Gyeong Hoon Kang
Research interests
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InterestsCpG island methylation, repetitive DNA hypomethylation, gastric carcinogenesis, Colorectal Cancer, Breast Cancer Management, H. pylori
Publications
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0.67Impact points
Expression of hMLH1, hMSH2 and hMSH6 in Small Intestinal Carcinomas.
Hepato-gastroenterology. 03/2012; 59(119).
Background/Aims: Although primary small intestinal carcinoma (SIC) is morphologically similar to colorectal carcinoma and shares many of the genetic changes of carcinogenesis, little is known about the role of defective mismatch repair (MMR) genes involved in the SIC. The aim of this study is to inv... [more] Background/Aims: Although primary small intestinal carcinoma (SIC) is morphologically similar to colorectal carcinoma and shares many of the genetic changes of carcinogenesis, little is known about the role of defective mismatch repair (MMR) genes involved in the SIC. The aim of this study is to investigate the role of defective MMR genes and correlation between clinicopathological factors and loss of MMR protein in SIC. Methodology: A total of 195 SIC cases were collected from 20 institutions in Korea and tissue microarrays (TMA) were made. The loss of expression of hMLH1, hMSH2 and hMSH6 was examined by immunohistochemistry (IHC). Results: The loss of expression of hMLH1, hMSH2 and hMSH6 was identified in 25/193 (13.0%), 25/193 (13%) and 29/195 (15%), respectively. The loss of hMSH2 expression was associated with retroperitoneal seeding. Patients with loss of hMSH6 expression had a tendency to invade deeply and a higher frequency of pancreas invasion. The loss of hMSH6 expression was associated less frequently with peritumoral adenoma. There was no survival difference by MMR protein expression status. Conclusions: The loss of MMR protein was associated with some distinct clinicopathological features. MMR pathway seems to be major pathway in carcinogenesis of SICs. MMR defect seems to be related with sporadic-microsatellite instability (MSI).
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3.48Impact points
Bile-Based Detection of Extrahepatic Cholangiocarcinoma with Quantitative DNA Methylation Markers and Its High Sensitivity.
The Journal of molecular diagnostics : JMD. 03/2012;
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 MethyLi... [more] 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.
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4.13Impact points
Postoperative Prognostic Predictors of Pancreatic Ductal Adenocarcinoma: Clinical Analysis and Immunoprofile on Tissue Microarrays.
Annals of surgical oncology. 03/2012;
BACKGROUND: Most pancreatic ductal adenocarcinomas (PDACs) metastasize even after curative resection. Our goal was to investigate the important factors affecting metastasis and overall survival (OS). METHODS: We studied 88 PDACs with R0 resection and evaluated immunohistochemical markers on tissue m... [more] BACKGROUND: Most pancreatic ductal adenocarcinomas (PDACs) metastasize even after curative resection. Our goal was to investigate the important factors affecting metastasis and overall survival (OS). METHODS: We studied 88 PDACs with R0 resection and evaluated immunohistochemical markers on tissue microarrays to assess the expression levels of the following: EGFR, amphiregulin, VEGF, p-c-met, MMP2, MMP7, MMP9, CXCR3, and CXCR4. RESULTS: The median OS in patients who had positive versus negative expression of AREG and MMP9 were 25 versus 16 months and 24 versus 13 months, respectively (P = 0.03, P = 0.006). However, the median OS in patients with positive versus negative expression of MMP2 was 22 versus 37 months (P = 0.04). Immunoprofiles also revealed that patients with positive expression of p-c-met or VEGF had significantly shorter distant metastasis-free survival. Adjuvant treatment, postoperative decrease of CA 19-9, angiolymphatic invasion, AREG, and MMP2 were independent prognostic factors affecting OS in multivariate analysis. CONCLUSIONS: Immunoprofiles revealed the groups with unfavorable tumor biology: negative expression of AREG and positive expression of MMP2. Also, high immunoreactivity of p-c-met or VEGF seemed to be associated with early distant organ metastasis in R0 resected PDACs; however, they still need to be further investigated. These results may give us useful insights in understanding the tumor biology and the patterns of PDAC dissemination.
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6.47Impact points
Prediction of the risk for gastric cancer using candidate methylation markers in the non-neoplastic gastric mucosae.
The Journal of pathology. 03/2012; 226(4):654-65.
