RÉSUMÉ
The role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in renal cell carcinoma (RCC) progression, metastasis, and resistance to therapies has not been investigated thoroughly. Transcription factor E3 (TFE3) expression is related to a poorer prognosis and tumor microenvironment in patients with RCC. This study aimed to determine the relationship between TFE3 and the PI3K/Akt pathway. TFE3 down-regulation was achieved by transient transfection of siRNA and shRNA in UOK146 cells. TFE3 overexpression was induced by transient transfection with pcDNA3.1 encoding the constitutively active form of TFE3. The cells were treated with mammalian target of rapamycin (mTOR) and PI3K inhibitors. Western blot was performed to detect TFE3, programmed death-ligand 1, phospho-Akt, and Akt. Phospho-Akt expression increased significantly upon TFE3 down-regulation, and decreased significantly upon up-regulation. When RCC cells were treated with a PI3K inhibitor (LY294002), TFE3 expression increased and phospho-Akt expression decreased. Data from this study indicate that TFE3 plays a role in the PI3K/Akt pathway in RCC. The results of this study suggest that PI3K/Akt inhibitors may aid in the treatment of patients with RCC by affecting the tumor microenvironment.
Sujet(s)
Facteurs de transcription à motifs basiques hélice-boucle-hélice et à glissière à leucines , Néphrocarcinome , Tumeurs du rein , Protéines proto-oncogènes c-akt , Transduction du signal , Sérine-thréonine kinases TOR , Microenvironnement tumoral , Humains , Néphrocarcinome/anatomopathologie , Néphrocarcinome/métabolisme , Néphrocarcinome/génétique , Sérine-thréonine kinases TOR/métabolisme , Microenvironnement tumoral/physiologie , Tumeurs du rein/anatomopathologie , Tumeurs du rein/métabolisme , Tumeurs du rein/génétique , Facteurs de transcription à motifs basiques hélice-boucle-hélice et à glissière à leucines/métabolisme , Protéines proto-oncogènes c-akt/métabolisme , Transduction du signal/physiologie , Lignée cellulaire tumorale , Phosphatidylinositol 3-kinases/métabolisme , Régulation de l'expression des gènes tumorauxRÉSUMÉ
Assigning a hepatocellular carcinoma (HCC) to an appropriate subtype is important because this guarantees the diagnosis and treatment and allows decisions regarding the prognosis of the patient. HCC subtyping is usually based on the World Health Organization (WHO) classification and the 2019 fifth edition is the latest version. However, the WHO classification system is still in evolution and has limited clinical relevance. We aimed to evaluate the clinical relevance of HCC subtyping and to reappraise some of the major subtypes of HCC. Our archived cases (n = 589) were reclassified according to the 2019 WHO system. The percentage of each subtype was mostly similar to that in the WHO classification. However, on the contrary to the 2019 WHO system, clear cell type HCC was associated with more frequent recurrence or metastasis. Meanwhile, macrotrabecular massive HCC was related to poor prognosis as demonstrated in the 2019 WHO system and should be described in the pathology report. For steatohepatitic HCC, there is a debate on whether it is a true subtype because the steatohepatitis morphology may or may not be present in the background liver. In our study, 44 % of steatohepatitic HCCs (n = 19/43) presented underlying steatohepatitis. Additionally, the background cirrhosis did not influence survival in the HCC patients, although the 2019 WHO system indicates the presence of cirrhosis as a poor prognostic factor. In conclusion, although it is not perfect yet, HCC subtyping based on the 2019 WHO system provides valuable information to manage patients with HCC.
