Bladder cancer is the second most common tumor in the urinary system after prostate cancer.It is highly heterogeneous and its developmental mechanism involves abnormal alterations in the structure and function of mult...Bladder cancer is the second most common tumor in the urinary system after prostate cancer.It is highly heterogeneous and its developmental mechanism involves abnormal alterations in the structure and function of multiple genomes.Researching the molecular classification of bladder cancer by using molecular biology techniques is important for defining the pathogenesis of the disease and selecting therapeutic schedule.This paper will review the progress of molecular classification studies of bladder cancer.展开更多
Gastric cancer(GC) is a highly aggressive and life-threatening malignancy.Even with radical surgical removal and front-line chemotherapy,more than half of GCs locally relapse and metastasize at a distant site.The dism...Gastric cancer(GC) is a highly aggressive and life-threatening malignancy.Even with radical surgical removal and front-line chemotherapy,more than half of GCs locally relapse and metastasize at a distant site.The dismal outcomes reflect the ineffectiveness of a one-size fits-all approach for a highly heterogeneous disease with diverse etiological causes and complex molecular underpinnings.The recent comprehensive genomic and molecular profiling has led to our deepened understanding of GC.The emerging molecular classification schemes based on the genetic,epigenetic,and molecular signatures are providing great promise for the development of more effective therapeutic strategies in a more personalized and precise manner.To this end,the Cancer Genome Atlas(TCGA) research network conducted a comprehensive molecular evaluation of primary GCs and proposed a new molecular classification dividing GCs into four subtypes:Epstein-Barr virus-associated tumors,microsatellite unstable tumors,genomically stable tumors,and tumors with chromosomal instability.This review primarily focuses on the TCGA molecular classification of GCs and discusses the implications on novel targeted therapy strategies.We believe that these fundamental findings will support the future application of targeted therapies and will guide our efforts to develop more efficacious drugs to treat human GCs.展开更多
BACKGROUND Gastric cancer(GC)is a highly heterogeneous disease,and the identification of molecular subtyping of gastric adenocarcinoma emerged as a promising option to define therapeutic strategies and prognostic subg...BACKGROUND Gastric cancer(GC)is a highly heterogeneous disease,and the identification of molecular subtyping of gastric adenocarcinoma emerged as a promising option to define therapeutic strategies and prognostic subgroups.However,the costs and technical complexity of molecular methodologies remains an obstacle to its adoption,and their clinical significance by other approaches needs further evidence.AIM To evaluate the clinicopathological characteristics and long-term survival of GC based on the subgroups of molecular classification by immunohistochemistry(IHC)and in situ hybridization(ISH).METHODS We retrospectively evaluated all patients who underwent D2-gastrectomy between 2009 and 2016 in a Western cohort of GC patients treated with curative intent.Microsatellite instability(MSI)status,E-cadherin,and p53 expression were analyzed by IHC,and Epstein-Barr virus(EBV)by ISH.Tissue microarrays were constructed for analysis.Clinicopathological characteristics and survival of GC were evaluated according to subtypes defined by The Cancer Genome Atlas(TCGA)Research Network Group and Asian Cancer Research Group(ACRG)classification systems.RESULTS A total of 287 GC patients were included.Based on IHC and ISH analysis,five profiles were defined as follows:E-cadherin aberrant(9.1%),MSI(20.9%),p53 aberrant(36.6%),EBV positivity(10.5%),and p53 normal(31%),which corresponded to tumors that showed no alteration in another profile.A flowchart according to the TCGA and ACRG classifications were used to define the subtypes,where clinical and pathological characteristics associated with GC subtypes were evidenced.Proximal location(P<0.001),total gastrectomy(P=0.001),and intense inflammatory infiltrate(P<0.001)were characteristics related to EBV subtype.MSI subtype was predominantly associated with advanced age(P=0.017)and the presence of comorbidities(P=0.011).While Laurén diffuse type(P<0.001)and advanced stage(P=0.029)were related to genomically stable(GS)subtype.GS tumors and microsatellite stable/epithelial to mesenchymal transition phenotype subtype had worse disease-free survival(DFS)and overall survival(OS)than other subtypes.Conversely,MSI subtype of GC had better survival in both classifications.Type of gastrectomy,pT and the TCGA subtypes were independent factors associated to DFS and OS.CONCLUSION The IHC/ISH analysis was able to distinguish immunophenotypic groups of GC with distinct characteristics and prognosis,resembling the subtypes of the molecular classifications.Accordingly,this method of classification may represent a viable option for use in a clinical setting.展开更多
Small cell lung cancer(SCLC)is a highly malignant tumor with a very poor prognosis;therefore,more effective treatments are urgently needed for patients afflicted with the disease.In recent years,emerging molecular cla...Small cell lung cancer(SCLC)is a highly malignant tumor with a very poor prognosis;therefore,more effective treatments are urgently needed for patients afflicted with the disease.In recent years,emerging molecular classifications based on key transcription factors of SCLC have provided more information on the tumor pathophysiology,metastasis,immune microenvironment,and acquired therapeutic resistance and reflected the intertumoral heterogeneity of the various SCLC phenotypes.Additionally,advances in genomics and single-cell sequencing analysis have further revealed the high intratumoral heterogeneity and plasticity of the disease.Herein,we review and summarize these recent lines of evidence and discuss the possible pathogenesis of SCLC.展开更多
Background:Gastric adenocarcinoma(GA)is a heterogeneous tumor,and the accurate classification of GA is important.Previous classifications are based on molecular analysis and have not focused on GA with the primitive e...Background:Gastric adenocarcinoma(GA)is a heterogeneous tumor,and the accurate classification of GA is important.Previous classifications are based on molecular analysis and have not focused on GA with the primitive enterocyte phenotype(GAPEP),a unique subtype with a poor prognosis and frequent liver metastases.New substituted molecular(SM)classifications based on immunohistochemistry(IHC)are needed.Methods:According to the IHC staining results,we divided 582 cases into six types:mismatch repair deficient(dMMR),Epstein-Barr virus associated(EBVa),the primitive enterocyte phenotype(PEP),the epithelial mes-enchymal transition(EMT)phenotype,not otherwise specified/P53 mutated(NOS/P53m)and not otherwise specified/P53 wild-type(NOS/P53w).We analyzed the clinicopathological features,the immune microenviron-ment(PD-L1,CD8)and expression of HER2 and VEGFR2 of those types.Results:There were 31(5.3%)cases of the dMMR type,13(2.2%)cases of the EBVa type,44(7.6%)cases of the PEP type,122(21.0%)cases of the EMT type,127(21.8%)cases of the NOS/P53m type and 245(42.1%)cases of the NOS/P53w type.Patients with the dMMR type had the best survival(P<0.001).Patients with the EBVa type were younger(P<0.001)and had higher PD-L1 and CD8 expression(P<0.001)than other patients.Patients with the EMT type exhibited poor differentiation and a higher rate of abdominal metastasis.Patients with the NOS/P53m and PEP types had the worst survival rates and the highest PD-L1/HER2/VEGFR2 expression levels among all patients(P<0.001).Conclusion:Different SM classifications have different clinicopathological features and expression patterns,which indicate the probable clinical treatment strategies for these subtypes.展开更多
