type of cancer immunotherapy for GC.Recent breakthrough results for ICIs have paved the way to a new era of cancer immunotherapy.In particular,inhibition of the PD-1/PD-L1 axis with ICIs,including nivolumab and pembrolizumab,has emerged as a novel treatment strategy for advanced GC.Unfortunately,these therapies are sometimes associated with often subtle,potentially fatal immune-related adverse events(irAEs),including dermatitis,diarrhea,colitis,endocrinopathy,hepatotoxicity,neuropathy and pneumonitis.We must be aware of these irAEs and improve the detection of these processes to prevent inappropriate discharges,emergency department revisits,and downstream complications.Recent studies have revealed that MSI-high or mismatch-repair-deficient tumors,regardless of their primary site,have a promising response to ICIs.So,it is important to detect MSI before applying ICIs for treatment of GC. 展开更多
关键词 Gastric cancer Immune checkpoint inhibitors microsatellite instability IMMUNOTHERAPY Immune-related adverse events
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Comparative effectiveness of immunotherapy and chemotherapy in patients with metastatic colorectal cancer stratified by microsatellite instability status
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作者 Chen-Gu Niu Jing Zhang +2 位作者 Aniket-Vijay Rao Utsav Joshi Patrick Okolo 《World Journal of Clinical Oncology》 2024年第4期540-547,共8页
BACKGROUND Immunotherapy have demonstrated promising outcomes in patients with high microsatellite instability(MSI)(MSI-H)metastatic colorectal cancer.However,the comparative effectiveness of Immunotherapy and chemoth... BACKGROUND Immunotherapy have demonstrated promising outcomes in patients with high microsatellite instability(MSI)(MSI-H)metastatic colorectal cancer.However,the comparative effectiveness of Immunotherapy and chemotherapy for patients with low MSI(MSI-L),and microsatellite stable(MSS)metastatic colorectal cancer remains unclear.AIM To investigate immunotherapy vs chemotherapy for treatment of MSI-L/MSS metastatic colorectal cancer,and to evaluate the success of immunotherapy against chemotherapy in managing MSI-H metastatic colorectal cancer during a follow-up of 50 months.METHODS We conducted a retrospective cohort study using the National Cancer Database(NCDB)to evaluate the overall survival(OS)of patients with metastatic colorectal cancer treated with immunotherapy or chemotherapy.The study population was stratified by MSI status(MSI-H,MSI-L,and MSS).Multivariable Cox proportional hazard models were used to assess the association between treatment modality and OS,adjusting for potential confounders.RESULTS A total of 21951 patients with metastatic colorectal cancer were included in the analysis,of which 2358 were MSI-H,and 19593 were MSI-L/MSS.In the MSI-H cohort,immunotherapy treatment(n=142)was associated with a significantly improved median OS compared to chemotherapy(n=860).After adjusting for potential confounders,immunotherapy treatment remained significantly associated with better OS in the MSI-H cohort[adjusted hazard ratio(aHR):0.57,95%confidence interval(95%CI):0.43-0.77,P<0.001].In the MSS cohort,no significant difference in median OS was observed between immunotherapy treatment and chemotherapy(aHR:0.94,95%CI:0.69-1.29,P=0.715).CONCLUSION In this population-based study using the NCDB,immunotherapy treatment was associated with significantly improved OS compared to chemotherapy in patients with MSI-H metastatic colorectal cancer,but not in those with MSI-L/MSS metastatic colorectal cancer.Further studies are warranted to determine the optimal therapeutic approach for patients with MSI-L/MSS metastatic colorectal cancer. 展开更多
关键词 IMMUNOTHERAPY CHEMOTHERAPY Metastatic colorectal cancer microsatellite instability National cancer database
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Discrepancy among microsatellite instability detection methodologies in non-colorectal cancer:Report of 3 cases
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作者 ElifŞenocak Taşçı İbrahim Yıldız +1 位作者 Sibel Erdamar LeylaÖzer 《World Journal of Clinical Cases》 SCIE 2023年第13期3105-3113,共9页