Sujet(s)
Carcinome hépatocellulaire , Stéatose hépatique , Tumeurs du foie , Humains , Carcinome hépatocellulaire/anatomopathologie , Pronostic , Tumeurs du foie/diagnostic , Tumeurs du foie/anatomopathologie , Stéatose hépatique/anatomopathologieRÉSUMÉ
BACKGROUND: Clear cell Renal cell carcinoma (ccRCC) is an immunogenic tumor. B7 family members, such as CTLA-4, PD-1, and PD-L1, are the main components of immune checkpoints that regulate various immune responses. Specifically, B7-H3 regulates T cell-mediated immune responses against cancer. This study aimed to analyze the association between B7-H3 and CTLA-4 expression and the prognostic factors of ccRCC to provide a basis for their potential use as predictive factors and in immunotherapy. METHODS: Formalin-fixed paraffin-embedded specimens were obtained from 244 ccRCC patients, and B7-H3, CTLA-4, and PD-L1 expressions were evaluated using immunohistochemical staining. RESULTS: B7-H3 and CTLA-4 were positive in 73 (29.9%) and 57 (23.4%) of the 244 patients, respectively. B7-H3 expression was significantly associated with PD-L1 expression (P < 0.0001); however, CTLA-4 expression was not (P = 0.842). Kaplan-Meier analysis showed that positive B7-H3 expression was associated with poor progression-free survival (PFS) (P < 0.0001), whereas CTLA-4 expression was not (P = 0.457). Multivariate analysis revealed that B7-H3 was correlated with poor PFS (P = 0.031), whereas CTLA-4 was not (P = 0.173). CONCLUSIONS: To the best of our knowledge, this study is the first to investigate B7-H3 and PD-L1 expression and survival in ccRCC. B7-H3 expression is an independent prognostic factor for ccRCC. Furthermore, multiple immune cell inhibitory targets, such as B7-H3 and PD-L1, can be used for therapeutic tumor regression in a clinical setting.
Sujet(s)
Néphrocarcinome , Tumeurs du rein , Humains , Antigène CD274/métabolisme , Marqueurs biologiques tumoraux/analyse , Néphrocarcinome/anatomopathologie , Estimation de Kaplan-Meier , Tumeurs du rein/anatomopathologie , PronosticRÉSUMÉ
BACKGROUND/AIM: Primary hepatic angiosarcoma (PHA) is a rare disease entity with variable morphologic features. Recent findings regarding ROS1 gene rearrangements in PHA may lead to new targeted therapies. PATIENTS AND METHODS: Thirteen cases (4 resected specimens and 9 biopsy samples) underwent histologic review and morphologic patterns were classified according to a previous study as 1) sinusoidal, 2) peliotic, 3) vasoformative, and 4) solid (epithelioid/spindled). ROS1 immunohistochemistry and investigation of the presence of a ROS1 fusion gene by reverse transcription-polymerase chain reaction were performed in available cases. RESULTS: Eight of 13 cases (62%) showed vasoformative patterns. Three cases (23%) were classified as sinusoidal and two (15%) as solid patterns. Mortality rate was 90% (9/10) except for three patients lost in follow up. Only one patient is still alive and has survived for 8 months with the disease. All cases tested did not have ROS1 expression (0/9) or a ROS1 fusion gene (0/4). CONCLUSION: We report 13 cases of PHA with 90% mortality. Vasoformative PHA is the most common histologic type. New findings on ROS1 fusion gene rearrangements could lead to the development of novel targeted therapeutics for PHA patients with dismal prognosis.
Sujet(s)
Réarrangement des gènes , Hémangiosarcome/diagnostic , Hémangiosarcome/génétique , Tumeurs du foie/diagnostic , Tumeurs du foie/génétique , Protein-tyrosine kinases/génétique , Protéines proto-oncogènes/génétique , Adolescent , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Enfant , Enfant d'âge préscolaire , Femelle , Hémangiosarcome/métabolisme , Hémangiosarcome/mortalité , Humains , Immunohistochimie , Corée , Tumeurs du foie/métabolisme , Tumeurs du foie/mortalité , Mâle , Adulte d'âge moyen , Grading des tumeurs , Stadification tumorale , Pronostic , Protein-tyrosine kinases/métabolisme , Protéines proto-oncogènes/métabolisme , Jeune adulteRÉSUMÉ
Background: Obesity, a chronic low-grade inflammatory state, increases the risk of cardiovascular disease. Elevated high-sensitivity C-reactive protein (hs-CRP) levels are associated with cardiovascular disease, type 2 diabetes, and metabolic syndrome in adults. This study aimed to determine the association of hs-CRP and cardiometabolic risk factors, including obesity, prediabetes, hypertension, and dyslipidemia, in the nationally representative data of Korean youth. Methods: Anthropometric, biochemical, physical activity (PA), and nutritional survey data were collected for 1,723 youths (918 boys, 53.5%), aged 10-18 years, from the Korea National Health and Nutrition Examination Survey (2015-2017). Participants were classified into three groups according to hs-CRP tertile. Abdominal obesity, impaired fasting glucose, elevated triglyceride, decreased high-density lipoprotein (HDL) cholesterol and elevated blood pressure, and prediabetes [glycated hemoglobin (HbA1c) 5.7%-6.4%] were compared according to sex and hs-CRP tertile. Results: The ranges of each hs-CRP tertile were ≤0.3, 0.31-0.5, and >0.5 mg/L, respectively. hs-CRP was positively associated with body mass index (BMI) z-score (P < 0.001) and HbA1c (P = 0.012), and negatively with HDL cholesterol (P = 0.029), after adjusting confounding variables, including age, sex, BMI, white blood cell count, PA, and nutritional factors. The upper tertile of hs-CRP was associated with obesity [adjusted odds ratio (aOR) 12.07, P < 0.001] and prediabetes (aOR 3.08, P = 0.002). Conclusions: Elevated hs-CRP is associated with high BMI z-score and HbA1c, and low HDL cholesterol in Korean children and adolescents. Hence, hs-CRP could be a reliable indicator for adiposity, prediabetes, and abnormal lipid metabolism in the pediatric population.