Aberrant DNA methylation is frequently found during gastric carcinogenesis. Recently, we identified potential methylation markers important for Helicobacter pylori-induced gastric carcinogenesis using an Illumina methylation chip assay. In this study, we evaluated the candidate genes as markers for ... [more] Aberrant DNA methylation is frequently found during gastric carcinogenesis. Recently, we identified potential methylation markers important for Helicobacter pylori-induced gastric carcinogenesis using an Illumina methylation chip assay. In this study, we evaluated the candidate genes as markers for gastric cancer (GC) in a large Korean population. DNA methylation of PTPN6, MOS, DCC, CRK, and VAV1 was evaluated in non-neoplastic gastric specimens using quantitative methylation-specific PCR in patients with GC (n = 207) and their age- and gender-matched controls (n = 207). Methylation levels in 125 GC samples were also compared. H. pylori infection status was categorized as negative, active, or past infection according to the results of endoscopy-based tests (CLOtest, histology, and culture), H. pylori serology, and serum pepsinogen test. In the controls, active H. pylori infection increased methylation levels in DCC, CRK, MOS, and VAV1 but decreased methylation levels in PTPN6 (all p < 0.05); the methylation levels in MOS remained increased in patients with past H. pylori infection compared to H. pylori-negative subjects (p < 0.001). Methylation levels in MOS in non-neoplastic gastric mucosae increased in the presence of GC, regardless of H. pylori infection status (p < 0.01). Methylation levels in all genes but DCC decreased significantly in GC specimens compared to neoplastic gastric mucosae (p < 0.01); however, methylation levels in GC tissues were not correlated with those in their background gastric mucosae. Hypomethylation of MOS in GC tissues was associated with tumour invasion, nodal metastasis, and undifferentiated histology (p < 0.05). To summarize, among the candidate genes, DNA methylation of MOS may reflect the duration of H. pylori exposure and may be a marker for the development of GC.
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2.54Impact points
Clinicopathologic and molecular characteristics of synchronous colorectal cancers: heterogeneity of clinical outcome depending on microsatellite instability status of individual tumors.
Diseases of the colon and rectum. 02/2012; 55(2):181-90.
The contribution of chromosomal instability, microsatellite instability, and epigenetic instability to the development of synchronous colorectal carcinomas is controversial. This study aimed to investigate the relative roles of microsatellite instability and epigenetic instability in the development... [more] The contribution of chromosomal instability, microsatellite instability, and epigenetic instability to the development of synchronous colorectal carcinomas is controversial. This study aimed to investigate the relative roles of microsatellite instability and epigenetic instability in the development of synchronous colorectal cancers. This was a retrospective study of medical records with histologic, immunohistochemical, and molecular examination of stored tissue samples. The study took place at Seoul National University Hospital, Korea. A total of 46 patients with synchronous colorectal cancers and 105 patients with solitary colorectal cancers were included. Clinicopathologic and molecular characteristics including microsatellite instability, mismatch repair gene expression, CpG island methylator phenotype, and mutation of KRAS and BRAF were analyzed. Patients with synchronous tumors were more likely to be men than those with solitary tumors and had a tendency toward colocalization of individual tumors in the left or right colon. MSI-deficient cancers were more frequent in synchronous than in solitary cancers. The frequencies of CpG island methylator phenotype-high and KRAS and BRAF mutations were not different between synchronous and solitary cancers. No differences between synchronous cancers and solitary cancers were observed in overall survival or progression-free survival. Within the synchronous cancer group, patients with individual tumors discordant for microsatellite instability status had the worst clinical outcome, whereas those with individual tumors concordant for microsatellite instability-deficient status had the best clinical outcome. The study was limited by its retrospective nature. Molecular analysis was performed only on cancerous lesions. Our findings suggest that microsatellite instability plays a more important role than does epigenetic instability in the development of synchronous colorectal cancers, and that information regarding concordant or discordant microsatellite instability status between individual tumors might help to predict clinical outcome of synchronous colorectal cancers.
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4.29Impact points
Distinct patterns of promoter CpG island methylation of breast cancer subtypes are associated with stem cell phenotypes.
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 02/2012; 25(2):185-96.
