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Association between Helicobacter pylori infection,mismatch repair,HER2 and tumor-infiltrating lymphocytes in gastric cancer

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World Journal of Gastrointestinal Oncology 2024年第6期16卷 2487-2503页

作者： Carlos A Castaneda Miluska Castillo Luis A Bernabe Joselyn Sanchez Matteo Fassan Katherine Tello Ignacio Ivan Wistuba Ivan Chavez Passiuri Eloy Ruiz Juvenal Sanchez Fernando Barreda Daniel Valdivia Yaqueline Bazan Milagros Abad-Licham Claudio Mengoa Hugo Fuentes Paola Montenegro Ebert Poquioma Raul Alatrista Claudio J Flores Luis Taxa Faculty of Health Sciences Universidad Cientifica del SurLima 15038Peru GECO PERU Grupo de Estudios Clinicos Oncologicos del PeruLima 15038Peru Department of Research Instituto Nacional de Enfermedades NeoplasicasLima 15038Peru Faculty of Human Medicine Universidad Ricardo PalmaLima 15039Peru Department of Medicine Surgical Pathology&Cytopathology UnitUniversity of PaduaPadua 35121Italy Department of Translational Molecular Pathology The University of Texas MD Anderson Cancer CenterHoustonTX 77030United States Department of Abdominal Surgery Instituto Nacional de Enfermedades NeoplasicasLima 15038Peru Department of Pathology Instituto Nacional de Enfermedades NeoplasicasLima 15038Peru Department of Medical Specialties Instituto Nacional de Enfermedades NeoplasicasLima 15038Peru Department of Pathology Instituto Regional de Enfermedades Neoplasicas del NorteTrujillo 13001Peru Faculty of Human Medicine Universidad Privada Antenor OrregoTrujillo 13008Peru Department of Surgery Instituto Regional de Enfermedades Neoplasicas del SurArequipa 04002Peru Department of Medical Oncology Instituto Nacional de Enfermedades NeoplasicasLima 15038Peru Department of Epidemiology Instituto Nacional de Enfermedades NeoplasicasLima 15038Peru Unidad de Investigación Básica y Traslacional Oncosalud-AUNALima 15038Peru Faculty of Medicine Universidad San Martin de PorresLima 15008Peru

BACKGROUND The influence of Helicobacter-pylori(H.pylori)infection and the characteristics of gastric cancer(GC)on tumor-infiltrating lymphocyte(TIL)levels has not been extensively studied.Analysis of infiltrating-immune-cell subtypes as well as survival is necessary to obtain comprehensive information.AIM To determine the rates of deficient mismatch-repair(dMMR),HER2-status and H.pylori infection and their association with TIL levels in GC.METHODS Samples from 503 resected GC tumors were included and TIL levels were evaluated following the international-TILs-working-group recommendations with assessment of the intratumoral(IT),stromal(ST)and invasive-border(IB)compartments.The density of CD3,CD8 and CD163 immune cells,and dMMR and HER2-status were determined by immunohistochemistry(IHC).H.pylori infection was evaluated by routine histology and quantitative PCR(qPCR)in a subset of samples.RESULTS dMMR was found in 34.4%,HER2+in 5%and H.pylori-positive in 55.7%of samples.High IT-TIL was associated with grade-3(P=0.038),while ST-TIL with grade-1(P<0.001),intestinal-histology(P<0.001)and no-recurrence(P=0.003).dMMR was associated with high TIL levels in the ST(P=0.019)and IB(P=0.01)compartments,and STCD3(P=0.049)and ST-CD8(P=0.05)densities.HER2-was associated with high IT-CD8(P=0.009).H.pylorinegative was associated with high IT-TIL levels(P=0.009)when assessed by routine-histology,and with high TIL levels in the 3 compartments(P=0.002-0.047)and CD8 density in the IT and ST compartments(P=0.001)when assessed by qPCR.A longer overall survival was associated with low IT-CD163(P=0.003)and CD8/CD3(P=0.001 in IT and P=0.002 in ST)and high IT-CD3(P=0.021),ST-CD3(P=0.003)and CD3/CD163(P=0.002).CONCLUSION TIL levels were related to dMMR and H.pylori-negativity.Low CD8/CD3 and high CD163/CD3 were associated with lower recurrence and longer survival.