Objective To investigate the molecular classification of endometrial cancer(EC)and atypical endometrial hyperplasia(AEH)patients treated with fertility-sparing treatment(FST),and its relationship with clinicopathologi...Objective To investigate the molecular classification of endometrial cancer(EC)and atypical endometrial hyperplasia(AEH)patients treated with fertility-sparing treatment(FST),and its relationship with clinicopathological factors and treatment efficacy.Methods:A total of 52EC and AEH patients who received FST and molecular classification tested by next generation sequencing in Peking University People's Hospital from June 2020 to December 2022,were retrospectively collected.We analyzed the relationship between molecular classification and clinicopathological factors and treatment outcomes.Results(1)Of the 52 patients,including 46EC and 6 AEH patients,42(80.8%)achieved complete remission(CR)after FST,with a median time to achieve CR of 9 months.Ten cases(23.8%)had recurrence.(2)Patients were distributed into 4 molecular subgroups as 39 cases(75%)of copy number low(CNL),7 cases(13.5%)of microsatellite instability-high(MSI-H),4 cases(7.7%)of POLE mutations(POLEmut),and 2 cases(3.8%)of copy number high(CNH).Patients with MSI-H subgroup had more family history of tumor(6/7),more with loss of expression of mismatch repair(MMR)protein(7/7),and higher expression level of Ki-67(3/3).(3)Patients with MSI-H subgroup had the lowest CR rate at 6 months(0/7,P=0.014),and survival analysis showed that such patients were less likely to achieve CR than those with CNL(P=0.022).For CNL patients,median 6-month CR rate was 40.6%.In addition,CR was obtained in 3(3/4)POLEmut patients and 2(2/2)CNH patients,respectively.Conclusions Molecular classification relates with the treatment response in patients with EC and AEH receiving FST.Patients with MSI-H subgroup have poor treatment efficacy,and patients with CNL need to be further divided to predict treatment benefit.There are also a few successful cases in POLEmut and CNH subtgroups,which needs further research.展开更多
On May 23, 2017, the US Food and Drug Administration （FDA） approved a treatment for cancer patients with positive microsatellite instability-high （MSI-H） markers or mismatch repair deficient （dMMR） markers. This...On May 23, 2017, the US Food and Drug Administration （FDA） approved a treatment for cancer patients with positive microsatellite instability-high （MSI-H） markers or mismatch repair deficient （dMMR） markers. This approach is the first approved tumor treatment using a common biomarker rather than specified tumor locations in the body. FDA previously approved Keytruda for treatment of several types of malignancies, such as metastatic melanoma, metastatic non-small-cell lung cancer, recurrent or metastatic head and neck cancer, refractory Hodgkin lymphoma, and urothelial carcinoma, all of which carry positive programmed death-l/ programmed death-ligand 1 biomarkers. Therefore, indications of Keytruda significantly expanded. Several types of malignancies are disclosed by MSI-H status due to dMMR and characterized by increased neoantlgen load, which elicits intense host immune response in tumor microenvironment, including portions of colorectal and gastric carcinomas. Currently, biomarker-based patient selection remains a challenge. Pathologists play important roles in evaluating histology and biomarker results and establishing detection methods. Taking gastric cancer as an example, its molecular classification is built on genome abnormalities, but it lacks acceptable clinical characteristics. Pathologists are expected to act as ＂genetic interpreters＂ or ＂genetic translators＂ and build a link between molecular subtypes with tumor histological features. Subsequently, by using their findings, oncologists will carry out targeted therapy based on molecular classification.展开更多
BACKGROUND Ependymoma with lipomatous differentiation is a rare type of ependymoma.The ZFTA fusion-positive supratentorial ependymoma is a novel tumor type in the 2021 World Health Organization classification of centr...BACKGROUND Ependymoma with lipomatous differentiation is a rare type of ependymoma.The ZFTA fusion-positive supratentorial ependymoma is a novel tumor type in the 2021 World Health Organization classification of central nervous system tumors.ZFTA fusion-positive lipomatous ependymoma has not been reported to date.CASE SUMMARY We reported a case of a 15-year-old Chinese male who had a sudden convulsion lasting approximately six minutes.Magnetic resonance imaging showed a round cystic shadow of approximately 1.9 cm×1.5 cm×1.9 cm under the right parieto-occipital cortex.Microscopic examination showed characteristic perivascular pseudorosettes and adipose differentiation in the cytoplasm.Immunohisto-chemical staining showed that the tumor cells were negative for cytokeratin,NeuN,Syn and p53,but positive for GFAP,vimentin and S-100 protein.Signi-ficant punctate intracytoplasmic EMA immunoreactivity was observed.The level of Ki-67 was about 5%.Genetic analysis revealed ZFTA:RELA fusion.A cranio-tomy with total excision of the tumor was performed.The follow-up time was 36 months,no evidence of disease recurrence was found in magnetic resonance imaging.CONCLUSION Based on these findings,the patient was diagnosed as a ependymoma with ZFTA fusion and lipomatous differentiation.This case report provides information on the microscopic morphological features of ependymoma with ZFTA fusion and lipomatous differentiation,which can help pathologists to make a definitive diagnosis of this tumor.展开更多
AIM:To assess the role and mechanism of metformin in inducing apoptosis of pancreatic cancer cells.METHODS:The human pancreatic cancer cell lines ASPC-1,BxPc-3,PANC-1 and SW1990 were exposed to metformin.The inhibitio...AIM:To assess the role and mechanism of metformin in inducing apoptosis of pancreatic cancer cells.METHODS:The human pancreatic cancer cell lines ASPC-1,BxPc-3,PANC-1 and SW1990 were exposed to metformin.The inhibition of cell proliferation and colony formation via apoptosis induction and S phase arrest in pancreatic cancer cell lines of metformin was tested.RESULTS:In each pancreatic cancer cell line tested,metformin inhibited cell proliferation in a dose dependent manner in MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assays).Flow cytometric analysis showed that metformin reduced the number of cells in G1 and increased the percentage of cells in S phase as well as the apoptotic fraction.Enzymelinked immunosorbent assay(ELISA) showed that metformin induced apoptosis in all pancreatic cancer cell lines.In Western blot studies,metformin induced poly-ADP-ribose polymerase(PARP) cleavage(an indicator of caspase activation) in all pancreatic cancer cell lines.The general caspase inhibitor(VAD-fmk) completely abolished metformin-induced PARP cleavage and apoptosis in ASPC-1 BxPc-3 and PANC-1,the caspase-8 specific inhibitor(IETD-fmk) and the caspase-9 specific inhibitor(LEHD-fmk) only partially abrogated metformin-induced apoptosis and PARP cleavage in BxPc-3 and PANC-1 cells.We also observed that metformin treatment dramatically reduced epidermal growth factor receptor(EGFR) and phosphorylated mitogen activated protein kinase(P-MAPK) in both a time-and dose-dependent manner in all cell lines tested.CONCLUSION:Metformin significantly inhibits cell proliferation and apoptosis in all pancreatic cell lines.And the metformin-induced apoptosis is associated with PARP cleavage,activation of caspase-3,-8,and-9 in a time-and dose-dependent manner.Hence,both caspase-8 and-9-initiated apoptotic signaling pathways contribute to metformin-induced apoptosis in pancreatic cell lines.展开更多