Although DNA methylation profiles in breast cancer have been connected to breast cancer molecular subtype, there have been no studies of the association of DNA methylation with stem cell phenotype. This study was designed to evaluate the promoter CpG island methylation of 15 genes in relation to bre... [more] Although DNA methylation profiles in breast cancer have been connected to breast cancer molecular subtype, there have been no studies of the association of DNA methylation with stem cell phenotype. This study was designed to evaluate the promoter CpG island methylation of 15 genes in relation to breast cancer subtype, and to investigate whether the patterns of CpG island methylation in each subtype are associated with their cancer stem cell phenotype represented by CD44+/CD24- and ALDH1 expression. We performed MethyLight analysis of the methylation status of 15 promoter CpG island loci involved in breast cancer progression (APC, DLEC1, GRIN2B, GSTP1, HOXA1, HOXA10, IGF2, MT1G, RARB, RASSF1A, RUNX3, SCGB3A1, SFRP1, SFRP4, and TMEFF2) and determined cancer stem cell phenotype by CD44/CD24 and ALDH1 immunohistochemistry in 36 luminal A, 33 luminal B, 30 luminal-HER2, 40 HER2 enriched, and 40 basal-like subtypes of breast cancer. The number of CpG island loci methylated differed significantly between subtypes, and was highest in the luminal-HER2 subtype and lowest in the basal-like subtype. Methylation frequencies and levels in 12 of the 15 genes differed significantly between subtypes, and the basal-like subtype had significantly lower methylation frequencies and levels in nine of the genes than the other subtypes. CD44+/CD24- and ALDH1+ putative stem cell populations were most enriched in the basal-like subtype. Methylation of promoter CpG islands was significantly lower in CD44+/CD24-cell (+) tumors than in CD44+/CD24-cell (-) tumors, even within the basal-like subtype. ALDH1 (+) tumors were also less methylated than ALDH1 (-) tumors. Our findings showed that promoter CpG island methylation was different in relation to breast cancer subtype and stem cell phenotype of tumor, suggesting that breast cancers have distinct patterns of CpG island methylation according to molecular subtypes and these are associated with different stem cell phenotypes of the tumor.
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2.41Impact points
Leptin, MUC2 and mTOR in appendiceal mucinous neoplasms.
Pathobiology : journal of immunopathology, molecular and cellular biology. 01/2012; 79(1):45-53.
Leptin contributes to mucin production in colonic epithelium and regulates carcinogenesis via various signalling pathways. We evaluated the proteins involved in mucin-producing carcinogenesis and putative targets for molecular therapy in appendiceal mucinous neoplasms. Immunohistochemistry and fluor... [more] Leptin contributes to mucin production in colonic epithelium and regulates carcinogenesis via various signalling pathways. We evaluated the proteins involved in mucin-producing carcinogenesis and putative targets for molecular therapy in appendiceal mucinous neoplasms. Immunohistochemistry and fluorescence in situ hybridization were performed in 22 cases of appendiceal mucinous adenoma, 20 mucinous neoplasms of uncertain malignant potential and 14 mucinous adenocarcinomas. Leptin, MUC2, MUC5AC, mTOR and ERK were more frequently immunopositive in mucinous adenocarcinomas compared with mucinous adenomas or mucinous neoplasms of uncertain malignant potential (p < 0.05). STAT3 revealed immunopositivity in 82% of tumours, regardless of tumour category. MUC2 immunopositivity was associated with pseudomyxoma peritonei (p < 0.05). None of the tumours exhibited c-kitimmunoexpression, amplification of Her2 or EGFR, or translocation of ALK. The mTOR-immunopositive group of patients had a lower rate of disease-free survival compared with the mTOR-immunonegative group (p < 0.05). Leptin may collaborate with MUC2 and MUC5AC in mucin-producing carcinogenesis in an mTOR-, STAT3- and ERK-dependent manner. STAT3 may be activated early during tumorigenesis. MUC2 and mTOR (but not c-kit, Her2, EGFR and ALK) may represent targets for molecular therapy in pseudomyxoma peritonei and appendiceal mucinous adenocarcinoma, respectively.
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4.41Impact points
Heterodimerization of Glycosylated Insulin-Like Growth Factor-1 Receptors and Insulin Receptors in Cancer Cells Sensitive to Anti-IGF1R Antibody.
PloS one. 01/2012; 7(3):e33322.
Identification of predictive biomarkers is essential for the successful development of targeted therapy. Insulin-like growth factor 1 receptor (IGF1R) has been examined as a potential therapeutic target for various cancers. However, recent clinical trials showed that anti-IGF1R antibody and chemothe... [more] Identification of predictive biomarkers is essential for the successful development of targeted therapy. Insulin-like growth factor 1 receptor (IGF1R) has been examined as a potential therapeutic target for various cancers. However, recent clinical trials showed that anti-IGF1R antibody and chemotherapy are not effective for treating lung cancer. In order to define biomarkers for predicting successful IGF1R targeted therapy, we evaluated the anti-proliferation effect of figitumumab (CP-751,871), a humanized anti-IGF1R antibody, against nine gastric and eight hepatocellular cancer cell lines. Out of 17 cancer cell lines, figitumumab effectively inhibited the growth of three cell lines (SNU719, HepG2, and SNU368), decreased p-AKT and p-STAT3 levels, and induced G 1 arrest in a dose-dependent manner. Interestingly, these cells showed co-overexpression and altered mobility of the IGF1R and insulin receptor (IR). Immunoprecipitaion (IP) assays and ELISA confirmed the presence of IGF1R/IR heterodimeric receptors in figitumumab-sensitive cells. Treatment with figitumumab led to the dissociation of IGF1-dependent heterodimeric receptors and inhibited tumor growth with decreased levels of heterodimeric receptors in a mouse xenograft model. We next found that both IGF1R and IR were N-linked glyosylated in figitumumab-sensitive cells. In particular, mass spectrometry showed that IGF1R had N-linked glycans at N913 in three figitumumab-sensitive cell lines. We observed that an absence of N-linked glycosylation at N913 led to a lack of membranous localization of IGF1R and figitumumab insensitivity. The data suggest that the level of N-linked glycosylated IGF1R/IR heterodimeric receptor is highly associated with sensitivity to anti-IGF1R antibody in cancer cells.