Sujet(s)
Adiposité , Protéine C-réactive/analyse , État prédiabétique/sang , Adolescent , Glycémie/métabolisme , Indice de masse corporelle , Enfant , Dyslipidémies/épidémiologie , Exercice physique , Femelle , Hémoglobine glyquée/analyse , Humains , Hypercholestérolémie/épidémiologie , Hypertension artérielle/épidémiologie , Hypertriglycéridémie/épidémiologie , Lipoprotéines HDL/sang , Mâle , Syndrome métabolique X , Obésité/épidémiologie , République de Corée/épidémiologie , Facteurs de risque , Enquêtes et questionnairesRÉSUMÉ
Gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue is a distinct entity in that Helicobacter pylori infection plays the most important causative role in the development of the disease. To investigate the genomic alteration in gastric marginal zone lymphoma that was resistant to the H. pylori eradication therapy, we analyzed 19 cases of the gastric marginal zone lymphoma using fluorescence in situ hybridization for MALT1, BCL10 rearrangement, and targeted sequencing using an Illumina platform. Major genetic alterations affected genes involved in nuclear factor (NF)-κB pathway activation and included MALT1 rearrangement (39%), and somatic mutations of TRAF3 (21%), TNFAIP3 (16%), and NOTCH1 (16%). In the MALT1 rearrangement-negative group, disruptive somatic mutations of TRAF3 were the most common alterations (4/12, 33%), followed by somatic mutations of TNFAIP3 (3/12, 25%), and NOTCH1 (3/12, 25%). The present study confirms that genes involved in activation of NF-κB-signaling pathways are a major driver in oncogenesis of H. pylori eradication-resistant gastric marginal zone lymphoma and revealed that TRAF3 mutation is a major contributor in MALT1 rearrangement-negative gastric marginal zone lymphoma.
Sujet(s)
Réarrangement des gènes , Lymphome B de la zone marginale/génétique , Protéine-1 de translocation de lymphome du tissu lymphoïde associé aux muqueuses/génétique , Tumeurs de l'estomac/génétique , Facteur-3 associé aux récepteurs de TNF/génétique , Protéine-3 induite par le facteur de nécrose tumorale alpha/génétique , Adulte , Protéine-10 du lymphome LLC à cellules B/génétique , Femelle , Infections à Helicobacter/génétique , Infections à Helicobacter/anatomopathologie , Séquençage nucléotidique à haut débit , Humains , Hybridation fluorescente in situ , Lymphome B de la zone marginale/anatomopathologie , Mâle , Adulte d'âge moyen , Mutation , Facteur de transcription NF-kappa B/génétique , Stadification tumorale , Études rétrospectives , Transduction du signal/génétique , Tumeurs de l'estomac/anatomopathologieRÉSUMÉ
OBJECTIVE: The hereditary nonpolyposis colorectal cancer is inherited syndrome characterized by the development of cancers in various organ system; these includes colorectum, endometrium, and less frequently, small bowel, stomach, urinary tract, ovaries, and brain. We aimed to investigate the clinicopathologic characteristics of hereditary nonpolyposis colorectal cancer patients who had both endometrial and colorectal cancers. METHODS: Between January 2004 and December 2013, 12 women diagnosed with endometrial and colorectal cancers in a single institution were included in this analysis. For these patients, clinical and molecular findings were analyzed retrospectively. RESULTS: All 12 women undertook microsatellite instability analysis, and 9 (75%) were confirmed of having microsatellite instability-high. Among 9 cases with immunohistochemical staining for MLH1 and MSH2, 6 were positive for the loss of mismatch repair protein. Mutational analyses for MLH1 and MSH2 were performed in 3 out of 12 patients; all of them showed germline mutation. CONCLUSION: This study suggests that there is a genetic background in patients with double primary malignancies in their endometrium and colorectum when analyzed with microsatellite instability studies, immunohistochemistry staining, and mutation studies. This finding supports the necessity of re-defining the high-risk groups in endometrial cancers clinically. This will also help diagnose malignancies in such patients in early stages, as well as counsel other family members.