Gliomas are the most common primary intracranial tumors in adults.Anaplastic gliomas(WHO gradeⅢ)and glioblastomas(WHO gradeⅣ)represent the major groups of malignant gliomas in the brain.Several diagnostic,predictive...Gliomas are the most common primary intracranial tumors in adults.Anaplastic gliomas(WHO gradeⅢ)and glioblastomas(WHO gradeⅣ)represent the major groups of malignant gliomas in the brain.Several diagnostic,predictive,and prognostic biomarkers for malignant gliomas have been reported over the last few decades,and these markers have made great contributions to the accuracy of diagnosis,therapeutic decision making,and prognosis of patients.However,heterogeneity in patient outcomes may still be observed,which highlights the insufficiency of a classification system based purely on histopathology.Great efforts have been made to incorporate new information about the molecular landscape of gliomas into novel classifications that may potentially guide treatment.In this review,we summarize three distinctive biomarkers,three most commonly altered pathways,and three classifications based on microarray data in malignant gliomas.展开更多
Gastric cancer (GC) is the fourth most common neoplasm and the second leading cause of cancer-related death worldwide. In Latin America (LA), the burden of this disease is higher and is the leading cause of cancer dea...Gastric cancer (GC) is the fourth most common neoplasm and the second leading cause of cancer-related death worldwide. In Latin America (LA), the burden of this disease is higher and is the leading cause of cancer death in some countries. Chemotherapy is the standard treatment for advanced-stage GC. However, the best regimen for specific populations, such as LA, is as yet unknown. Cisplatin and fluoropyrimidine continue to be the standard of care in light of the findings of phase III studies, while docetaxel, cisplatin, and 5-fluorouracil (5-FU) are alternatives for patients with suitable overall health. Oxaliplatin or irinotecan with fluoropyrimidine can also be used in elderly patients who are not candidates for cisplatin, or have a limited performance status. This review examines studies conducted in LA. Patients from LA are under-represented in multicenter trials of chemotherapy and targeted therapies. The major challenges currently lie in implementing strategies in which patients are selected on the basis of regional, racial or molecular characteristics, to consider the molecular subtype of GC for enrolment, and in selecting patients according to prognostic factors to optimize the benefits of chemotherapy.展开更多
Background:Breast cancer is a major public health concern for women around the world.Breast cancer incidence increases with age,and this is an important factor for the management of this disease.The aim of this study ...Background:Breast cancer is a major public health concern for women around the world.Breast cancer incidence increases with age,and this is an important factor for the management of this disease.The aim of this study was to assess the clinical profiles of female Iraqi breast cancer patients in their fifth decade,and to evaluate patients'molecular profiles and 5-year disease-free survival(DFS).Methods:A retrospective study was conducted at Baghdad Oncology Teaching Hospital between 1 January 2012 and 12 December 2016.Of 979 individuals seen,285 were aged between 40 and 49 years.Results:The median age at diagnosis was 45 years.The highest incidence of breast cancer occurred among women in their fifth(40-49 years old)and sixth(50-59 years old)decades of life(29%and 28%,respectively).The most common stages at diagnosis were stages II and III,with 40.8%and 39.5%,respectively.Luminal A-like cancers were seen in 124 women(58.5%)and 29 women(13.7%)presented with triple-negative cancers.De novo metastatic disease comprised just 6.7%of the group studied.The median DFS was 48 months(95%CI:41.4-54.5 months).Conclusions:The highest incidence of breast cancer occurred among women in their fifth and sixth decades of life.The most common diagnosis was stage II breast cancer of the luminal A molecular subtype.HER-2(human epidermal growth factor receptor 2)overexpression and triple-negative were the least common subtypes.The median DFS was 48 months.展开更多
Detailed characterizations of genomic alterations have not identified subtype-specific vulnerabilities in adult gliomas. Mapping gliomas into developmental programs may uncover new vulnerabilities that are not strictl...Detailed characterizations of genomic alterations have not identified subtype-specific vulnerabilities in adult gliomas. Mapping gliomas into developmental programs may uncover new vulnerabilities that are not strictly related to genomic alterations. After identifying conserved gene modules co-expressed with EGFR or PDGFRA (EM or PM), we recently proposed an EM/PM classification scheme for adult gliomas in a histological subtype- and grade-independent manner. By using cohorts of bulk samples, paired primary and recurrent samples, multi-region samples from the same glioma, single-cell RNA-seq samples, and clinical samples, we here demonstrate the temporal and spatial stability of the EM and PM subtypes. The EM and PM subtypes, which progress in a subtype-specific mode, are robustly maintained in paired longitudinal samples. Elevated activities of cell proliferation, genomic instability and microenvironment, rather than subtype switching, mark recurrent gliomas. Within individual gliomas, the EM/PM subtype was preserved across regions and single cells. Malignant cells in the EM and PM gliomas were correlated to neural stem cell and oligodendrocyte progenitor cell compartment, respectively. Thus, while genetic makeup may change during progression and/or within different tumor areas, adult gliomas evolve within a neurodevelopmental framework of the EM and PM molecular subtypes. The dysregulated developmental pathways embedded in these molecular subtypes may contain subtype-specific vulnerabilities.展开更多