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4.41Impact points
Mesenchymal Stem Cells Transfer Mitochondria to the Cells with Virtually No Mitochondrial Function but Not with Pathogenic mtDNA Mutations.
PloS one. 01/2012; 7(3):e32778.
It has been reported that human mesenchymal stem cells (MSCs) can transfer mitochondria to the cells with severely compromised mitochondrial function. We tested whether the reported intercellular mitochondrial transfer could be replicated in different types of cells or under different experimental c... [more] It has been reported that human mesenchymal stem cells (MSCs) can transfer mitochondria to the cells with severely compromised mitochondrial function. We tested whether the reported intercellular mitochondrial transfer could be replicated in different types of cells or under different experimental conditions, and tried to elucidate possible mechanism. Using biochemical selection methods, we found exponentially growing cells in restrictive media (uridine(-) and bromodeoxyuridine [BrdU](+)) during the coculture of MSCs (uridine-independent and BrdU-sensitive) and 143B-derived cells with severe mitochondrial dysfunction induced by either long-term ethidium bromide treatment or short-term rhodamine 6G (R6G) treatment (uridine-dependent but BrdU-resistant). The exponentially growing cells had nuclear DNA fingerprint patterns identical to 143B, and a sequence of mitochondrial DNA (mtDNA) identical to the MSCs. Since R6G causes rapid and irreversible damage to mitochondria without the removal of mtDNA, the mitochondrial function appears to be restored through a direct transfer of mitochondria rather than mtDNA alone. Conditioned media, which were prepared by treating mtDNA-less 143B ρ(0) cells under uridine-free condition, induced increased chemotaxis in MSC, which was also supported by transcriptome analysis. Cytochalasin B, an inhibitor of chemotaxis and cytoskeletal assembly, blocked mitochondrial transfer phenomenon in the above condition. However, we could not find any evidence of mitochondrial transfer to the cells harboring human pathogenic mtDNA mutations (A3243G mutation or 4,977 bp deletion). Thus, the mitochondrial transfer is limited to the condition of a near total absence of mitochondrial function. Elucidation of the mechanism of mitochondrial transfer will help us create a potential cell therapy-based mitochondrial restoration or mitochondrial gene therapy for human diseases caused by mitochondrial dysfunction.
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4.72Impact points
ALU and LINE-1 hypomethylations in multistep gastric carcinogenesis and their prognostic implications.
International journal of cancer. Journal international du cancer. 11/2011;
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... [more] 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.
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2.74Impact points
The CpG island methylator phenotype may confer a survival benefit in patients with stage II or III colorectal carcinomas receiving fluoropyrimidine-based adjuvant chemotherapy.
BMC cancer. 08/2011; 11:344.
Colorectal carcinoma (CRC) with CpG island methylator phenotype (CIMP) is recognized as a distinct subgroup of CRC, and CIMP status affects prognosis and response to chemotherapy. Identification of CIMP status in CRC is important for proper patient management. In Eastern countries, however, the clin... [more] Colorectal carcinoma (CRC) with CpG island methylator phenotype (CIMP) is recognized as a distinct subgroup of CRC, and CIMP status affects prognosis and response to chemotherapy. Identification of CIMP status in CRC is important for proper patient management. In Eastern countries, however, the clinicopathologic and molecular characteristics and prognosis of CRCs with CIMP are still unclear. A total of 245 patients who underwent their first surgical resection for sporadic CRC were enrolled and CIMP status of the CRCs was determined using the quantitative MethyLight assay. The clinicopathologic and molecular characteristics were reviewed and compared according to CIMP status. In addition, the three-year recurrence-free survival (RFS) of 124 patients with stage II or stage III CRC was analyzed in order to assess the effectiveness of fluoropyrimidine-based adjuvant chemotherapy with respect to CIMP status. CIMP-high CRCs were identified in 34 cases (13.9%), and were significantly associated with proximal tumor location, poorly differentiated carcinoma, mucinous histology, and high frequencies of BRAF mutation, MGMT methylation, and MSI-high compared to CIMP-low/negative carcinomas. For patients with stage II or III CIMP-low/negative CRCs, no significant difference was found in RFS between those undergoing surgery alone and those receiving surgery with fluoropyrimidine-based adjuvant chemotherapy. However, for patients with CIMP-high CRCs, patients undergoing surgery with fluoropyrimidine-based adjuvant chemotherapy (n = 17; three-year RFS: 100%) showed significantly better RFS than patients treated with surgery alone (n = 7; three-year RFS: 71.4%) (P = 0.022). Our results suggest that selected patients with CIMP-high CRC may benefit from fluoropyrimidine-based adjuvant chemotherapy with longer RFS. Further large scale-studies are required to confirm our results.