RÉSUMÉ
OBJECTIVE: This study aimed to compare perioperative and postoperative morbidity of older and younger women undergoing sacrocolpopexy (SCP). METHODS: A retrospective study included 271 patients who underwent laparotomic SCP for symptomatic pelvic organ prolapse from November 2008 to June 2013 at our institution. By the review of medical records, perioperative and postoperative data including the length of the surgery, estimated blood loss, blood transfusion, the length of hospital stay, wound complications and febrile morbidity were collected. In addition, cardiovascular, pulmonary, gastrointestinal, genitourinary, or neurological adverse events were retrieved. The need for an indwelling urinary catheter or performance of clean intermittent self-catheterization, mesh erosion rate and the number of days required for each were included in the postoperative outcomes. For the outcome variable analyzed in this study, the patients was dichomotized into women aged 65 and older and those younger than 65. RESULTS: One hundred and thirty-five (49.8%) patients were younger than 65 and 136 (50.2%) were aged 65 and older. Older women had higher body mass index, vaginal parity and prior surgery for hysterectomy than younger women (P<0.05). And older women had higher baseline comorbidities, such as hypertension, diabetes, cardiac disease (P<0.05), and their American society of Anesthesiologist class was higher (P<0.001). In the perioperative and postoperative complication, older group showed no differences in most of the operation-related complication rates, but gastrointestinal complication rate. Also, mesh erosion rate was not found to be significantly different between the two groups at the last visit. CONCLUSION: Older women undergoing laparotomic SCP have similar perioperative and postoperative morbidities as younger women, suggesting surgeons can counsel older and younger women similarly in terms of operative risks.
RÉSUMÉ
Spleen tyrosine kinase (SYK) has predominantly been studied in hematopoietic cells, where it is involved in immunoreceptor-mediated signaling. However, SYK expression has been shown in numerous non-hematopoietic cells, and its downregulation has been shown to be involved in tumor formation and progression. SYK methylation has been demonstrated to identify a subset of hepatocellular carcinoma (HCC) cases with poor prognosis, but little is known regarding the biological role of SYK in HCC. We found that SYK methylation is a common event in HCC, and is inversely associated with its expression. We established stable HCC cell lines with inducible SYK expression vectors, and compared the differential RNA expression profiles of HCC cell lines with or without the induction of SYK. Gene ontology analysis revealed that the SYK-regulated genes were enriched for genes involved in cell adhesion. Accordingly, we found that the induction of SYK expression increased the adhesion of cells to fibronectin and decreased cell migration and invasion, and that cessation of SYK overexpression increased cell migration and invasion. Our findings suggest that SYK is involved in regulating cell to matrix adhesions, and that SYK loss affects the migration, and invasion of HCC cells.
Sujet(s)
Carcinome hépatocellulaire/étiologie , Ilots CpG , Méthylation de l'ADN , Tumeurs du foie/étiologie , Régions promotrices (génétique) , Protein-tyrosine kinases/antagonistes et inhibiteurs , Adulte , Sujet âgé , Carcinogenèse , Carcinome hépatocellulaire/enzymologie , Carcinome hépatocellulaire/mortalité , Lignée cellulaire tumorale , Prolifération cellulaire , Régulation négative , Femelle , Analyse de profil d'expression de gènes , Humains , Antigènes CD29/physiologie , Protéines et peptides de signalisation intracellulaire/génétique , Protéines et peptides de signalisation intracellulaire/physiologie , Tumeurs du foie/enzymologie , Tumeurs du foie/mortalité , Mâle , Adulte d'âge moyen , Invasion tumorale , Protein-tyrosine kinases/génétique , Protein-tyrosine kinases/physiologie , Rate/enzymologie , Syk kinaseRÉSUMÉ
Dual-specificity phosphatase 5 (DUSP5), which regulates the duration and magnitude of ERK1/2 phosphoactivation within the mitogen-activated protein kinase (MAPK) cascade, has recently been proposed to be a tumor suppressor. However, the epigenetic regulation of DUSP5 and its critical roles in gastric cancer (GC) remain unknown. We compared differential RNA expression profiles of GC cell lines with or without treatment with the DNA demethylating agent 5-aza-2'-deoxycytidine. DUSP5 expression was dramatically decreased by DNA methylation. Hypermethylation of the DUSP5 promoter was detected in GC tissue samples, but not in normal healthy gastric mucosa samples. Restoring DUSP5 expression in DUSP5-silenced GC cell lines decreased their growth and colony-forming ability by causing arrest in the transition from G1 to S phase in the cell cycle as a result of dephosphorylation of ERK1/2 in the nucleus. Moreover, in a set of surgically resected GC cases (n = 179), GCs with DUSP5 promoter region hypermethylation (30.2%) exhibited significantly shortened survival, compared with GCs without DUSP5 methylation (P = 0.009). These results suggest that silencing of DUSP5 by promoter hypermethylation causes increased maintenance of phosphorylated ERK1/2, driving cell proliferation and contributing to gastric carcinogenesis. Furthermore, DUSP5 methylation may serve as a prognostic marker for GC, but this requires validation in a larger set of GC samples.