BACKGROUND Microsatellite instability(MSI)is a predictive biomarker for cancer immunotherapy.The tumor-agnostic nature of MSI makes it a denominator for immunotherapy in several solid tumors.It can be assessed using n... BACKGROUND Microsatellite instability(MSI)is a predictive biomarker for cancer immunotherapy.The tumor-agnostic nature of MSI makes it a denominator for immunotherapy in several solid tumors.It can be assessed using next-generation sequencing(NGS),fluorescent multiplex PCR,and immunohistochemistry(IHC).CASE SUMMARY Here,we report 3 cases with discordant MSI results detected using different methods.A cholangiocellular carcinoma case revealed proficient mismatch repair(MMR)by IHC but high MSI(MSI-H)by liquid NGS.A cervical cancer case revealed deficient MMR by IHC,microsatellite stable by PCR,and MSI-H by NGS.Lastly,an endometrial cancer case revealed proficient MMR by IHC but MSI-H by NGS.CONCLUSION IHC for MMR status is the first choice due to several advantages.However,in cases of indeterminate IHC results,molecular testing by MSI-PCR is preferred.Recently,NGS-based MSI assays are being widely used to detect MSI-H tumors.All three methods have high accuracy;however,the inconsistencies between them may lead to misdiagnosis. 展开更多
关键词 DISCORDANCE IMMUNOHISTOCHEMISTRY microsatellite instability Nextgeneration sequencing Case report
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Bat 26 Microsatellite Instability in Oral Cavity Cancers in Senegal
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作者 Mame Diarra Samb Fatimata Mbaye +2 位作者 Mouhamadou Makhtar Ndiaye Silly Toure Mbacke Sembene 《Journal of Cancer Therapy》 CAS 2023年第1期25-37,共13页
Oral cavity cancers are part of head and neck cancers. They have become frequent in the world in general and Senegal in particular. This study evaluates microsatellite instability tumors in oral cavity cancers in Sene... Oral cavity cancers are part of head and neck cancers. They have become frequent in the world in general and Senegal in particular. This study evaluates microsatellite instability tumors in oral cavity cancers in Senegal. Forty cancerous tissues, 20 healthy tissues, and 12 blood tissues were included in this study. These tissues were collected from each patient during the biopsy after obtaining consent. DNA extraction, Polymerase Chain Reaction (PCR) and sequencing were carried out to obtain sequences. Mutation surveyor, Bioedit and Dnasp software were used to perform our analyses. High instability was found in 57.5% of patients with cancer. Moreover, 90% of the patients had the same motif on healthy and cancerous tissue. Furthermore, 26.12%, 20.72%, and 11.71% polymorphic sites were found in cancerous, healthy and blood tissue respectively. Thus, a similarity between cancerous and healthy tissues seems to exist. This implies that instability of the Bat 26 microsatellite could occur early in the occurrence of oral cavity cancers. 展开更多
关键词 CANCER Oral Cavity microsatellite instability Bat 26 Senegal
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Genetic changes of p53,K-ras,and microsatellite instability in gallbladder carcinoma in high-incidence areas of Japan and Hungary 被引量:9
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作者 Masayuki Nagahashi Yoichi Ajioka +10 位作者 Istvan Lang Zoltan Szentirmay Miklos Kasler Hiroto Nakadaira Naoyuki Yokoyama Gen Watanabe Ken Nishikura Toshifumi Wakai Yoshio Shirai Katsuyoshi Hatakeyama Masaharu Yamamoto 《World Journal of Gastroenterology》 SCIE CAS CSCD 2008年第1期70-75,共6页
AIM: To disclose geographic differences in genetic changes involved in gallbladder carcinogenesis between two distinct high-incidence areas of Japan and Hungary. METHODS: We examined 42 cases of gallbladder carcinom... AIM: To disclose geographic differences in genetic changes involved in gallbladder carcinogenesis between two distinct high-incidence areas of Japan and Hungary. METHODS: We examined 42 cases of gallbladder carcinoma: 22 Japanese and 20 Hungarian cases, p53 mutations at exons 5 to 8 and K-ras mutations at codon 12 were tested by direct sequencing. Microsatellite instability was determined from fluorescent dye-labeled PCR amplifications of flve-microsatellite markers (BAT-25, BAT-26, D2S123, DSS346, and D17S250). RESULTS: Mutations of p53 were detected in 11 of 22 Japanese cases and 6 of 18 Hungarian cases (11/22 vs 6/18, P = 0.348). Transition at CpG sites was found in none of 11 Japanese cases and 2 of 6 Hungarian cases; the difference was marginally significant (0/11 vs 2/6,P = 0.110). K-ras mutations were detected in only one of the Hungarian cases. Eight of 19 (42.1%) ]apanese cases were MSI-high (presence of novel peaks in more than one of the five loci analyzed), whereas only 1 of 15 (6.7%) Hungarian cases was MSI-high (P = 0.047). CONCLUSION: It appears that the p53 mutations and MSI differ in patients with gallbladder carcinoma between two distinct high-incidence areas. Geographic variation might exist in the process of gallbladder carcinogenesis. 展开更多
关键词 GALLBLADDER Gallbladder Neoplasms K-RAS microsatellite instability P53
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Endoscopic and clinicopathologic characteristics of early gastric cancer with high microsatellite instability 被引量:6
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作者 Jaehoon Jahng Young Hoon Youn +8 位作者 Kwang Hyun Kim Junghwan Yu Yong Chan Lee Woo Jin Hyung Sung Hoon Noh Hyunki Kim Hoguen Kim Hyojin Park Sang In Lee 《World Journal of Gastroenterology》 SCIE CAS CSCD 2012年第27期3571-3577,共7页
AIM: To investigate endoscopic and clinicopathologic characteristics of early gastric cancer (EGC) according to microsatellite instability phenotype. METHODS: Data were retrospectively collected from a single tert... AIM: To investigate endoscopic and clinicopathologic characteristics of early gastric cancer (EGC) according to microsatellite instability phenotype. METHODS: Data were retrospectively collected from a single tertiary referral center. Of 981 EGC patients surgically treated between December 2003 and October 2007, 73 consecutive EGC patients with two or more microsatellite instability (MSI) mutation [high MSI (MSI-H)] and 146 consecutive EGC patients with one or no MSI mutation (non-MSI-H) were selected. The endoscopic and clinicopathologic features were compared between the MSI-H and non-MSI-H EGC groups.RESULTS: In terms of endoscopic characteristics, MSI-H EGCs more frequently presented with elevated pattern (OR 4.38, 95% Cl: 2.40-8.01, P 〈 0.001), moderate- to-severe atrophy in the surrounding mucosa (OR 1.91, 95% CI: 1.05-3.47, P = 0.033), antral location (OR 3.99, 95% CI: 2.12-7.52, P 〈 0.001) and synchronous le- sions, compared to non-MSI-H EGCs (OR 2.65, 95% CI: 1.16-6.07, P = 0.021). Other significant clinicopatholog- ic characteristics of MSI-H EGC included predominance of female sex (OR 2.77, 95% CI: 1.53-4.99, P 〈 0.001), older age (〉 70 years) (OR 3.30, 95% CI: 1.57-6.92, P = 0.002), better histologic differentiation (OR 2.35, 95% Cl: 1.27-4.34, P = 0.007), intestinal type by Lau- ren classification (OR 2.34, 95% CI: 1.15-4.76, P = 0.019), absence of a signet ring cell component (OR 2.44, 95% CI: 1.02-5.86, P = 0.046), presence of mu- cinous component (OR 5.06, 95% Cl: 1.27-20.17, P = 0.022), moderate-to-severe lymphoid stromal reaction (OR 3.95, 95% CI: 1.59-9.80, P = 0.003), and co-exist- ing underlying adenoma (OR 2.66, 95% CI: 1.43-4.95, P = 0.002). CONCLUSION: MSI-H EGC is associated with unique endoscopic and clinicopathologic characteristics includ- ing frequent presentation in protruded type, co-exist- ing underlying adenoma, and synchronous lesions. 展开更多
关键词 microsatellite instability Early gastric can-cer Endoscopic characteristic Advanced gastric cancer
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Clinicopathological Features of Non-familial Colorectal Cancer with High-frequency Microsatellite Instability 被引量:1
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作者 Peng Jin Xiao-ming Meng Jian-qiu Sheng Zi-tao Wu Lei Fu He-juan An Ying Han Shi-rong Li 《Chinese Medical Sciences Journal》 CAS CSCD 2010年第4期228-232,共5页