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2.85Impact points
Genome-wide DNA methylation profiles in noncancerous gastric mucosae with regard to Helicobacter pylori infection and the presence of gastric cancer.
Helicobacter. 06/2011; 16(3):179-88.
To determine genome-wide DNA methylation profiles induced by Helicobacter pylori (H. pylori) infection and to identify methylation markers in H. pylori-induced gastric carcinogenesis. Gastric mucosae obtained from controls (n = 20) and patients with gastric cancer (n = 28) were included. A wide pane... [more] To determine genome-wide DNA methylation profiles induced by Helicobacter pylori (H. pylori) infection and to identify methylation markers in H. pylori-induced gastric carcinogenesis. Gastric mucosae obtained from controls (n = 20) and patients with gastric cancer (n = 28) were included. A wide panel of CpG sites in cancer-related genes (1505 CpG sites in 807 genes) was analyzed using Illumina bead array technology. Validation of the results of Illumina bead array technique was performed using methylation-specific PCR method for four genes (MOS, DCC, CRK, and PTPN6). The Illumina bead array showed that a total of 359 CpG sites (269 genes) were identified as differentially methylated by H. pylori infection (p < .0001). The correlation between methylation-specific PCR and bead array analysis was significant (p < .0001, Spearman coefficient = 0.5054). Methylation profiles in noncancerous gastric mucosae of the patients with gastric cancer showed quite distinct patterns according to the presence or absence of the current H. pylori infection; however, 10 CpG sites were identified to be hypermethylated and three hypomethylated in association with the presence of gastric cancer regardless of H. pylori infection (p < .01). Genome-wide methylation profiles showed a number of genes differentially methylated by H. pylori infection. Methylation profiles in noncancerous gastric mucosae from the patients with gastric cancer can be affected by H. pylori-induced gastritis. Differentially methylated CpG sites in this study needs to be validated in a larger population using quantitative methylation-specific PCR method.
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2.65Impact points
Phase II study of biweekly S-1 and oxaliplatin combination chemotherapy in metastatic colorectal cancer and pharmacogenetic analysis.
Cancer chemotherapy and pharmacology. 06/2011; 67(6):1323-31.
To evaluate the efficacy and safety of S-1 in combination with oxaliplatin in a biweekly schedule as first-line treatment in metastatic colorectal cancer and the association between genetic polymorphisms and treatment outcomes. Eligibility included age 18-75 years, at least one measurable lesion, no... [more] To evaluate the efficacy and safety of S-1 in combination with oxaliplatin in a biweekly schedule as first-line treatment in metastatic colorectal cancer and the association between genetic polymorphisms and treatment outcomes. Eligibility included age 18-75 years, at least one measurable lesion, no prior chemotherapy except adjuvant chemotherapy, and Eastern Cooperative Oncology Group Performance Status (PS) 0-2. S-1 40 mg/m(2) b.i.d. on days 1-7 with 85 mg/m(2) of oxaliplatin on day 1 was repeated every 2 weeks. Genomic DNA from whole blood was analyzed for 15 single-nucleotide polymorphisms (SNPs) among 8 genes. Fifty-two patients (median age 63 years, range 37-74) were enrolled: 37 men and 15 women; 44 with a PS of 0 and 8 with a PS of 1; and 41 with initially metastatic cancer and 11 with relapsed disease. Among 51 evaluable patients, objective response rate was 47.1% [95% confidence interval (CI) 32.9-61.2]. Median follow-up duration was 17.1 months (range 3.9-28.2 months). Median progression-free survival (PFS) was 6.4 months (95% CI 4.8-8.1), and median overall survival had not been reached yet. Reported grade 3 toxicities were neutropenia (7.7%), thrombocytopenia (5.8%), sensory neuropathy (7.7%) and diarrhea (1.9%). There was no grade 4 toxicity or neutropenic fever. Patients with A/G or G/G genotype in GSTP1 Ile105Val SNP had longer PFS than patients with A/A (median 8.3 vs. 6.1 months, P = 0.04). Biweekly S-1 with oxaliplatin is effective and has improved tolerability and convenience compared to other fluoropyrimidine with oxaliplatin combinations. GSTP1 Ile105Val SNP is associated with treatment outcomes.