Gastric cancer (GC) is a major public health issue. It is considered the 5th most common cancer diagnosed worldwide and it is one of the main causes of malignant disease-associated morbidity and mortality. The corners...Gastric cancer (GC) is a major public health issue. It is considered the 5th most common cancer diagnosed worldwide and it is one of the main causes of malignant disease-associated morbidity and mortality. The cornerstone of curative treatment is still surgery, and since the rate of relapse is high, a multidisciplinary approach is warranted in most developed countries. And while there have been recent developments in the perioperative scenario namely the FLOT regimen, little has advanced considering patient selection. We have reviewed the major trials in this setting and provide some insights from recently reported microsatellite instability (MSI) in a subgroup analysis in the MAGIC trial patients that seem to suggest an opportunity to patient selection. Furthermore, GC subtyping may prove helpful selecting candidates to immunotherapy or even multimodal therapy in the future. As the paradigm is moving towards a precision oncology model, GC patient selection remains one the biggest challenges in oncology but seems closer to clinical practice reality as new developments are being reported.展开更多
Genetic abnormalities,such as PTEN,PIK3CA,CTNNB1,ARID1A,and ERBB2,which frequently occur in endometrial cancer(EC),are potential therapeutic targets.In 2013,integrated genomic analysis conducted by The Cancer Genome A...Genetic abnormalities,such as PTEN,PIK3CA,CTNNB1,ARID1A,and ERBB2,which frequently occur in endometrial cancer(EC),are potential therapeutic targets.In 2013,integrated genomic analysis conducted by The Cancer Genome Atlas identified four molecular subtypes,including POLE ultra-mutated,microsatellite instability hypermutated,copy-number low,and copy-number high,which strongly correlate with prognosis.Surrogate markers-based molecular classification methods have been developed to make these molecular classifications accessible and affordable,achieving classification into POLEmut,mismatch repair deficient(MMRd),p53abn,and no specific molecular profile(NSMP)with normal p53 expression.Although POLEmut EC has aggressive pathologic features,there are few cases of advanced and/or recurrence.Therefore,the possibility of de-escalating adjuvant therapy can be considered.Additionally,immune checkpoint inhibitors(ICI)may be a candidate for treating advanced and recurrent POLEmut EC because of their high immunogenicity.MMRd EC shows an intermediate prognosis between those of POLEmut and p53abn EC.MMRd EC is generally characterized by high immunogenicity similar to POLEmut EC,suggesting that ICI can also be a potential therapeutic agent.Among the four molecular subtypes,p53abn EC has the worst prognosis.However,some p53abn tumors have the molecular hallmark of homologous recombination deficiency and could be treated with poly(ADP-ribose)polymerase inhibitors.In addition,some p53abn tumors overexpress the human epidermal growth factor receptor 2,which can also be a potential therapeutic target.NSMP EC are a heterogeneous population because they lack characteristic molecular biological features.Approximately half of the NSMP EC show high expression of estrogen receptor/progesterone receptor,suggesting the possibility of hormonal therapy.In addition,the PI3K/AKT/mTOR pathway frequently altered in EC may be a therapeutic target.This review summarizes the molecular biological characteristics and potential therapeutic agents in molecularly featured EC.Several clinical trials are in progress to stratify EC into molecular classifications and demonstrate the efficacy and safety of molecularly matched treatment and management strategies.展开更多
Background Early stage （FIGO stage Ⅰ-Ⅱ） endometrioid endometrial adenocarcinoma （EEA） is very common in clinical practice.However,patients with the early stage EEA show various clinical behaviors due to biologic...Background Early stage （FIGO stage Ⅰ-Ⅱ） endometrioid endometrial adenocarcinoma （EEA） is very common in clinical practice.However,patients with the early stage EEA show various clinical behaviors due to biological heterogeneity.Hence,we aimed to discover distinct classes of tumors based on gene expression profiling,and analyze whether the molecular classification correlated with the histopathological stages or other clinical parameters.Methods Hierarchical clustering was performed for class discovery in 28 eady stage EEA samples using a special cDNA microarray chip containing 492 genes designed for endometrial cancer.Correlations between clinicopathologic parameters and our classification were analyzed.And the significance analysis of microarrays （SAM） array was used to identify the signature genes according to the tumor grade and myometrial invasion.Results Three tumor subtypes （subtypes Ⅰ,Ⅱ and Ⅲ） were identified by hierarchical clustering,each subtype had different clinicopathological factors,such as tumor grade,myometrial invasion status,and FIGO stage.Moreover,SAM analysis showed 34 up-regulated genes in high grade tumors,and 38 up-regulated genes and 1 down-regulated in deep myometrial invasive tumors.The overlap genes between these two high-risk factors were markedly up-regulated in subtype Ⅰ,but down-regulated in subtype Ⅲ.Conclusion We have identified novel molecular subtypes in early stage EEA.Differential gene signatures characterize each tumor subtype,which could be used for recognizing the tumor risk and providing a basis for further treatment stratification.展开更多
Esophageal squamous cell carcinoma(ESCC)is one of the most common types of gastrointestinal cancers,and the fourth leading cause of cancer-related deaths in China.Early detection and intervention in time may dramatica...Esophageal squamous cell carcinoma(ESCC)is one of the most common types of gastrointestinal cancers,and the fourth leading cause of cancer-related deaths in China.Early detection and intervention in time may dramatically increase the survival of the patients by initiating treatment regimens during earlier stages of ESCC or even during precancerous stages.Molecular classification will be useful for subtyping esophageal tumors or precancerous lesions to improve current therapeutics or early intervention of the disease.In this review,we summarize the findings in investigating the molecular alterations and clinical relevance of ESCC.展开更多
Hepatocellular carcinoma(HCC)is a highly complex disease that is generally resistant to commonly used chemotherapy and radiotherapy.Consequently,there is an urgent need for the development of new treatment strategies ...Hepatocellular carcinoma(HCC)is a highly complex disease that is generally resistant to commonly used chemotherapy and radiotherapy.Consequently,there is an urgent need for the development of new treatment strategies for this devastating disease.In the past decade,tremendous progress has been achieved in the molecular stratification of HCCs for diagnosis,prognosis,and therapeutic decision-making.To date,the molecular classification of HCCs has been carried out through transcriptomic,genetic and epigenetic profiling of tumors.Such research has led to identification of several potential molecular targets in HCC,and subsequently,development of novel systemic agents for the treatment of HCC has begun in earnest.In this article,we review the current knowledge of the molecular pathogenesis of HCC and outline potential areas for application of this knowledge in a clinical setting.As a typical virus and inflammation-associated cancer,both host immune response and tumor microenvironment have crucial roles in HCC pathogenesis.In addition,we examine the potential of immunotherapy and strategies targeting various components of the tumor microenvironment,as well as novel molecular and cellular targets in HCC such as cancer stem cells.展开更多
基金National Natural Science Foundation of China (No.82060461)Innovation Research Team Project of Hainan Nature Foundation (No.820CXTD447)Clinical Medical Center construction project of Hainan Province.