关键词： Lymphocytes Macrophages Gastric cancer Helicobacter pylori HER2 mismatch repair

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Spatial transcriptome unveils a discontinuous inflammatory pattern in proficient mismatch repair colorectal adenocarcinoma

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Fundamental Research 2023年第4期3卷 640-646页

作者： Rongxin Zhang Yu Feng Wenjuan Ma Yanying Guo Mei Luo Young Li Yupeng Zang Xuan Dong Shixun Lu Qiang Guo Qumiao Xu Huanyi Chen Yijian Li Longqi Liu Ao Chen Gong Chen Xun Xu Department of Colorectal Surgery Sun Yat-sen University Cancer CentreGuangzhou 510060GuangdongChina BGI-Shenzhen Beishan Industrial ZoneShenzhen 518083China State Key Laboratory of Oncology in South China Guangzhou 510060GuangdongChina Collaborative Innovation Center of Cancer Medicine Guangzhou 510060GuangdongChina Intensive Care Unit Department Sun Yat-sen University Cancer CentreGuangzhou 510060GuangdongChina College of Life Sciences University of Chinese Academy of SciencesBeijing 100049China Department of Pathology Sun Yat-sen University Cancer CentreGuangzhou 510060GuangdongChina Shenzhen Bay Laboratory Shenzhen 518000China Department of Biology University of CopenhagenCopenhagen DK-2200Denmark Guangdong Provincial Key Laboratory of Genome Read and Write Shenzhen 518120China

The preexistence of immune cells in the tumor microenvironment substantiates the efficacy of immunotherapy in cancer patients.Although the complex intratumoral immune heterogeneity has been extensively studied in single cell resolution,hi-res spatial investigations are limited.In this study,we performed a spatial transcriptome analysis of 4 colorectal adenocarcinoma specimens and 2 paired distant normal specimens to identify the molecular pattern involved in a discontinuous inflammatory response in pathologically annotated cancer regions.Based on the location of spatially varied gene expression,we unmasked the spatially-varied immune ecosystem and identified the locoregional“warmed-up”immune response in predefined“cold”tumor with substantial infiltration of immune components.This“warmed-up”immune profile was found to be associated with the in-situ copy number variance and the tissue remodeling process.Further,“warmed-up”signature genes indicated improved overall survival in CRC patients obtained from TCGA database.

关键词： Colorectal adenocarcinoma mismatch repair Inflammation Spatial transcriptomics Tumor microenvironment

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mismatch repair enzyme expression in primary and castrate resistant prostate cancer

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Asian Journal of Urology 2016年第4期3卷 223-228页

作者： Belinda Nghiem Xiaotun Zhang Hung-Ming Lam Lawrence DTrue Ilsa Coleman Celestia SHigano Peter SNelson Colin CPritchard Colm Morrissey Department of Urology University of WashingtonSeattleWAUSA State Key Laboratory of Quality Research in Chinese Medicine Macao Institute for Applied Research in Medicine and HealthMacao University of Science and TechnologyMacao(SAR)China Department of Pathology University of WashingtonSeattleWAUSA Divison of Human Biology Fred Hutchinson Cancer Research CenterSeattleWAUSA Department of Medicine University of WashingtonSeattleWAUSA Department of Laboratory Medicine University of WashingtonSeattleWAUSA

Objective:Although the utility of immunohistochemistry(IHC)for assessing mismatch repair(MMR)protein expression has been demonstrated in solid tumors including primary prostate cancer(PCa),its utility has not been assessed in castration-resistant PCa(CRPC).Methods:Tissue microarrays were constructed from 127 radical prostatectomies and 155 CRPC metastases from 50 patients.MMR(MLH1,MSH2,MSH6,and PMS2)expression was assessed by IHC and gene expression arrays.Associations between MMR protein expression in PCa and CRPC and biochemical recurrence(BCR)or time from diagnosis to death respectively were determined.Results:There was no correlation between levels of MMR protein and BCR.Absence of MSH2 and MSH6 was the most pronounced at 15%and 22%in PCa and 17.8%and 16%in CRPC patients,respectively.MSH2 and MSH6 protein were absent in 9.4%and 8%of PCa and CRPC respectively.Absence of individual MMR proteins did not correlate with BCR or time from diagnosis to death.However absent MSH2/MSH6 in CRPC was associated with shorter time to death(pZ0.0006).Loss of MSH2 was verified at the gene expression level.This finding correlated with microsatellite instability previously reported in this CRPC cohort.