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2.56Impact points
Aberrant CpG island hypermethylation in pediatric gastric mucosa in association with Helicobacter pylori infection.
Archives of pathology & laboratory medicine. 06/2011; 135(6):759-65.
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 ... [more] 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. 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. 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. 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). 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.
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2.56Impact points
Four molecular subtypes of colorectal cancer and their precursor lesions.
Archives of pathology & laboratory medicine. 06/2011; 135(6):698-703.
In addition to chromosomal instability and microsatellite instability (MSI), a third pathway, epigenetic instability, has been implicated in progression to colorectal carcinogenesis. CpG island methylator phenotype (CIMP) refers to a subset of colorectal cancers (CRCs) that occur through the epigene... [more] In addition to chromosomal instability and microsatellite instability (MSI), a third pathway, epigenetic instability, has been implicated in progression to colorectal carcinogenesis. CpG island methylator phenotype (CIMP) refers to a subset of colorectal cancers (CRCs) that occur through the epigenetic instability pathway and that are characterized by widespread hypermethylation of promoter CpG island loci, resulting in the inactivation of several tumor suppressor genes or tumor-related genes. Colorectal cancers can be classified into 4 molecular subtypes according to their CIMP and MSI statuses: CIMP+/MSI+, CIMP+/MSI-, CIMP-/MSI+, and CIMP-/MSI-. There are differences between Western (United States and European Union) and Eastern (Korea and China) populations in the number of CRCs that are MSI+, and in the number of MSI+ CRCs that are CIMP+. To review the clinicopathologic and molecular features of the 4 molecular subtypes of CRCs and their precursor lesions, and to emphasize geographic differences in CRCs between Eastern and Western populations. This article is based on the author's own experimental data and a literature review of relevant articles indexed in PubMed (US National Library of Medicine). The 4 molecular subtypes of CRC that are defined by their CIMP and MSI statuses are characterized by their own distinct clinicopathologic and molecular features and precursor lesions. In particular, the clinicopathologic features of MSI+ CRCs differ depending on the CIMP status. Further understanding of the heterogeneity in CRC molecular pathways may help to explain the diverse morphologic features of CRCs.
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2.03Impact points
Differential clinicopathological features in microsatellite instability-positive colorectal cancers depending on CIMP status.
Virchows Archiv : an international journal of pathology. 04/2011; 459(1):55-63.
Microsatellite instability-positive (MSI+) colorectal cancers (CRCs) are divided into CpG island methylator phenotype-positive (CIMP+) and CpG island methylator phenotype-negative (CIMP-) tumors. The repertoire of inactivated genes in CIMP+/MSI+ CRCs overlaps with but is likely to differ from that o... [more] Microsatellite instability-positive (MSI+) colorectal cancers (CRCs) are divided into CpG island methylator phenotype-positive (CIMP+) and CpG island methylator phenotype-negative (CIMP-) tumors. The repertoire of inactivated genes in CIMP+/MSI+ CRCs overlaps with but is likely to differ from that of CIMP-/MSI+ CRCs. Because epigenotypic differences are likely to be manifested as phenotypic differences, CIMP+/MSI+ CRCs are expected to differ from CIMP-/MSI+ CRCs in some clinicopathological features. This study aimed to characterize both common and different features between the two subtypes. A total of 72 MSI+ CRCs were analyzed for their methylation status in eight CIMP panel markers using MethyLight assay. CIMP+/MSI+ and CIMP-/MSI+ CRCs were compared regarding clinicopathologic features and mutation in KRAS/BRAF. An independent set of MSI+ CRCs (n = 97) was analyzed for their relationship of CIMP+ status with clinical outcome. Eighteen cases (25%) were CIMP+, and this CIMP+ subtype was highly correlated with older age (P < 0.001). Polypoid gross appearance without ulceration was observed only in CIMP-/MSI+ CRCs (18.5%, P = 0.057). CIMP+/MSI+ CRCs were closely associated with poor differentiation, medullary appearance, signet ring cell appearance, and acinar-form appearance, whereas the CIMP-/MSI+ subtype was closely associated with intraglandular eosinophilic mucin and stratified nuclei (all P values <0.05). Patients with CIMP+/MSI+ CRCs showed worse overall survival than patients with CIMP-/MSI+ CRCs. Our results demonstrate heterogeneity in the clinicopathological features of MSI+ CRCs depending on CIMP status. The observation that CIMP+ and CIMP- subtypes showed different clinical behaviors may provide a clue for establishing subtype-specific therapeutic strategies for these two subtypes.