Objective To explore the clinicopathological features of non-familial colorectal cancer with high-frequency microsatellite instability (MSI-H). Methods One hundred and fifty patients with colorectal cancer who had no ... Objective To explore the clinicopathological features of non-familial colorectal cancer with high-frequency microsatellite instability (MSI-H). Methods One hundred and fifty patients with colorectal cancer who had no family history were enrolled in this study from June 2006 to June 2008. Five standard microsatellite loci including BAT25, BAT26, D2S123, D5S346, and D17S250 were amplified with immunofluorescent polymerase chain reaction. The patient information including age, sex, and tumor location was recorded. Pathological features including differentiation, mucinous differentiation, histological heterogeneity, and Crohn's-like reaction were observed under light microscope. The presence of tumor-infiltrating lymphocytes (TLs, CD4+ and CD8+) was detected by means of immunohistochemistry. A regression equation was obtained by stepwise logistic regression analysis to evaluate the relationship between MSI-H phenotype in colorectal cancer ands pathological features. Results MSI-H phenotype occurred in 13.33% of the 150 patients with non-familial colorectal cancer. Poor differentiation, histological heterogeneity, Crohn's-like reaction, and presence of TLs were found to be independent factors to identify MSI-H non-familial colorectal cancer. Logistic regression equation showed an overall sensitivity of 70.0%, specificity of 99.2%, and accuracy of 95.3% in identifying MSI-H non-familial colorectal cancer. Conclusion MSI-H non-familial colorectal cancer manifests specific pathological features, which may be relied upon for effective identification of that disease. 展开更多
关键词 colorectal cancer microsatellite instability PHENOTYPE clinical pathology
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Analysis of microsatellite instability in stool DNA of patients with colorectal cancer using denaturing high performance liquid chromatography
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作者 Seok-Byung Lim Seung-Yong Jeong +10 位作者 Il-Jin Kim Dae Yong Kim Kyung Hae Jung Hee Jin Chang Hyo Seong Choi Dae Kyung Sohn Hio Chung Kang Yong Shin Sang-Geun Jang Jae-Hyun Park Jae-Gahb Park 《World Journal of Gastroenterology》 SCIE CAS CSCD 2006年第41期6689-6692,共4页
AIM: To evaluate the usefulness of denaturing high performance liquid chromatography (DHPLC) for analyzing microsatellite instability (MSI) status in stool DNA of patients with colorectal cancer. METHODS: A tota... AIM: To evaluate the usefulness of denaturing high performance liquid chromatography (DHPLC) for analyzing microsatellite instability (MSI) status in stool DNA of patients with colorectal cancer. METHODS: A total of 80 cancer tissues from patients with primary sporadic colorectal tumor (proximal cancer: 27, distal cancer: 53) and matched stool (which were employed for comparison with the tissues) were analyzed for MSI status in BAT 26. DNA samples extracted from stool were evaluated by nested polymerase chain reaction (PCR) and DHPLC for MSI analysis. RESULTS: Six cases (7.5%) of MSI were identified in BAT 26 from 80 cancer tissues. All the stool DNA samples from patients whose cancer tissue showed IVlSI also displayed MSI in BAT 26. CONCLUSION: As MSI is one of the established fecal DNA markers to screen colorectal cancer, we propose to use DHPLC for the IVlSI analysis in fecal DNA. 展开更多
关键词 Colorectal cancer Denaturing high performance liquid chromatography Fecal DNA MicrosateUite instability STOOL
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Study on the Correlation between the Expression of Angiogenic Factor VEGF and Microsatellite Instability in Gastric Adenocarcinoma
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作者 刘文韬 陈国玉 +1 位作者 夏建国 杨力 《Journal of Nanjing Medical University》 2004年第2期94-97,共4页
Objective: To investigate the correlation between the microsatellite instability (MSI) and the expression of vascular endothelial growth factor (VEGF) in gastric adenocarcinoma. Methods: PCR SSCP method was used to d... Objective: To investigate the correlation between the microsatellite instability (MSI) and the expression of vascular endothelial growth factor (VEGF) in gastric adenocarcinoma. Methods: PCR SSCP method was used to detect MSI of thirty cases with gastric adenocarcinoma at five loci in each patient. Expression of VEGF was examined by the method of immunohistochemistry. Results: The positive of MSI was in 13 patients out of 30 patients (43.4%) in our study. Positive VEGF Immunostaining was detected in 18 patients (60.0%). VEGF was decreased in microsatellite instability high (MSI H) gastric adenocarcinoma. Conclusion: MSI H and microsatellite stable (MSS) gastric adenocarcinoma may follow a different pathway of angiogenesis. The low frequency of VEGF expression among MSI H cancer may partially explain why these cancers are less aggressive. 展开更多