关键词： mismatch repair Castration resistant prostate cancer MLH1 MSH2 MSH6 PMS2

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Expression status of GATA3 and mismatch repair proteins in upper tract urothelial carcinoma

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Frontiers of Medicine 2019年第6期13卷 730-740页

作者： Yue Wang Jinxia Zhang Yunfan Wang Shufang Wang Yu Zhang Qi Miao Fei Gao Huiying He Department of Pathology Peking University Shougang HospitalBeijing 100144China Department of Pathology School of Basic Medical SciencesPeking University Third HospitalPeking University Health Science CenterBeijing 100083China

GATA binding protein 3 (GATA3) and mismatch repair (MMR) deficiency contribute to the development of urothelial carcinoma. However, the combined expression of GATA3 and microsatellite instability (MSI) in upper tract urothelial carcinoma (UTUC) and its prognostic value have not been investigated. Here, we immunohistochemically stained GATA3 and MMR proteins in 108 UTUC samples. GATA3 was positive in 74 cases, and its expression was significantly lower than in adjacent benign urothelium (P<0.001). Loss of GATA3 expression was statistically associated with adverse clinicopathologic parameters, such as advanced stage, lymphovascular invasion, neural invasion, lymph node metastasis, and extensive necrosis. Cancer-specific survival (CSS, P=0.028) and disease-free survival (DFS, P=0.024) were significantly shorter in patients with GATA3 negative tumors than in patients with GATA3 positive tumors. The absence of MMR proteins was observed in 8.3% of the cases, and focal staining was identified in 13.0%. When using “lax criteria” which resulted in counting cases as negative where MMR staining was in fact focally positive (<5%), we found that GATA3 was inversely associated with MSI (P=0.005). Moreover, GATA3−/microsatellite stability (MS) tumors were correlated with advanced pT stage (P<0.001) and poor outcome (P=0.019 for CSS, P=0.016 for DFS) compared with GATA3+/MSI ones. The GATA3−/MSI cases had unfavorable clinical outcomes compared with GATA3+/MSI cases (P=0.008 for CSS, P=0.023 for DFS). This finding raises a question as to whether GATA3 interacts with MSI through the TGF-β signaling pathway and regulates UTUC progression.

关键词： upper tract urothelial carcinoma GATA binding protein 3 mismatch repair microsatellite instability prognosis

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The Effect of Curcumin on mismatch repair(MMR) Proteins hMSH2 and hMLH1 after Ultraviolet(UV) Irradiation on HL-60 Cells

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2003年第2期23卷 124-126页

作者：陈燕吴裕丹陈文娟何静 The Institute of Hematology Xiehe Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430022

To understand the expression and effect of mismatch repair genes, hMSH2 and hMLH1, and to investigate anti-leukemic cell proliferation mechanism of curcumin, the levels of both genes were detected by multiple comparative RT-PCR. The protein of hMSH2 was determined by flow cy-tometry (FCM) and the gene mutation of hMSH2 and hMLH1 were detected by PCR-SSCP and mi-crosatellite instability assay. After UV irradiation, the gene expression of hMSH2 and hMLHl was not increased and showed no response. This phenomenon was not ascribed to gene mutation, because PCP-SSCP and microsatellite instability assay revealed no abnormal gel-shift band in both genes. After irradiation and addition of curcumin, the expression of hMSH2 mRNA increased and the cellular apoptotic rate also increased at the same time. The difference was statistically significant as compared with groups without addition of curcumin and control groups (P<0. 05). Our results suggested that when MMR system was inhibited by the same agents, curcumin can remove this suppression and switch to cellular apoptosis.

关键词： leukemia HL-60 mismatch repair gene curcumin

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Lynch syndrome pre-screening and comprehensive characterization in a multi-center large cohort of Chinese patients with colorectal cancer

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Cancer Biology & Medicine 2022年第8期19卷 1235-1248页

作者： Yan Li Lihong Fan Jianming Zheng Xiu Nie Yu Sun Qin Feng Shenyi Lian Wenqi Bai Weijing Cai Yanan Yang Bo Su Yanfeng Xi Dongmei Lin Department of Pathology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China Department of Respiration Medicine Shanghai Tenth People’s HospitalSchool of MedicineTongji UniversityShanghai 200072China Department of Pathology Changhai Hospital of ShanghaiShanghai 200433China Department of Pathology Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education)Peking University Cancer Hospital&InstituteBeijing 100142China Department of Colorectal Surgery Shanxi Cancer HospitalTaiyuan 030013China Shanghai Tongshu Biotechnology Co. LtdShanghai 200120China Department of Biochemistry and Molecular Biology Mayo ClinicRochesterMN 55905USA Central Laboratory Shanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai 200433China Department of Pathology Shanxi Cancer HospitalTaiyuan 030013China