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2.03Impact points
DNA methylation profile during multistage progression of pulmonary adenocarcinomas.
Virchows Archiv : an international journal of pathology. 04/2011; 459(2):201-11.
Multiple genetic and epigenetic alterations are known to be involved in the carcinogenesis of peripheral pulmonary adenocarcinoma (ADC). However, epigenetic abnormalities have not been extensively investigated in the following multistage progression sequence: atypical adenomatous hyperplasia (AAH) t... [more] Multiple genetic and epigenetic alterations are known to be involved in the carcinogenesis of peripheral pulmonary adenocarcinoma (ADC). However, epigenetic abnormalities have not been extensively investigated in the following multistage progression sequence: atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS), to invasive ADC. To determine the potential role of promoter methylation during ADC development of the lung, we examined methylation status in 20 normal, 20 AAH, 30 AIS, and 60 ADC lung tissues and compared methylation status among the lesions. The MethyLight assay was used to determine the methylation status of 18 CpG island loci, which were hypermethylated in ADC compared to noncancerous lung tissues. The mean number of methylated CpG island loci was significantly higher in ADC than in AAH and AIS, (p < 0.003 between ADC and AAH, p < 0.005 between ADC and AIS). Aberrant methylation of HOXA1, TMEFF2, and RARB was frequently observed in preinvasive lesions, including AAH and AIS. Furthermore, methylation of PENK, BCL2, RUNX3, DLEC1, MT1G, GRIN2B, CDH13, CCND2, and HOXA10 was significantly more frequent in invasive ADC than AAH or AIS. Our results indicate that epigenetic alterations are involved in the multistep progression of pulmonary ADC development, and aberrant CpG island methylation accumulates during multistep carcinogenesis. In addition, aberrant methylation of HOXA1, TMEFF2, and RARB occurred in preinvasive lesions, which indicates that epigenetic alterations of these genes are involved in the early stages of pulmonary ADC development. In contrast, hypermethylation of PENK, BCL2, RUNX3, DLEC1, MT1G, GRIN2B, CDH13, CCND2, and HOXA10 was more frequent in invasive ADC than in preinvasive lesions, which indicates that methylation of these genes occurs later during tumor invasion in the AAH-AIS-ADC sequence.
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2.10Impact points
High survivin expression as a predictor of poor response to preoperative chemoradiotherapy in locally advanced rectal cancer.
International journal of colorectal disease. 03/2011; 26(8):1019-23.
To evaluate seven molecular markers including cyclooxygenase -2, epidermal growth factor receptor, Ki-67, p21, survivin, thymidylate synthase, and vascular endothelial growth factor for prediction of response to preoperative chemoradiotherapy in locally advanced rectal cancer. Fifty-four patients wi... [more] To evaluate seven molecular markers including cyclooxygenase -2, epidermal growth factor receptor, Ki-67, p21, survivin, thymidylate synthase, and vascular endothelial growth factor for prediction of response to preoperative chemoradiotherapy in locally advanced rectal cancer. Fifty-four patients with clinical T3-4 and/or node-positive rectal cancer who underwent preoperative chemoradiotherapy followed by surgical resection were enrolled into this study. Preoperative chemoradiotherapy consisted of 50.4 Gy of pelvic irradiation with concomitant 5-fluorouracil or oral capecitabine. Expression of molecular markers in pretreatment paraffin-embedded tumor biopsy specimens was assessed by immunohistochemical staining on the tissue microarray. Tumor downstaging was used as an endpoint for evaluation of tumor response. Tumor downstaging was observed in 22 patients (41%), and pathologic complete remission in 7 patients (13%). Among seven molecular markers, only survivin expression was significantly related with tumor downstaging: 26% with high survivin expression (>75% in extent) vs. 72% with low survivin expression (p = 0.0011). However, other six molecular markers were found not to have any correlation with tumor downstaging. High survivin expression in pretreatment tumor biopsy was associated with less tumor downstaging after preoperative chemoradiotherapy for locally advanced rectal cancer.
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1.19Impact points
Bowel sonography in sepsis with pathological correlation: an experimental study.
Pediatric radiology. 02/2011; 41(2):237-43.