关键词 gastric adenocarcinoma microsatellite instability vascular endothelial growth factor ANGIOGENESIS
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Characterization of six tumorsuppressor genes and microsatellite instability in hepatocellular carcinomain southern African blacks 被引量:21
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作者 Martins C Kedda MA Kew MC 《World Journal of Gastroenterology》 SCIE CAS CSCD 1999年第6期470-476,共7页
AIM To analyse cumulative loss of heterozygosity (LOH) of chromosomal regions and tumor suppressor genes in hepatocellular carcinomas (HCCs) from 20 southern African blacks. METHODS p53, RB1, BRCA1, BRCA2, WT1 and E c... AIM To analyse cumulative loss of heterozygosity (LOH) of chromosomal regions and tumor suppressor genes in hepatocellular carcinomas (HCCs) from 20 southern African blacks. METHODS p53, RB1, BRCA1, BRCA2, WT1 and E cadherin genes were analysed for LOH, and p53 gene was also analysed for the codon 249 mutation, in tumor and adjacent non tumorous liver tissues using molecular techniques and 10 polymorphic microsatellite markers. RESULTS p53 codon 249 mutation was found in 25% of the subjects, as was expected, because many patients were from Mozambique, a country with high aflatoxin B 1 exposure. LOH was found at the RB1, BRCA2 and WT1 loci in 20%(4/*!20) of the HCCs, supporting a possible role of these genes in HCC. No LOH was evident in any of the remaining genes. Reports of mutations of p53 and RB1 genes in combination, described in other populations, were not confirmed in this study. Change in microsatellite repeat number was noted at 9/*!10 microsatellite loci in different HCCs, and changes at two or more loci were detected in 15%(3/*!20) of subjects. CONCLUSION We propose that microsatellite/genomic instability may play a role in the pathogenesis of a subset of HCCs in black Africans. 展开更多
关键词 carcinoma hepatocellular southern African BLACKS CUMULATIVE LOH TUMOR SUPPRESSOR genes microsatellite genomic instability liver neoplasms
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Potential roles of tumor suppressor genes and microsatellite instability in hepatocellular carcinogenesis in southern African blacks 被引量:13
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作者 Roberts LR LaRusso NF 《World Journal of Gastroenterology》 SCIE CAS CSCD 2000年第1期37-41,共5页
MAJOR POINTS OF THE COMMENTED ARTICLECumulative loss of heterozygosity(LOH)ofchromosomal regions and tumor suppressor geneshas been reported in hepatocellular carcinomas(HCCs) from China,Japan,and Korea.In thisissue o... MAJOR POINTS OF THE COMMENTED ARTICLECumulative loss of heterozygosity(LOH)ofchromosomal regions and tumor suppressor geneshas been reported in hepatocellular carcinomas(HCCs) from China,Japan,and Korea.In thisissue of the World Journal of Gastroenterology,Martins et al report an analysis of LOH andmicrosatellite instability in HCCs from a group of 展开更多
关键词 SUBJECT headings liver NEOPLASMS carcinoma HEPATOCELLULAR tumor supressor gene microsatellite instability
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Era of universal testing of microsatellite instability in colorectal cancer 被引量:18
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作者 Xuchen Zhang Jia Li 《World Journal of Gastrointestinal Oncology》 SCIE CAS 2013年第2期12-19,共8页