文摘Bladder cancer is the second most common tumor in the urinary system after prostate cancer.It is highly heterogeneous and its developmental mechanism involves abnormal alterations in the structure and function of multiple genomes.Researching the molecular classification of bladder cancer by using molecular biology techniques is important for defining the pathogenesis of the disease and selecting therapeutic schedule.This paper will review the progress of molecular classification studies of bladder cancer.
基金supported by the National Natural Science Foundation of China(No.81502523)
文摘Gastric cancer(GC) is a highly aggressive and life-threatening malignancy.Even with radical surgical removal and front-line chemotherapy,more than half of GCs locally relapse and metastasize at a distant site.The dismal outcomes reflect the ineffectiveness of a one-size fits-all approach for a highly heterogeneous disease with diverse etiological causes and complex molecular underpinnings.The recent comprehensive genomic and molecular profiling has led to our deepened understanding of GC.The emerging molecular classification schemes based on the genetic,epigenetic,and molecular signatures are providing great promise for the development of more effective therapeutic strategies in a more personalized and precise manner.To this end,the Cancer Genome Atlas(TCGA) research network conducted a comprehensive molecular evaluation of primary GCs and proposed a new molecular classification dividing GCs into four subtypes:Epstein-Barr virus-associated tumors,microsatellite unstable tumors,genomically stable tumors,and tumors with chromosomal instability.This review primarily focuses on the TCGA molecular classification of GCs and discusses the implications on novel targeted therapy strategies.We believe that these fundamental findings will support the future application of targeted therapies and will guide our efforts to develop more efficacious drugs to treat human GCs.
基金Supported by Fundação de Amparo à Pesquisa do Estado de São Paulo(FAPESP agency),No.2016/25524-0.
文摘BACKGROUND Gastric cancer(GC)is a highly heterogeneous disease,and the identification of molecular subtyping of gastric adenocarcinoma emerged as a promising option to define therapeutic strategies and prognostic subgroups.However,the costs and technical complexity of molecular methodologies remains an obstacle to its adoption,and their clinical significance by other approaches needs further evidence.AIM To evaluate the clinicopathological characteristics and long-term survival of GC based on the subgroups of molecular classification by immunohistochemistry(IHC)and in situ hybridization(ISH).METHODS We retrospectively evaluated all patients who underwent D2-gastrectomy between 2009 and 2016 in a Western cohort of GC patients treated with curative intent.Microsatellite instability(MSI)status,E-cadherin,and p53 expression were analyzed by IHC,and Epstein-Barr virus(EBV)by ISH.Tissue microarrays were constructed for analysis.Clinicopathological characteristics and survival of GC were evaluated according to subtypes defined by The Cancer Genome Atlas(TCGA)Research Network Group and Asian Cancer Research Group(ACRG)classification systems.RESULTS A total of 287 GC patients were included.Based on IHC and ISH analysis,five profiles were defined as follows:E-cadherin aberrant(9.1%),MSI(20.9%),p53 aberrant(36.6%),EBV positivity(10.5%),and p53 normal(31%),which corresponded to tumors that showed no alteration in another profile.A flowchart according to the TCGA and ACRG classifications were used to define the subtypes,where clinical and pathological characteristics associated with GC subtypes were evidenced.Proximal location(P<0.001),total gastrectomy(P=0.001),and intense inflammatory infiltrate(P<0.001)were characteristics related to EBV subtype.MSI subtype was predominantly associated with advanced age(P=0.017)and the presence of comorbidities(P=0.011).While Laurén diffuse type(P<0.001)and advanced stage(P=0.029)were related to genomically stable(GS)subtype.GS tumors and microsatellite stable/epithelial to mesenchymal transition phenotype subtype had worse disease-free survival(DFS)and overall survival(OS)than other subtypes.Conversely,MSI subtype of GC had better survival in both classifications.Type of gastrectomy,pT and the TCGA subtypes were independent factors associated to DFS and OS.CONCLUSION The IHC/ISH analysis was able to distinguish immunophenotypic groups of GC with distinct characteristics and prognosis,resembling the subtypes of the molecular classifications.Accordingly,this method of classification may represent a viable option for use in a clinical setting.
基金supported by grants from the Jilin Scientific and Technological Development Program(CN)(No.20190303146SF)General Program of National Natural Science Foundation of China(No.81874052)
文摘Small cell lung cancer(SCLC)is a highly malignant tumor with a very poor prognosis;therefore,more effective treatments are urgently needed for patients afflicted with the disease.In recent years,emerging molecular classifications based on key transcription factors of SCLC have provided more information on the tumor pathophysiology,metastasis,immune microenvironment,and acquired therapeutic resistance and reflected the intertumoral heterogeneity of the various SCLC phenotypes.Additionally,advances in genomics and single-cell sequencing analysis have further revealed the high intratumoral heterogeneity and plasticity of the disease.Herein,we review and summarize these recent lines of evidence and discuss the possible pathogenesis of SCLC.
基金supported by the Peking Union Medical College Youth Fund(2017320030)the Beijing Hope Run Special Fund(No.LC2018A12),the CAMS Initiative for Innovative Medicine(CIFMS)(No.2016-I2M-3-005)+1 种基金the Medical and Health Science and Tech-nology Innovation Project of the Chinese Academy of Medical Sci-ences(2016-12M-1-007)the China International Medical Exchange Foundation Xiansheng Anti-Tumor Therapy Special Research Fund(cimf-f-h001-314).
