DNA Sequence Copy Number Aberrations Associated with Histological Subtypes and DNA Ploidy in Gastric Carcinoma

Oga, Atsunori; Park, Chan Kum; Kawauchi, Shigeto; Furuya, Tomoko; Sasaki, Kohsuke

doi:10.1111/j.1349-7006.2001.tb01156.x

Cited by 12 publications

(18 citation statements)

References 34 publications

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“…(19,20) Each type reveals different characteristics with regard to clinicopathological parameters and genetic differences, and candidate genes responsible for those phenotypic differences have been proposed. (2,(21)(22)(23)(24) The ability of CGH-arrays to differentiate among histological types of renal cancer (25) suggested that we might be able to identify novel genes involved in different histological types of GC by CGH-array analysis. According to the degree of differentiation, we classified 28 of our GC cell lines into well-differentiated and undifferentiated types, on the basis of the diagnoses of the primary tumors from which they were derived, and compared their patterns of copy-number aberrations.…”

Section: Resultsmentioning

confidence: 99%

“…(6) Furthermore, according to association between chromosomal aberrations and histological subtypes (well-and undifferentiated type) of GC cell lines, our data also included the loci, which had been detected by analyses of primary GC samples, such as gain of 20q and loss of 8p in intestinal type GC and gain of 7q in diffuse tumors. (20,21) However, small copy-number changes, even gain or loss of only one copy within a small region that was never detected by conventional CGH, were revealed by our custom-made CGHarray. We were able to discriminate independent amplifications of multiple target genes in the same region, such as CDK6 and MET at 7q, which formerly were recognized as one amplicon by conventional CGH.…”

Section: Discussionmentioning

confidence: 99%

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Screening of DNA copy‐number aberrations in gastric cancer cell lines by array‐based comparative genomic hybridization

et al. 2005

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We performed genome-wide screening for deoxyribonucleic acid copy-number aberrations in 31 gastric cancer (GC) cell lines by using custom-made comparative genomic hybridization (CGH)-array. Copy-number gains were frequently detected at 1q, 3q, 5p, 7p, 7q, 8q, 11q, 17q, 20p, 20q, Xp and Xq, and losses at 3p, 4p, 4q, 8p, 9p, 18p and 18q. With respect to histological subtypes, copy-number gains at 1p, 16p, 20p, 20q and 22q, and losses at 8p, 10p, 10q and 18q were significantly frequent in cell lines derived from tumors of the well-differentiated type, whereas copy-number gains at 1q, 7p, 7q, Xp and Xq were frequent in the undifferentiated type. Homozygous deletions were seen at five loci, whereas high-level amplifications were detected in 15 of the 31 GC cell lines; these had occurred at 24 loci, including the segment containing CDK6 (7q21.2). Amplification of that gene had never been reported in GC before. Immunohistochemical studies showed increased levels of CDK6 protein in 54 of the 292 primary GC samples we examined (18.5%). Cytoplasmic localization of CDK6, as well as CDK6 over-expression, was more frequent in well-differentiated GC than in undifferentiated tumors. Nuclear expression of CDK6 was more frequent in early stage GC than in advanced tumors, suggesting that nuclear localization of CDK6 is likely to be a prognostic factor for GC. Taken together, our data indicate that CDK6 might be involved in the pathogenesis of GC and, more generally, that CGH-arrays have a powerful potential for identifying novel cancer-related genetic changes in a variety of tumors. (Cancer Sci 2005; 96: 100-110)

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Screening of DNA copy‐number aberrations in gastric cancer cell lines by array‐based comparative genomic hybridization

et al. 2005

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“…Interestingly, in this study, we have shown that the increased risk of lymph node metastasis associated with the homozygous 279R-574P haplotype is mainly in the diffuse type of gastric cancer. Several reports from other laboratories have suggested that the MMP-9 overexpression mainly occurs in the intestinal type (7,34) and that the association of overexpression with lymph node metastasis is restricted to the intestinal type (20). Combined with the findings from this study, a hypothesis can be constituted that the quantitative and qualitative aspects exert their effects complementarily.…”

Section: Discussionmentioning

confidence: 99%

Associations of Matrix Metalloproteinase-9 Protein Polymorphisms with Lymph Node Metastasis but not Invasion of Gastric Cancer