Sujet(s)
Transformation cellulaire néoplasique/génétique , Ilots CpG/génétique , Méthylation de l'ADN/génétique , Régulation négative/génétique , Dual-specificity phosphatases/génétique , Régions promotrices (génétique)/génétique , Tumeurs de l'estomac/génétique , Azacitidine/pharmacologie , Mouvement cellulaire/effets des médicaments et des substances chimiques , Mouvement cellulaire/génétique , Noyau de la cellule/effets des médicaments et des substances chimiques , Noyau de la cellule/enzymologie , Prolifération cellulaire/effets des médicaments et des substances chimiques , Transformation cellulaire néoplasique/anatomopathologie , Régulation négative/effets des médicaments et des substances chimiques , Dual-specificity phosphatases/métabolisme , Épigenèse génétique/effets des médicaments et des substances chimiques , Extracellular Signal-Regulated MAP Kinases/métabolisme , Femelle , Points de contrôle de la phase G1 du cycle cellulaire/effets des médicaments et des substances chimiques , Points de contrôle de la phase G1 du cycle cellulaire/génétique , Muqueuse gastrique/métabolisme , Muqueuse gastrique/anatomopathologie , Analyse de profil d'expression de gènes , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Études d'associations génétiques , Humains , Mâle , Adulte d'âge moyen , Analyse multifactorielle , Phosphorylation/effets des médicaments et des substances chimiques , Pronostic , Reproductibilité des résultats , Tumeurs de l'estomac/enzymologie , Tumeurs de l'estomac/anatomopathologieRÉSUMÉ
Extrahepatic cholangiocarcinoma (EHC) is usually difficult to diagnose by bile cytology because of cellular disintegration. However, DNA samples from bile fluid can provide sufficient materials to screen for the presence of EHC. We developed DNA methylation marker panels that can be used for MethyLight assay-based detection of EHC in bile fluid specimens. The methylation status of 59 DNA methylation markers was investigated in 20 EHC and 20 non-neoplastic gallbladder tissue samples with MethyLight assay to determine cancer-specific DNA methylation markers. Through assaying cancer-specific DNA methylation markers in a training set (n = 40) and validation set (n = 45) of bile fluid specimens from patients with EHC or those without cancer, we selected suitable marker panels that were assessed for their performance in a third set (test set; n = 40). Four marker panels showed a sensitivity of 60% or more and a specificity of 100% in both the training and validation sets, whereas bile cytology displayed a sensitivity of 40% to 46% and a specificity of 100%. In an independent test set of bile fluid samples, a five-gene panel (CCND2, CDH13, GRIN2B, RUNX3, and TWIST1) detected EHC at a sensitivity of 83%, which was far higher than that of bile cytology (46%, P = 0.004). Using bile fluids, a methylation assay consisting of a five-gene panel may be useful for detecting EHC and in helping to increase the sensitivity of preoperative diagnoses.