Objective:Lynch syndrome(LS)pre-screening methods remain under-investigated in colorectal cancers(CRCs)in Asia.Here,we aimed to systematically investigate LS pre-screening and comprehensively characterize LS CRCs.Methods:Microsatellite instability(MSI)and germline variants of DNA mismatch repair(MMR)genes were examined in 406 deficient MMR(dMMR)and 250 proficient MMR CRCs.The genetic differences between LS and sporadic CRCs were studied with whole exome sequencing analysis.Results:The incidence of dMMR in Chinese patients with CRCs was 13.8%.Consistency analysis between MMR immunohistochemistry(IHC)and MSI testing showed the kappa value was 0.758.With next-generation sequencing(NGS),germline variants were detected in 154 CRCs.Finally,88 patients with CRC were identified as having LS by Sanger sequencing.Among them,we discovered 21 previously unreported pathogenic germline variants of MMR genes.Chinese patients with LS,compared with sporadic CRCs,tended to be early-onset,right-sided,early-stage and mucinous.Overall,the performance of MMR IHC and MSI testing for LS pre-screening was comparable:the area under the ROC curve for dMMR,MSI-H,and MSI-H/L was 0.725,0.750,and 0.745,respectively.dMMR_MSI-H LS and sporadic CRCs showed substantial differences in somatic genetic characteristics,including different variant frequencies of APC,CREBBP,and KRAS,as well as different enriched pathways of VEGF,Notch,TGFβR,mTOR,ErbB,and Rac protein signal transduction.Conclusions:MMR IHC and MSI testing were effective methods for LS pre-screening.The revealed clinical and somatic genetic characteristics in LS CRCs may have the potential to improve the performance of LS pre-screening in combination with dMMR/MSI.

关键词： Microsatellite instability mismatch repair sequencing Lynch syndrome somatic genetic characteristics

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Genitourinary manifestations of Lynch syndrome in the urological practice

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Asian Journal of Urology 2022年第4期9卷 443-450页

作者： Chiara Lonati Claudio Simeone Nazareno Suardi Philippe ESpiess Andrea Necchi Marco Moschini Urology Unit ASST Spedali Civili di BresciaDepartment of Medical and Surgical SpecialtiesRadiological Science and Public HealthUniversity of BresciaBresciaItaly Department of Urology Luzerner KantonsspitalLucerneSwitzerland Department of Genitourinary Oncology H.Lee Moffitt Cancer Center and Research InstituteTamplaFLUSA University Vita-Salute San Raffaele MilanItaly Department of Medical Oncology IRCCS San Raffaele Hospital and Scientific InstituteMilanItaly Division of Experimental Oncology/Unit of Urology Urological Research InstituteIRCCS Ospedale San RaffaeleMilanItaly

Objective:Lynch syndrome(LS)is an autosomal dominant hereditary disorder resulting from germline mutation in at least one of the four mismatch repair genes or in EPCAM gene.From a clinical perspective,LS patients exhibit an increased predisposition to multiple primary malignancies and early age of onset compared to general population.We aimed to provide a comprehensive overview of all the genitourinary manifestations of LS,focusing on incidence,diagnosis,clinical features,therapeutic strategies,and screening protocols.Methods:Previous literature was assessed through Medline,Scopus,and Google Scholar data-bases.A narrative review of the most relevant articles from January 1996 to June 2021 on urological manifestations of LS was provided.Results:In the LS tumor spectrum,upper tract urothelial carcinoma(UTUC)represents the third most frequent malignancy,and the first most common cancer in the urological field,with an approximately 14-fold increased risk of developing UTUC compared to general population.LS diagnosis among patients experiencing UTUC as first malignancy is a step-by-step process,including(i)clinical criteria,(ii)molecular testing,and(iii)genetic testing to confirm the hereditary disorder.The current European Association of Urology(EAU)guidelines recommend to perform molecular testing among UTUC patients under 65 years old,or UTUC patients with personal history of LS-related tumor,or UTUC patients with one first-degree relative under the age of 50 years with LS-related tumor,or UTUC patients with two first-degree relatives with LS-related tumor regardless of age of onset.Newly diagnosed LS patients should be referred to a multidisci-plinary management,including gastroenterologists and gynecologists.Finally,considering the increased risk of metachronous recurrence,treatments other than radical nephroureterectomy may be a valuable therapeutic alternative.Whether urological malignancies other than UTUC should be included in the LS tumor spectrum is still controversial.Conclusion:Considering the strict asso

关键词： Hereditary disease Hereditary nonpolyposis colorectal cancer Lynch syndrome mismatch repair Upper tract urothelial carcinoma

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C. tropicalis promotes chemotherapy resistance in colon cancer through increasing lactate production to regulate the mismatch repair system

C. tropicalis promotes chemotherapy resistance in colon canc...

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2021年中国肿瘤标志物学术大会暨第十五届肿瘤标志物青...