文摘Background:Gastric adenocarcinoma(GA)is a heterogeneous tumor,and the accurate classification of GA is important.Previous classifications are based on molecular analysis and have not focused on GA with the primitive enterocyte phenotype(GAPEP),a unique subtype with a poor prognosis and frequent liver metastases.New substituted molecular(SM)classifications based on immunohistochemistry(IHC)are needed.Methods:According to the IHC staining results,we divided 582 cases into six types:mismatch repair deficient(dMMR),Epstein-Barr virus associated(EBVa),the primitive enterocyte phenotype(PEP),the epithelial mes-enchymal transition(EMT)phenotype,not otherwise specified/P53 mutated(NOS/P53m)and not otherwise specified/P53 wild-type(NOS/P53w).We analyzed the clinicopathological features,the immune microenviron-ment(PD-L1,CD8)and expression of HER2 and VEGFR2 of those types.Results:There were 31(5.3%)cases of the dMMR type,13(2.2%)cases of the EBVa type,44(7.6%)cases of the PEP type,122(21.0%)cases of the EMT type,127(21.8%)cases of the NOS/P53m type and 245(42.1%)cases of the NOS/P53w type.Patients with the dMMR type had the best survival(P<0.001).Patients with the EBVa type were younger(P<0.001)and had higher PD-L1 and CD8 expression(P<0.001)than other patients.Patients with the EMT type exhibited poor differentiation and a higher rate of abdominal metastasis.Patients with the NOS/P53m and PEP types had the worst survival rates and the highest PD-L1/HER2/VEGFR2 expression levels among all patients(P<0.001).Conclusion:Different SM classifications have different clinicopathological features and expression patterns,which indicate the probable clinical treatment strategies for these subtypes.
基金National Key Technology Research and Developmental Program of China(Program Nos.2022YFC2704400,2022YFC2704405)the Biomedical Ethics Committee of Peking University People's Hospital(approval number:IRB00001052-19142).
文摘Objective To investigate the molecular classification of endometrial cancer(EC)and atypical endometrial hyperplasia(AEH)patients treated with fertility-sparing treatment(FST),and its relationship with clinicopathological factors and treatment efficacy.Methods:A total of 52EC and AEH patients who received FST and molecular classification tested by next generation sequencing in Peking University People's Hospital from June 2020 to December 2022,were retrospectively collected.We analyzed the relationship between molecular classification and clinicopathological factors and treatment outcomes.Results(1)Of the 52 patients,including 46EC and 6 AEH patients,42(80.8%)achieved complete remission(CR)after FST,with a median time to achieve CR of 9 months.Ten cases(23.8%)had recurrence.(2)Patients were distributed into 4 molecular subgroups as 39 cases(75%)of copy number low(CNL),7 cases(13.5%)of microsatellite instability-high(MSI-H),4 cases(7.7%)of POLE mutations(POLEmut),and 2 cases(3.8%)of copy number high(CNH).Patients with MSI-H subgroup had more family history of tumor(6/7),more with loss of expression of mismatch repair(MMR)protein(7/7),and higher expression level of Ki-67(3/3).(3)Patients with MSI-H subgroup had the lowest CR rate at 6 months(0/7,P=0.014),and survival analysis showed that such patients were less likely to achieve CR than those with CNL(P=0.022).For CNL patients,median 6-month CR rate was 40.6%.In addition,CR was obtained in 3(3/4)POLEmut patients and 2(2/2)CNH patients,respectively.Conclusions Molecular classification relates with the treatment response in patients with EC and AEH receiving FST.Patients with MSI-H subgroup have poor treatment efficacy,and patients with CNL need to be further divided to predict treatment benefit.There are also a few successful cases in POLEmut and CNH subtgroups,which needs further research.
文摘On May 23, 2017, the US Food and Drug Administration （FDA） approved a treatment for cancer patients with positive microsatellite instability-high （MSI-H） markers or mismatch repair deficient （dMMR） markers. This approach is the first approved tumor treatment using a common biomarker rather than specified tumor locations in the body. FDA previously approved Keytruda for treatment of several types of malignancies, such as metastatic melanoma, metastatic non-small-cell lung cancer, recurrent or metastatic head and neck cancer, refractory Hodgkin lymphoma, and urothelial carcinoma, all of which carry positive programmed death-l/ programmed death-ligand 1 biomarkers. Therefore, indications of Keytruda significantly expanded. Several types of malignancies are disclosed by MSI-H status due to dMMR and characterized by increased neoantlgen load, which elicits intense host immune response in tumor microenvironment, including portions of colorectal and gastric carcinomas. Currently, biomarker-based patient selection remains a challenge. Pathologists play important roles in evaluating histology and biomarker results and establishing detection methods. Taking gastric cancer as an example, its molecular classification is built on genome abnormalities, but it lacks acceptable clinical characteristics. Pathologists are expected to act as ＂genetic interpreters＂ or ＂genetic translators＂ and build a link between molecular subtypes with tumor histological features. Subsequently, by using their findings, oncologists will carry out targeted therapy based on molecular classification.
文摘BACKGROUND Ependymoma with lipomatous differentiation is a rare type of ependymoma.The ZFTA fusion-positive supratentorial ependymoma is a novel tumor type in the 2021 World Health Organization classification of central nervous system tumors.ZFTA fusion-positive lipomatous ependymoma has not been reported to date.CASE SUMMARY We reported a case of a 15-year-old Chinese male who had a sudden convulsion lasting approximately six minutes.Magnetic resonance imaging showed a round cystic shadow of approximately 1.9 cm×1.5 cm×1.9 cm under the right parieto-occipital cortex.Microscopic examination showed characteristic perivascular pseudorosettes and adipose differentiation in the cytoplasm.Immunohisto-chemical staining showed that the tumor cells were negative for cytokeratin,NeuN,Syn and p53,but positive for GFAP,vimentin and S-100 protein.Signi-ficant punctate intracytoplasmic EMA immunoreactivity was observed.The level of Ki-67 was about 5%.Genetic analysis revealed ZFTA:RELA fusion.A cranio-tomy with total excision of the tumor was performed.The follow-up time was 36 months,no evidence of disease recurrence was found in magnetic resonance imaging.CONCLUSION Based on these findings,the patient was diagnosed as a ependymoma with ZFTA fusion and lipomatous differentiation.This case report provides information on the microscopic morphological features of ependymoma with ZFTA fusion and lipomatous differentiation,which can help pathologists to make a definitive diagnosis of this tumor.