Sujet(s)
Bile/cytologie , Cholangiocarcinome/diagnostic , Cholangiocarcinome/génétique , Méthylation de l'ADN , Techniques de diagnostic moléculaire/méthodes , Marqueurs biologiques tumoraux/génétique , Ilots CpG/génétique , ADN tumoral/analyse , ADN tumoral/génétique , Vésicule biliaire/cytologie , Marqueurs génétiques , Humains , Inclusion en paraffine , Régions promotrices (génétique) , Sensibilité et spécificité , Fixation tissulaireRÉSUMÉ
Focal CpG island hypermethylation and diffuse genomic hypomethylation signify the changes in the DNA methylation status in cancer cells. ALU and LINE-1 repetitive DNA elements comprise ~28% of the human genome. PCR-based measurements of these repetitive DNA elements can be used as a surrogate marker of the genomewide methylation content. Our study aimed to identify the timing of ALU and LINE-1 hypomethylations during multistep gastric carcinogenesis and their prognostic implications in gastric cancer (GC). In our study, we analyzed the methylation statuses of ALU and LINE-1 in 249 cases of gastric biopsy samples and another independent set of 198 cases of advanced GC by pyrosequencing. Regardless of the Helicobacter pylori infection status, a significant decrease in the ALU methylation levels was noted during the transitions from chronic gastritis to intestinal metaplasia and from gastric adenoma to GC. LINE-1 methylation decreased during the transition from intestinal metaplasia to gastric adenoma and no further decrease occurred during the transition from gastric adenoma to GC. A low LINE-1 methylation status was strongly associated with poor prognosis in GC. A multivariate analysis revealed that LINE-1 methylation status was an independent prognostic factor. Our findings suggest that ALU and LINE-1 hypomethylations are early events during multistep gastric carcinogenesis. Furthermore, the LINE-1 methylation status can be used as a molecular biomarker to define a subset of GC patients with poor prognosis.
Sujet(s)
Séquences Alu/génétique , Méthylation de l'ADN , Éléments LINE/génétique , Tumeurs de l'estomac/génétique , Sujet âgé , Ilots CpG , Femelle , Humains , Mâle , Adulte d'âge moyen , Pronostic , Tumeurs de l'estomac/étiologie , Tumeurs de l'estomac/mortalité , Tumeurs de l'estomac/anatomopathologieRÉSUMÉ
CONTEXT: Helicobacter pylori infection is primarily acquired during childhood and persists throughout life in the absence of eradication with antibiotics. Helicobacter pylori infection induces methylation in the promoter CpG island loci in gastric epithelial cells. Thus, aberrant CpG island hypermethylation in gastric epithelial cells likely occurs early in life, although there are no existing data supporting this notion. OBJECTIVES: To identify whether aberrant CpG island hypermethylation occurs in pediatric stomach mucosa in association with H pylori infection and to compare methylation profiles of samples from pediatric and adult stomach tissues. DESIGN: We analyzed pediatric (n = 47) and adult (n = 38) gastric mucosa samples for their methylation status in 12 promoter CpG island loci using the MethyLight assay and compared the number of methylated genes and the methylation levels in individual genes between H pylori -positive and H pylori -negative sample results and between pediatric and adult samples. RESULTS: The average number of methylated genes was significantly higher in H pylori -infected pediatric samples than in H pylori -negative pediatric samples (3.4 versus 0.3, P < .001) and in H pylori -infected adult samples than in H pylori -negative adult samples (7.6 versus 0.9, P < .001). Seven genes showed significantly higher methylation levels in H pylori -infected pediatric samples than in H pylori -negative pediatric samples (all values were P < .05). CONCLUSIONS: These results indicate that CpG island hypermethylation occurs in pediatric gastric mucosa in association with H pylori infection and that the genes affected by H pylori -associated hypermethylation were similar in pediatric and adult samples.
Sujet(s)
Ilots CpG/génétique , Méthylation de l'ADN/génétique , Muqueuse gastrique/anatomopathologie , Infections à Helicobacter/génétique , Infections à Helicobacter/anatomopathologie , Adolescent , Adulte , Sujet âgé , Antigènes CD , Biopsie , Cadhérines/génétique , Enfant , Enfant d'âge préscolaire , Femelle , Muqueuse gastrique/métabolisme , Extinction de l'expression des gènes , Infections à Helicobacter/métabolisme , Helicobacter pylori/immunologie , Helicobacter pylori/isolement et purification , Humains , Agranulocytes/anatomopathologie , Mâle , Adulte d'âge moyen , Granulocytes neutrophiles/anatomopathologie , Analyse de séquence d'ADN , Inhibiteur tissulaire de métalloprotéinase-3/génétiqueRÉSUMÉ
Promoter CpG island hypermethylation has become recognized as an important mechanism for inactivating tumor suppressor genes or tumor-related genes in human cancers of various tissues. Gene inactivation in association with promoter CpG island hypermethylation has been reported to be four times more frequent than genetic changes in human colorectal cancers. Hepatocellular carcinoma is also one of the human cancer types in which aberrant promoter CpG island hypermethylation is frequently found. However, the number of genes identified to date as hypermethylated for hepatocellular carcinoma (HCC) is fewer than that for colorectal cancer or gastric cancer, which can be attributed to fewer attempts to perform genome-wide methylation profiling for HCC. In the present study, we used bead-array technology and coupled methylation-specific PCR to identify new genes showing cancer-specific methylation in HCC. Twenty-four new genes have been identified as hypermethylated at their promoter CpG island loci in a cancer-specific manner. Of these, TNFRSF10C, HOXA9, NPY, and IRF5 were frequently hypermethylated in hepatocellular carcinoma tissue samples and their methylation was found to be closely associated with inactivation of gene expression. Further study will be required to elucidate the clinicopathological implications of these newly found DNA methylation markers in hepatocellular carcinoma.