Colorectal cancer (CRC) incidence and mortality are constantly decreasing, but CRC still remains the third most prevalent cancer and the third most common cause of cancer death in both males and females in the United ... Colorectal cancer (CRC) incidence and mortality are constantly decreasing, but CRC still remains the third most prevalent cancer and the third most common cause of cancer death in both males and females in the United States. Recent rapid declines in CRC incidence rates have largely been attributed to increases in screening that can detect and remove precancerous polyps, and the decrease in death rates for CRC largely reflects improvements in early detection, treatment and the understanding of molecular/genetic basis of CRC. One of the important molecular/genetic findings is the presence of microsatellite instability (MSI) in CRCs. Many studies have shown the importance of MSI testing in diagnosing Lynch syndrome and predicting prognosis and response to chemotherapeutic agents in CRCs. Increased emphasis has been placed on the importance of MSI testing for all newly diagnosed individuals with CRCs. Both immunohistochemical staining (IHC) and polymerase chain reaction (PCR)-based MSI testing show high sensitivity and specificity in detecting MSI. The current clinical guidelines and histopathology features are indicative of, but not reliable in diagnosing Lynch syndrome and CRCs with MSI. Currently, there are evidences that universal testing for MSI starting with either IHC or PCR-based MSI testing is cost effective, sensitive, specific and is getting widely accepted. 展开更多
关键词 COLORECTAL cancer LYNCH syndrome UNIVERSAL TESTING DNA MISMATCH repair microsatellite instability
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Microsatellite instability,MMR gene expression and proliferation kinetics in colorectal cancer with famillial predisposition 被引量:14
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作者 Bao Ping Wu Ya Li Zhang +2 位作者 Dian Yuan Zhou Chun Fang Gao Zhuo Sheng Lai 《World Journal of Gastroenterology》 SCIE CAS CSCD 2000年第6期902-905,共4页
INTRODUCTIONGenetic instability is a conunon property of manyhuman cancers,including those of HNPCC.A novel form of genetic instability involving somaticalterations,such as deletions and insertions insimple repeated s... INTRODUCTIONGenetic instability is a conunon property of manyhuman cancers,including those of HNPCC.A novel form of genetic instability involving somaticalterations,such as deletions and insertions insimple repeated sequences,has been found.Microsatellitcs are relatively short runs of tandemlyrepeated sequences scattered throughout 展开更多
关键词 colorectal neoplasms microsatellite instability gene expression FAMILIAL PREDISPOSITION proliferation kinetics immunohistochemistry POLYMERASE chain reaction flow CYTOMETRY
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Helicobacter pylori and EBV in gastric carcinomas:Methylation status and microsatellite instability 被引量:6
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作者 Adriana Camargo Ferrasi Nídia Alice Pinheiro +7 位作者 Silvia Helena Barem Rabenhorst Otávia Luisa Caballero Maria Aparecida Marchesan Rodrigues Fabrício de Carvalho Celso Vieira de Souza Leite Marcia Valéria Pitombeira Ferreira Marcos Aurélio Pessoa Barros Maria Inês de Moura Campos Pardini 《World Journal of Gastroenterology》 SCIE CAS CSCD 2010年第3期312-319,共8页
AIM:To verify the methylation status of CDH1, DAPK, COX2, hMLH1 and CDKN2A genes and to evaluate their association with Helicobacter pylori (H. pylori)-cagA+ and Epstein Barr virus (EBV) infections in gastric adenocar... AIM:To verify the methylation status of CDH1, DAPK, COX2, hMLH1 and CDKN2A genes and to evaluate their association with Helicobacter pylori (H. pylori)-cagA+ and Epstein Barr virus (EBV) infections in gastric adenocarcinomas.METHODS: Methylation-specific PCR (MSP) assay was performed in 89 primary gastric carcinomas (intestinal and diffuse types). Microsatellite instability (MSI) analysis was performed using the BAT26 primer set and PCR products were analyzed with the ABI PRISM 3100 Genetic Analyzer using Genescan 3.7 software (Applied Biosystems). Detection of H. pylori and genotyping were performed by PCR, using specifi c primers for ureaseC and cagA genes. The presence of EBV was assessed by in situ hybridization. Statistical analyses were performed using the χ2 or Fisher's exact test.RESULTS: The most frequent hypermethylated gene was COX-2 (63.5%) followed by DAPK (55.7%), CDH1 (51%), CDKN2A (36%) and hMLH1 (30.3%). Intestinal and diffuse adenocarcinomas showed different methylation profiles and there was an association between methylation of E-CDH1 and H. pylori-cagA+ in the intestinal adenocarcinoma type. MSI was correlated with hMLH1 methylation. There was an inverse correlation between DAPK hypermethylation and MSI.CONCLUSION: We found a strong association between CDH1 methylation and H. pylori-cagA+ in intestinal-type gastric cancer, association of MSI and better prognosis and an heterogeneous COX-2 overexpression. 展开更多