基金Supported by The National Natural Science Foundation of China,No.30700360
文摘AIM:To assess the role and mechanism of metformin in inducing apoptosis of pancreatic cancer cells.METHODS:The human pancreatic cancer cell lines ASPC-1,BxPc-3,PANC-1 and SW1990 were exposed to metformin.The inhibition of cell proliferation and colony formation via apoptosis induction and S phase arrest in pancreatic cancer cell lines of metformin was tested.RESULTS:In each pancreatic cancer cell line tested,metformin inhibited cell proliferation in a dose dependent manner in MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assays).Flow cytometric analysis showed that metformin reduced the number of cells in G1 and increased the percentage of cells in S phase as well as the apoptotic fraction.Enzymelinked immunosorbent assay(ELISA) showed that metformin induced apoptosis in all pancreatic cancer cell lines.In Western blot studies,metformin induced poly-ADP-ribose polymerase(PARP) cleavage(an indicator of caspase activation) in all pancreatic cancer cell lines.The general caspase inhibitor(VAD-fmk) completely abolished metformin-induced PARP cleavage and apoptosis in ASPC-1 BxPc-3 and PANC-1,the caspase-8 specific inhibitor(IETD-fmk) and the caspase-9 specific inhibitor(LEHD-fmk) only partially abrogated metformin-induced apoptosis and PARP cleavage in BxPc-3 and PANC-1 cells.We also observed that metformin treatment dramatically reduced epidermal growth factor receptor(EGFR) and phosphorylated mitogen activated protein kinase(P-MAPK) in both a time-and dose-dependent manner in all cell lines tested.CONCLUSION:Metformin significantly inhibits cell proliferation and apoptosis in all pancreatic cell lines.And the metformin-induced apoptosis is associated with PARP cleavage,activation of caspase-3,-8,and-9 in a time-and dose-dependent manner.Hence,both caspase-8 and-9-initiated apoptotic signaling pathways contribute to metformin-induced apoptosis in pancreatic cell lines.
基金supported by grants from National High Technology Research and Development Program(No.2012AA02A508)International Science and Technology Cooperation Program(No.2012DFA30470)National Natural Science Foundation of China(Grant No.81201993).
文摘Gliomas are the most common primary intracranial tumors in adults.Anaplastic gliomas(WHO gradeⅢ)and glioblastomas(WHO gradeⅣ)represent the major groups of malignant gliomas in the brain.Several diagnostic,predictive,and prognostic biomarkers for malignant gliomas have been reported over the last few decades,and these markers have made great contributions to the accuracy of diagnosis,therapeutic decision making,and prognosis of patients.However,heterogeneity in patient outcomes may still be observed,which highlights the insufficiency of a classification system based purely on histopathology.Great efforts have been made to incorporate new information about the molecular landscape of gliomas into novel classifications that may potentially guide treatment.In this review,we summarize three distinctive biomarkers,three most commonly altered pathways,and three classifications based on microarray data in malignant gliomas.
文摘Gastric cancer (GC) is the fourth most common neoplasm and the second leading cause of cancer-related death worldwide. In Latin America (LA), the burden of this disease is higher and is the leading cause of cancer death in some countries. Chemotherapy is the standard treatment for advanced-stage GC. However, the best regimen for specific populations, such as LA, is as yet unknown. Cisplatin and fluoropyrimidine continue to be the standard of care in light of the findings of phase III studies, while docetaxel, cisplatin, and 5-fluorouracil (5-FU) are alternatives for patients with suitable overall health. Oxaliplatin or irinotecan with fluoropyrimidine can also be used in elderly patients who are not candidates for cisplatin, or have a limited performance status. This review examines studies conducted in LA. Patients from LA are under-represented in multicenter trials of chemotherapy and targeted therapies. The major challenges currently lie in implementing strategies in which patients are selected on the basis of regional, racial or molecular characteristics, to consider the molecular subtype of GC for enrolment, and in selecting patients according to prognostic factors to optimize the benefits of chemotherapy.
文摘Background:Breast cancer is a major public health concern for women around the world.Breast cancer incidence increases with age,and this is an important factor for the management of this disease.The aim of this study was to assess the clinical profiles of female Iraqi breast cancer patients in their fifth decade,and to evaluate patients'molecular profiles and 5-year disease-free survival(DFS).Methods:A retrospective study was conducted at Baghdad Oncology Teaching Hospital between 1 January 2012 and 12 December 2016.Of 979 individuals seen,285 were aged between 40 and 49 years.Results:The median age at diagnosis was 45 years.The highest incidence of breast cancer occurred among women in their fifth(40-49 years old)and sixth(50-59 years old)decades of life(29%and 28%,respectively).The most common stages at diagnosis were stages II and III,with 40.8%and 39.5%,respectively.Luminal A-like cancers were seen in 124 women(58.5%)and 29 women(13.7%)presented with triple-negative cancers.De novo metastatic disease comprised just 6.7%of the group studied.The median DFS was 48 months(95%CI:41.4-54.5 months).Conclusions:The highest incidence of breast cancer occurred among women in their fifth and sixth decades of life.The most common diagnosis was stage II breast cancer of the luminal A molecular subtype.HER-2(human epidermal growth factor receptor 2)overexpression and triple-negative were the least common subtypes.The median DFS was 48 months.
基金supported by the National Natural Science Foundation of China(Nos.81773015 and 82072789)the National Key Research and Development Program of China(No.2019YFE0108100)the Erik Philip-Sörensen Foundation.
文摘Detailed characterizations of genomic alterations have not identified subtype-specific vulnerabilities in adult gliomas. Mapping gliomas into developmental programs may uncover new vulnerabilities that are not strictly related to genomic alterations. After identifying conserved gene modules co-expressed with EGFR or PDGFRA (EM or PM), we recently proposed an EM/PM classification scheme for adult gliomas in a histological subtype- and grade-independent manner. By using cohorts of bulk samples, paired primary and recurrent samples, multi-region samples from the same glioma, single-cell RNA-seq samples, and clinical samples, we here demonstrate the temporal and spatial stability of the EM and PM subtypes. The EM and PM subtypes, which progress in a subtype-specific mode, are robustly maintained in paired longitudinal samples. Elevated activities of cell proliferation, genomic instability and microenvironment, rather than subtype switching, mark recurrent gliomas. Within individual gliomas, the EM/PM subtype was preserved across regions and single cells. Malignant cells in the EM and PM gliomas were correlated to neural stem cell and oligodendrocyte progenitor cell compartment, respectively. Thus, while genetic makeup may change during progression and/or within different tumor areas, adult gliomas evolve within a neurodevelopmental framework of the EM and PM molecular subtypes. The dysregulated developmental pathways embedded in these molecular subtypes may contain subtype-specific vulnerabilities.