Sujet(s)
Carcinome hépatocellulaire/génétique , Méthylation de l'ADN , Tumeurs du foie/génétique , Antimétabolites antinéoplasiques/usage thérapeutique , Azacitidine/analogues et dérivés , Azacitidine/usage thérapeutique , Carcinome hépatocellulaire/traitement médicamenteux , Lignée cellulaire tumorale , Ilots CpG , Décitabine , Protéines liées au GPI/génétique , Analyse de profil d'expression de gènes , Protéines à homéodomaine/génétique , Humains , Facteurs de régulation d'interféron/génétique , Tumeurs du foie/traitement médicamenteux , Neuropeptide Y/génétique , Séquençage par oligonucléotides en batterie , Régions promotrices (génétique) , Membre-10c de la superfamille des récepteurs au TNF , Récepteurs leurres aux facteurs de nécrose tumorale/génétiqueRÉSUMÉ
CpG island methylator phenotype (CIMP) refers to a subset of colorectal cancers (CRCs) that are characterized by concordant hypermethylation of multiple CpG island loci. CIMP+ CRCs have peculiar clinicopathological features. However, controversy exists over prognostic implications of CIMP in CRCs. We analyzed 320 cases of CRCs for their CIMP status using the MethyLight assay and determined clinicopathological features and prognostic implications of CIMP alone or in combination with microsatellite instability (MSI). With methylation of five or more markers among eight markers examined, CIMP+ tumors were significantly associated with female gender, proximal tumor location, poor differentiation, nodal metastasis, more advanced cancer, BRAF mutations, MSI, and poor prognosis (all P values <0.05). Ogino's combined eight-marker panel outperformed the Ogino and the Laird five-marker panels in detecting these features. Of the four molecular subtypes generated by the combination of CIMP and MSI status, the CIMP+/MSI- subtype showed the worst clinical outcome (P = 0.0003). However, poor prognosis of CIMP+/MSI- subtype was found to be attributed to BRAF mutation. In conclusion, the CIMP+/MSI- subtype tends to present with distinct clinicopathological and molecular features and shows the worst clinical outcome among the four molecular subtypes of CRCs.
Sujet(s)
Tumeurs colorectales/génétique , Ilots CpG/génétique , Méthylation de l'ADN , Protéines proto-oncogènes B-raf/génétique , Adulte , Sujet âgé , Tumeurs colorectales/anatomopathologie , Femelle , Humains , Estimation de Kaplan-Meier , Mâle , Instabilité des microsatellites , Adulte d'âge moyen , Pronostic , Protéines proto-oncogènes/génétique , Protéines proto-oncogènes p21(ras) , Protéines G ras/génétiqueRÉSUMÉ
Biliary intraepithelial neoplasia (BilIN) is the premalignant lesion of extrahepatic cholangiocarcinoma (EHC), and there are no published data regarding epigenetic changes throughout disease progression from normal biliary epithelia to BilIN to EHC. The objective of this study was to identify the occurrence of CpG island hypermethylation and repetitive DNA hypomethylation in BilIN. A total of 50 EHCs, 31 BilINs, and 31 normal cystic duct samples were analyzed for their methylation status in seven genes and two repetitive DNA elements. The number of methylated genes increased with disease progression (normal bile duct, 0.6; BilIN, 2.0; EHC, 3.6; P < 0.001). The methylation level of examined genes was significantly higher in BilIN than in normal samples (TMEFF2, HOXA1, NEUROG1, and RUNX3, P < 0.05) and in EHC than in BilIN samples (TMEFF2, HOXA1, NEUROG1, RUNX3, RASSF1A, and APC, P < 0.05). Long interspersed nucleotide element-1 (LINE-1) and juxtacentromeric satellite 2 (SAT2) methylation levels were markedly lower in EHC than in normal duct and BilIN samples, and BilIN samples showed a decrease of SAT2 methylation levels but no decrease of LINE-1 methylation levels compared to normal samples. These findings suggest that most of cancer-specific CpG island hypermethylation occur in the stage of BilIN and that CpG island hypermethylation seems to occur earlier than repetitive DNA element hypomethylation.