Yang¹,

Zhu²,

Chen

et al. 2008

Clinical Cancer Research

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Purpose: Like most cancers, gastric cancer has a complex multistep etiology that involves both environmental and genetic factors. Matrix metalloproteinase-9 (MMP-9) is frequently overexpressed in gastric cancer. We investigated the effect of the genetic differences in MMP-9 coding region on the occurrence and progression of gastric cancer. Experimental Design: A case-control study was conducted in a population of 74 patients and 100 healthy people in southeast China. Individuals were genotyped for two single nucleotide polymorphisms (SNP) in MMP-9: R279Q and P574R. Genotypic distributions between patient and control groups were compared for correlations with cancer occurrence. Associations between genotypic distributions and several clinicopathologic features were also analyzed using univariate tests, multivariate logistic regression modeling, and stratified analyses. Results: Significant associations were revealed between both SNPs and lymph node metastasis [P = 0.012 and 0.025; odds ratio (OR), 3.4 and 2.8, respectively]. After adjustment using logistic regression for the potential confounding effects of gender, age, and location of the tumors, homozygous MMP-9 279RR and 574PP are more evidently associated with lymph node metastasis with OR adjusted of 5.7 [95% confidence interval (95% CI), 1.80-18.34] and 4.2 (95% CI, 1.37-12.69). The homozygous 279R-574P haplotype showed a stronger association by an OR adjusted of 6.1 (95% CI, 1.92-12.29) and was also associated with the 1-year postoperative mortality (OR adjusted , 6.5; 95% CI, 1.18-35.74). Interestingly, our data also suggested that the MMP-9 polymorphisms seem to result in higher risk of lymph node metastasis through a pathway independent of cancer invasion because no positive associations were found between these polymorphisms and cancer invasion (OR, 0.59 < 1). The stratified analyses indicated a synergistic interaction between the MMP-9 polymorphisms and the type of diffuse in affecting lymph node metastasis (OR, 13.4; P between strata = 0.04). Significant association between both SNPs and the overall occurrence of gastric cancer was not observed. Conclusion:The present study has shown significant associations between the two nonsynonymous MMP-9 polymorphisms with lymph node metastasis in gastric cancer, especially with the diffuse type. The relatively large values of ORs and disassociation with cancer invasion suggest that the genetic differences of MMP-9 protein play an important and specific role in lymph node metastases, and therefore, further investigation of the underlying molecular mechanism is warranted. Matrix metalloproteinases (MMP) have been well documentedto have important functions in cancer invasion and metastasis mediated principally by their activities in degrading extracellular matrix and basement membrane (1). Recent studies also suggested that MMPs have other functions related to cancer development and progression, such as activating growth factors (2, 3). Together with MMP-2, MMP-9 is a gelatinase and belongs to a subfamil...

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“…iGCs form cohesive gland-like tubular structures, whereas dGCs exhibit minimal cell cohesion with frequent invasion into surrounding tissues (11). Although amplifications at 17q12-21 and 20q and losses at 8p and 9p are more frequently observed in iGC, 8p and 12q gains are associated with dGC (12,13), arguing that iGC and dGC may represent molecularly distinct entities. Furthermore, ERBB2/HER2 amplifications are observed in iGC but not dGCs, raising the possibility that only the former may be candidates for Trastuzumab (anti-HER2) therapy (14).…”

Section: Introductionmentioning

confidence: 94%

Integrative Genomics IdentifiesRAB23as an Invasion Mediator Gene in Diffuse-Type Gastric Cancer

Hou

Grabsch

et al. 2008

Cancer Research

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Recurrent genomic amplifications and deletions are frequently observed in primary gastric cancers (GC). However, identifying specific oncogenes and tumor suppressor genes within these regions can be challenging, as they often cover tens to hundreds of genes. Here, we combined high-resolution array-based comparative genomic hybridization (aCGH) with gene expression profiling to target genes within focal high-level amplifications in GC cell lines, and identified RAB23 as an amplified and overexpressed Chr 6p11p12 gene in Hs746T cells. High RAB23 protein expression was also observed in some lines lacking RAB23 amplification, suggesting additional mechanisms for up-regulating RAB23 besides gene amplification. siRNA silencing of RAB23 significantly reduced cellular invasion and migration in Hs746T cells, whereas overexpression of RAB23 enhanced cellular invasion in AGS cells. RAB23 amplifications in primary gastric tumors were confirmed by both fluorescence in situ hybridization and genomic qPCR, and in two independent patient cohorts from Hong Kong and the United Kingdom RAB23 expression was significantly associated with diffuse-type GC (dGC) compared with intestinal-type GC (iGC). These results provide further evidence that dGC and iGC likely represent two molecularly distinct tumor types, and show that investigating focal chromosomal amplifications by combining highresolution aCGH with expression profiling is a powerful strategy for identifying novel cancer genes in regions of recurrent chromosomal aberration. [Cancer Res 2008;68(12): 4623-30]

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DNA Sequence Copy Number Aberrations Associated with Histological Subtypes and DNA Ploidy in Gastric Carcinoma

Cited by 12 publications

References 34 publications

Screening of DNA copy‐number aberrations in gastric cancer cell lines by array‐based comparative genomic hybridization

Screening of DNA copy‐number aberrations in gastric cancer cell lines by array‐based comparative genomic hybridization

Associations of Matrix Metalloproteinase-9 Protein Polymorphisms with Lymph Node Metastasis but not Invasion of Gastric Cancer

Integrative Genomics IdentifiesRAB23as an Invasion Mediator Gene in Diffuse-Type Gastric Cancer

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