文摘Gastric cancer (GC) is a major public health issue. It is considered the 5th most common cancer diagnosed worldwide and it is one of the main causes of malignant disease-associated morbidity and mortality. The cornerstone of curative treatment is still surgery, and since the rate of relapse is high, a multidisciplinary approach is warranted in most developed countries. And while there have been recent developments in the perioperative scenario namely the FLOT regimen, little has advanced considering patient selection. We have reviewed the major trials in this setting and provide some insights from recently reported microsatellite instability (MSI) in a subgroup analysis in the MAGIC trial patients that seem to suggest an opportunity to patient selection. Furthermore, GC subtyping may prove helpful selecting candidates to immunotherapy or even multimodal therapy in the future. As the paradigm is moving towards a precision oncology model, GC patient selection remains one the biggest challenges in oncology but seems closer to clinical practice reality as new developments are being reported.
基金Japan Agency for Medical Research and Development(AMED)under Grant Number JP 22lk0201099s0404.
文摘Genetic abnormalities,such as PTEN,PIK3CA,CTNNB1,ARID1A,and ERBB2,which frequently occur in endometrial cancer(EC),are potential therapeutic targets.In 2013,integrated genomic analysis conducted by The Cancer Genome Atlas identified four molecular subtypes,including POLE ultra-mutated,microsatellite instability hypermutated,copy-number low,and copy-number high,which strongly correlate with prognosis.Surrogate markers-based molecular classification methods have been developed to make these molecular classifications accessible and affordable,achieving classification into POLEmut,mismatch repair deficient(MMRd),p53abn,and no specific molecular profile(NSMP)with normal p53 expression.Although POLEmut EC has aggressive pathologic features,there are few cases of advanced and/or recurrence.Therefore,the possibility of de-escalating adjuvant therapy can be considered.Additionally,immune checkpoint inhibitors(ICI)may be a candidate for treating advanced and recurrent POLEmut EC because of their high immunogenicity.MMRd EC shows an intermediate prognosis between those of POLEmut and p53abn EC.MMRd EC is generally characterized by high immunogenicity similar to POLEmut EC,suggesting that ICI can also be a potential therapeutic agent.Among the four molecular subtypes,p53abn EC has the worst prognosis.However,some p53abn tumors have the molecular hallmark of homologous recombination deficiency and could be treated with poly(ADP-ribose)polymerase inhibitors.In addition,some p53abn tumors overexpress the human epidermal growth factor receptor 2,which can also be a potential therapeutic target.NSMP EC are a heterogeneous population because they lack characteristic molecular biological features.Approximately half of the NSMP EC show high expression of estrogen receptor/progesterone receptor,suggesting the possibility of hormonal therapy.In addition,the PI3K/AKT/mTOR pathway frequently altered in EC may be a therapeutic target.This review summarizes the molecular biological characteristics and potential therapeutic agents in molecularly featured EC.Several clinical trials are in progress to stratify EC into molecular classifications and demonstrate the efficacy and safety of molecularly matched treatment and management strategies.
文摘Background Early stage （FIGO stage Ⅰ-Ⅱ） endometrioid endometrial adenocarcinoma （EEA） is very common in clinical practice.However,patients with the early stage EEA show various clinical behaviors due to biological heterogeneity.Hence,we aimed to discover distinct classes of tumors based on gene expression profiling,and analyze whether the molecular classification correlated with the histopathological stages or other clinical parameters.Methods Hierarchical clustering was performed for class discovery in 28 eady stage EEA samples using a special cDNA microarray chip containing 492 genes designed for endometrial cancer.Correlations between clinicopathologic parameters and our classification were analyzed.And the significance analysis of microarrays （SAM） array was used to identify the signature genes according to the tumor grade and myometrial invasion.Results Three tumor subtypes （subtypes Ⅰ,Ⅱ and Ⅲ） were identified by hierarchical clustering,each subtype had different clinicopathological factors,such as tumor grade,myometrial invasion status,and FIGO stage.Moreover,SAM analysis showed 34 up-regulated genes in high grade tumors,and 38 up-regulated genes and 1 down-regulated in deep myometrial invasive tumors.The overlap genes between these two high-risk factors were markedly up-regulated in subtype Ⅰ,but down-regulated in subtype Ⅲ.Conclusion We have identified novel molecular subtypes in early stage EEA.Differential gene signatures characterize each tumor subtype,which could be used for recognizing the tumor risk and providing a basis for further treatment stratification.
基金supported by the National High Technology Research and Development Program of China(Grant Nos.2012AA02A503,2012AA020206).
文摘Esophageal squamous cell carcinoma(ESCC)is one of the most common types of gastrointestinal cancers,and the fourth leading cause of cancer-related deaths in China.Early detection and intervention in time may dramatically increase the survival of the patients by initiating treatment regimens during earlier stages of ESCC or even during precancerous stages.Molecular classification will be useful for subtyping esophageal tumors or precancerous lesions to improve current therapeutics or early intervention of the disease.In this review,we summarize the findings in investigating the molecular alterations and clinical relevance of ESCC.
基金supported by the Major Program of National Natural Science Foundation of China(No.81030038)National Key Sci-Tech Project(No.2008ZX10002-019)+3 种基金FANEDD(No.201183)Shanghai Rising-Star Program(No.10QA1401300)National Natural Science Foundation of China(No.81071992&No.30901432)“Chen Guang”project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation(No.11CG02).
文摘Hepatocellular carcinoma(HCC)is a highly complex disease that is generally resistant to commonly used chemotherapy and radiotherapy.Consequently,there is an urgent need for the development of new treatment strategies for this devastating disease.In the past decade,tremendous progress has been achieved in the molecular stratification of HCCs for diagnosis,prognosis,and therapeutic decision-making.To date,the molecular classification of HCCs has been carried out through transcriptomic,genetic and epigenetic profiling of tumors.Such research has led to identification of several potential molecular targets in HCC,and subsequently,development of novel systemic agents for the treatment of HCC has begun in earnest.In this article,we review the current knowledge of the molecular pathogenesis of HCC and outline potential areas for application of this knowledge in a clinical setting.As a typical virus and inflammation-associated cancer,both host immune response and tumor microenvironment have crucial roles in HCC pathogenesis.In addition,we examine the potential of immunotherapy and strategies targeting various components of the tumor microenvironment,as well as novel molecular and cellular targets in HCC such as cancer stem cells.