关键词 Gastric cancer METHYLATION microsatellite instability Helicobacter pylori Epstein Barr virus
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Interrelationship between microsatellite instability and microRNA in gastrointestinal cancer 被引量:16
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作者 Hiroyuki Yamamoto Yasushi Adachi +4 位作者 Hiroaki Taniguchi Hiroaki Kunimoto Katsuhiko Nosho Hiromu Suzuki Yasuhisa Shinomura 《World Journal of Gastroenterology》 SCIE CAS CSCD 2012年第22期2745-2755,共11页
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
关键词 microsatellite instability MICRORNA DNA mis-match repair Frameshiff mutation MicroRNA processing
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Causes and consequences of microsatellite instability in gastric carcinogenesis 被引量:15
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作者 Sérgia Velho Maria Sofia Fernandes +2 位作者 Marina Leite Ceu Figueiredo Raquel Seruca 《World Journal of Gastroenterology》 SCIE CAS 2014年第44期16433-16442,共10页
Loss of DNA mismatch repair(MMR) function, due to somatic or germline epi/genetic alterations of MMR genes leads to the accumulation of numerous mutations across the genome, creating a molecular phenotype known as mic... Loss of DNA mismatch repair(MMR) function, due to somatic or germline epi/genetic alterations of MMR genes leads to the accumulation of numerous mutations across the genome, creating a molecular phenotype known as microsatellite instability(MSI). In gastric cancer(g C), MSI occurs in about 15% to 30% of the cases. This review summarizes the current knowledge on the molecular mechanisms underlying the acquisition of MSI in g C as well as on the clinic, pathologic and molecular consequences of the MSI phenotype. Additionally, current therapeutic strategies for g C and their applicability in the MSI subset are also discussed. 展开更多
关键词 Gastric cancer microsatellite instability Mismatch repair genes ONCOGENES Helicobacter pylori
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Telomerase activity in colorectal cancer,prognostic factor and implications in the microsatellite instability pathway 被引量:8
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作者 M Vidaurreta ML Maestro +4 位作者 S Rafael S Veganzones MT Sanz-Casla J Cerdán M Arroyo 《World Journal of Gastroenterology》 SCIE CAS CSCD 2007年第28期3868-3872,共5页
AIM: To determine whether the telomerase activity is related to the Microsatellite instability (MSI) genetic pathway and whether it means a difference in the survival.METHODS: The population consisted of 97 colore... AIM: To determine whether the telomerase activity is related to the Microsatellite instability (MSI) genetic pathway and whether it means a difference in the survival.METHODS: The population consisted of 97 colorectal cancer patients. MSI determination was performed in accordance with the NCI criteria using PCR and Genescan. Telomerase activity was determined by the TRAP-assay, an ELISA procedure based on the amplification of telomeric repeat sequences.RESULTS: 6.2% showed high MSI (MSI-H), 10.3% showed low MSI (MSI-L) and 83.5% did not show this alteration (MSS). Positive telomerase activity was detected in 92.8% of the patients. 83.3% of MSI-H tumors showed positive telomerase against 93.8% of MSS tumors. In the overall survival analysis the absence of telomerase activity conferred a better prognosis.CONCLUSION: Previous works have shown that tumors which develop via the MSI pathway present a better prognosis. No link between telomerase activity and MSl status is observed, although sample sizes are small. Patients with telomerase negative tumors had better overall survival than patients with telomerase positive tumors. 展开更多
关键词 microsatellite instability TELOMERASE Colorectal cancer PROGNOSIS