Sujet(s)
Tumeurs des canaux biliaires/génétique , Cholangiocarcinome/génétique , Facteurs de transcription à motif basique hélice-boucle-hélice/génétique , Tumeurs des canaux biliaires/anatomopathologie , Conduits biliaires extrahépatiques , Cholangiocarcinome/anatomopathologie , Sous-unité alpha 3 du facteur CBF/génétique , Ilots CpG , Méthylation de l'ADN , Évolution de la maladie , Protéines à homéodomaine/génétique , Éléments LINE , Protéines membranaires/génétique , Protéines tumorales/génétique , Protéines de tissu nerveux/génétique , États précancéreux/génétique , Facteurs de transcription/génétique , Protéines suppresseurs de tumeurs/génétiqueRÉSUMÉ
PURPOSE: This study aims to determine the relationship between CpG island DNA hypermethylation and global genomic DNA hypomethylation and their prognostic implications in hepatocellular carcinoma. The association of DNA methylation changes with clinicopathologic factors and the chronological ordering of DNA methylation changes along multistep hepatocarcinogenesis were also assessed. EXPERIMENTAL DESIGN: Hepatocellular carcinoma (n = 20) and nonneoplastic liver samples (n = 72) were analyzed for their methylation status at 41 CpG island loci and 3 repetitive DNA elements (LINE-1, ALU, and SAT2) using MethyLight or combined bisulfite restriction analysis. After selection of 19 CpG island loci showing cancer-specific DNA methylation, another set of 99 hepatocellular carcinoma samples was analyzed for these loci. RESULTS: The number of methylated genes in hepatocellular carcinoma was significantly higher in hepatocellular carcinoma patients with a cirrhotic liver than in hepatocellular carcinoma patients with a noncirrhotic liver (9.9 versus 7.0, P = 0.001). Hepatocellular carcinoma from female patients showed a higher number of methylated genes than hepatocellular carcinoma from male patients (11.2 versus 8.4, P = 0.006). The genes CRABP1 and SYK showed significant association between CpG island hypermethylation and patients' poor survival. SAT2 hypomethylation occurred earlier than LINE-1 or ALU hypomethylation along the multistep hepatocarcinogenesis. Depending on the type of CpG island locus, a direct, inverse, or no relationship between CpG island hypermethylation and repetitive DNA hypomethylation was observed in hepatocellular carcinomas. CONCLUSION: The varying relationships between the hypermethylation of individual CpG island loci and the hypomethylation of repetitive elements suggests that they are not mechanically linked. SYK and CRABP1 hypermethylation may serve as useful tumor markers for prognostication of hepatocellular carcinoma patients.
Sujet(s)
Carcinome hépatocellulaire/génétique , Ilots CpG , Méthylation de l'ADN , Tumeurs du foie/génétique , Carcinome hépatocellulaire/mortalité , Carcinome hépatocellulaire/anatomopathologie , Femelle , Humains , Foie/métabolisme , Tumeurs du foie/mortalité , Tumeurs du foie/anatomopathologie , Mâle , Adulte d'âge moyenRÉSUMÉ
The aim of this study was to investigate HFE gene mutations, blood iron indices, and their clinical correlates in a Korean population. In 484 prospectively enrolled health-check examinees, HFE gene mutations and iron indices with clinical and laboratory variables were analyzed. Although neither the C282Y nor S65C gene mutation were found, the H63D heterozygote was detected in 41 subjects (8.5%). The mean serum ferritin and transferrin saturation (TS) were 136.2 +/- 129.8 microg/dl and 39.2 +/- 15.7%, respectively. The H63D genotype was not significantly associated with iron indices. High serum ferritin was associated with old age, the male gender, high body mass index (BMI), and the presence of nonalcoholic fatty liver disease (NAFLD). High TS was associated with the male gender and alcohol drinking. HFE gene mutation is rare; however, TS seems to be higher in Koreans compared to Caucasians or other ethnic groups. Serum ferritin reflects iron store as well as the presence of NAFLD.