Sepsis predisposes full-term infants to necrotizing enterocolitis (NEC). As such, experimental induction of NEC was applied to a sepsis model to evaluate the potential role of US in the early diagnosis of NEC in full-term infants. To evaluate the resistive index (RI) of the superior mesenteric arter... [more] Sepsis predisposes full-term infants to necrotizing enterocolitis (NEC). As such, experimental induction of NEC was applied to a sepsis model to evaluate the potential role of US in the early diagnosis of NEC in full-term infants. To evaluate the resistive index (RI) of the superior mesenteric artery (SMA) on Doppler sonography in experimentally induced sepsis and correlate it with the pathological findings. Fifteen 1-week-old New Zealand white rabbits (control group n = 3, sepsis group n = 12) were used in this study. We injected 1 mg/kg of E. coli O55-B5 lipopolysaccharide (LPS) into 12 rabbits to induce sepsis. Then we conducted grayscale evaluation of the caliber of the abdominal aorta as well as bowel wall thickness and echogenicity. In addition, we measured peak systolic and end-diastolic velocities and SMA RI on Doppler sonography. Pathological findings were analyzed and correlated with RI readings. Peak systolic and end-diastolic velocities and SMA RI values were analyzed statistically at each hour using the Wilcoxon rank sum test; the control and sepsis groups were compared using the Mann-Whitney test. The bowel wall thickness in the sepsis group was significantly increased after LPS injection. The caliber of the abdominal aorta in the sepsis group was significantly decreased after LPS injection. There were echogenic foci (<10 in axial plane) in the bowel wall after LPS injection. Peak systolic velocity in the sepsis group was not significantly changed, but end-diastolic velocity was decreased. SMA RIs in the sepsis group were significantly increased post-LPS injection from baseline. In the control group there were no significant changes in bowel wall thickness, abdominal aorta caliber, bowel wall echogenicity or peak systolic and end-diastolic velocities and RIs. Pathologically, eight of the 12 rabbits in the sepsis group showed grade 1 intestinal injury, three showed grade 2 injury and one showed grade 3 injury. SMA RIs were higher in grades 2 and 3 than in grade 1 when measured at 2 h and 4 h. Sepsis caused necrotic injury in the animal models, and these findings were accompanied by significant changes on Doppler US. These findings could facilitate early detection of intestinal injury in septic infants with NEC.
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4.41Impact points
Epigenetic subgroups of esophageal and gastric adenocarcinoma with differential GATA5 DNA methylation associated with clinical and lifestyle factors.
PloS one. 01/2011; 6(10):e25985.
Adenocarcinomas located near the gastroesophageal junction have unclear etiology and are difficult to classify. We used DNA methylation analysis to identify subtype-specific markers and new subgroups of gastroesophageal adenocarcinomas, and studied their association with epidemiological risk factors... [more] Adenocarcinomas located near the gastroesophageal junction have unclear etiology and are difficult to classify. We used DNA methylation analysis to identify subtype-specific markers and new subgroups of gastroesophageal adenocarcinomas, and studied their association with epidemiological risk factors and clinical outcomes. We used logistic regression models and unsupervised hierarchical cluster analysis of 74 DNA methylation markers on 45 tumor samples (44 patients) of esophageal and gastric adenocarcinomas obtained from a population-based case-control study to uncover epigenetic markers and cluster groups of gastroesophageal adenocarcinomas. No distinct epigenetic differences were evident between subtypes of gastric and esophageal cancers. However, we identified two gastroesophageal adenocarcinoma subclusters based on DNA methylation profiles. Group membership was best predicted by GATA5 DNA methylation status. We analyzed the associations between these two epigenetic groups and exposure using logistic regression, and the associations with survival time using Cox regression in a larger set of 317 tumor samples (278 patients). There were more males with esophageal and gastric cardia cancers in Cluster Group 1 characterized by higher GATA5 DNA methylation values (all p<0.05). This group also showed associations of borderline statistical significance with having ever smoked (p-value = 0.07), high body mass index (p-value = 0.06), and symptoms of gastroesophageal reflux (p-value = 0.07). Subjects in cluster Group 1 showed better survival than those in Group 2 after adjusting for tumor differentiation grade, but this was not found to be independent of tumor stage. DNA methylation profiling can be used in population-based studies to identify epigenetic subclasses of gastroesophageal adenocarcinomas and class-specific DNA methylation markers that can be linked to epidemiological data and clinical outcome. Two new epigenetic subgroups of gastroesophageal adenocarcinomas were identified that differ to some extent in their survival rates, risk factors of exposure, and GATA5 DNA methylation.
Following (12)
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Peter W Laird
University of Southern California -
Sang-Kyu Ye
Seoul National University -
Hyang-Sook Yoo
Korea Research Institute of Bioscience & Biotechnology KRIBB -
Jim C Norman
Beatson Institute for Cancer Research -
Godefridus J Peters
VU University Medical Center, Amsterdam
Topics (3)