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Microsatellite instability and MLH1 promoter hypermethylation in colorectal cancer 被引量:7
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作者 Yaron Niv 《World Journal of Gastroenterology》 SCIE CAS CSCD 2007年第12期1767-1769,共3页
Colorectal cancer (CRC) is caused by a series of genetic or epigenetic changes, and in the last decade there has been an increased awareness that there are multiple forms of colorectal cancer that develop through di... Colorectal cancer (CRC) is caused by a series of genetic or epigenetic changes, and in the last decade there has been an increased awareness that there are multiple forms of colorectal cancer that develop through different pathways. Microsatellite instability is involved in the genesis of about 15% of sporadic colorectal cancers and most of hereditary nonpolyposis cancers. Tumors with a high frequency of microsatellite instability tend to be diploid, to possess a mucinous histology, and to have a surrounding lymphoid reaction. They are more prevalent in the proximal colon and have a fast pass from polyp to cancer. Nevertheless, they are associated with longer survival than stage-matched tumors with microsateUite stability. Resistance of colorectal cancers with a high frequency of microsatellite instability to 5-fluorouracilbased chemotherapy is well established. Silencing the MLH1 gene expression by its promoter methylation stops the formation of MLH1 protein, and prevents the normal activation of the DNA repair gene. This is an important cause for genomic instability and cell proliferation to the point of colorectal cancer formation. Better knowledge of this process will have a huge impact on colorectal cancer management, prevention, treatment and prognosis. 展开更多
关键词 MLH1 METHYLATION Colorectal cancer microsatellite instability CpG island methylator phenotype Chromosomal instability
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Microsatellite instability in gastric cancer and pre-cancerous lesions 被引量:7
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作者 Ping Liu Xiao-Yong Zhang +1 位作者 Yun Shao Dao-Fu Zhang 《World Journal of Gastroenterology》 SCIE CAS CSCD 2005年第31期4904-4907,共4页
AIM: To investigate the microsatellite instability (MSI) in cancer and pre-cancerous lesions of the stomach and its mechanisms underlying the development of gastric cancer.METHODS: Thirty-six gastric cancer samples we... AIM: To investigate the microsatellite instability (MSI) in cancer and pre-cancerous lesions of the stomach and its mechanisms underlying the development of gastric cancer.METHODS: Thirty-six gastric cancer samples were obtained from patients undergoing surgery. Forty-one gastric mucosa samples with dysplasia and 51 with intestinal metaplasia (IM) were obtained from patients with chronic gastritis undergoing gastro-endoscopy. Genomic DNA was extracted from the samples. Silver staining single strand conformation polymorphis-polymerize chain reaction (SSCP-PCR) was used to screen MSI markers at 5 loci (Bat-25, Bat-26, D5S346, D17S250, and D2S123)in fresh tissues and formalin-fixed, paraffin-embedded samples and their corresponding normal gastric mucosa.RESULTS: The abnormal shifting of the single-strand DNA (MSI) was identified in 21 out of 36 (58.3%) gastric cancers.Seven cases showed high-level MSI (two or more loci altered) and 14 showed low-level MSI (one locus altered).Gastric cancer with MSI had a tendency to be located in the distal stomach. MSI was also detected in 11 out of 41(26.8%) dysplasia samples and in 9 of 51 (17.6%) IM samples respectively. Three cases of dysplasia and one case of IM showed high-level MSI. Eight cases of dysplasia and 8 cases of IM displayed low-level MSI. MIS in IM was found only in moderate or severe-grade IM. No association was detected between MSI and dysplasia grade.CONCLUSION: Accumulation of MSI in dysplasia and intestinal metaplasia of gastric mucosa may be an early molecular event during gastric carcinogenesis and may contribute to the acquisition of transformed cell phenotype and the development of gastric cancer. 展开更多
关键词 Stomach neoplasms Gastric dysplasia Intestinal metaplasia microsatellite instability PCR-SSCP
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