作者： Junxing Qu Ting Wang Medical School of Nanjing University

Background: Due to chemotherapeutic drug resistance, tumor recurrence is common in patients with colorectal cancer（CRC） and drug-resistant patients are often accompanied by defects in the mismatch repair system（MMR）. "Warburg effect" is a metabolic feature of most tumor cells and is a potential cause of chemotherapy resistance. However, whether lactate, the main glycolysis product, can participate in CRC chemoresistance by regulating MMR has not been reported. Previous studies have shown that Candida tropicalis（C. tropicalis） is closely related to the development of CRC, but whether this conditional pathogenic fungus is involved in chemotherapy needs further investigation.Methods: In this paper, a mouse CRC xenograft tumor model was established. The effect of oxaliplatin in C. tropicalis treated and non-treated groups was evaluated by comparing tumor weight and tumor volume, we also detected the expression of main functional proteins of MMR and glycolysis flux in tumor tissues. Furthermore, we stimulated the colon cancer cell line SW480 with C. tropicalis to explore the mechanism by which C. tropicalis affects the glycolysis and regulates MMR to induce chemotherapy resistance in CRC cells.Results: We found that C. tropicalis promoted CRC chemotherapy resistance to oxaliplatin, it also can markedly up-regulate the glycolysis level and restrain the expression of functional MMR proteins in tumor tissues. Furthermore, inhibition of lactate production can reverse the chemotherapy resistance notably caused by C. tropicalis. Mechanistically, we found that lactate can regulate the function of the MMR through the GPR81-cAMP-PKA-CREB axis to facilitate the chemotherapy resistance of CRC to oxaliplatin.Conclusion: This study clarified that the conditional pathogenic fungus C. tropicalis can prompt CRC chemoresistance by increasing production of lactate to inhibit the MMR, and provided novel ideas for improving CRC chemotherapy effect.

关键词： Candida.tropicalis chemoresistance glycolysis lactate mismatch repair

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Recruitment of mismatch repair proteins to DNA double-strand breaks in human cell

Recruitment of mismatch repair proteins to DNA double-strand...

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江苏省遗传学会第七届二次代表大会暨学术研讨会

作者： Akira Yasui Department of Molecular Genetics Institute of DevelopmentAging and Cancer Tohoku UniversityJapan

＜正＞mismatch repair （MMR） proteins contribute to genome stability by excising DNA mismatches that occur as the result of misincorporation by DNA polymerase.

关键词： mismatch repair double strand breaks in situ analysis Laser micro-irradiation

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microRNA-21 downregulates oncogene PLAG1 post-transcriptionally in DNA mismatch repair-deficient colorectal cancer

microRNA-21 downregulates oncogene PLAG1 post-transcriptiona...

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中国遗传学会第八次代表大会暨学术讨论会

作者：梅倩孙树汉 Institute of Medical Genetics Second Military Medical University800 Xiang’Yin Road

microRNA(miRNA)deregulations can contribute to cancer development by modulating the expression of critical genes.Our aims were to characterize the post-transcriptional profile of mismatch repair(MMR)-deficient colon cancer(CRC)and reveal the pathophysiologic role of aberrantly miRNA.A genome-wide miRNA microarray and quantitative real-time PCR were used to identify differently expressed miRNAs in MMR-deficient CRC cell lines and tissues.Eight miRNAs were identified deregulated both in cells and tissues.We defined a target gene and biologically functional effect of an up-regulated miRNA,miR-21 was up-regulated in all MMR-deficient cell lines and tissues compared to their MMR-proficient counterparts.Meanwhile,the 3’-UTR of Pleomorphic adenoma gene 1(PLAG1)is the functional target of miR-21 and we found an inverse correlation between miR-21 and expression of oncogene PLAG1.These results show that PLAG1 is a target gene of miR-21.Moreover,enhanced expression of miR-21 by transfection with precursor miR-21 decreased proliferation of colon cancer cells HT29 and Caco2,and the results were consistent with PLAGi knock-clown,which increased cell apoptosis.Furthermore,we determined the expression of insulin-like growth factor 2(IGF2),target gene of PLAG1,in all above samples. We found that expression of IGF2 is coincident with that of PLAG1.miR-21 might contribute to the better prognosis of MMR-deficient CRCs by modulating expression of PLAG1 and the IGF2 mitogenic pathway.This is the first study to show that PLAG1 is negatively regulated by miR-21, and that up-regulated miR-21 has an important role in MMR-deficient CRCs.

关键词： mismatch repair colorectal cancer microRNA target gene PLAG1

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