Genetic Alterations in Primary Gastric Carcinomas Correlated with Clinicopathological Variables by Array Comparative Genomic Hybridization

Kang, Ji Un; Kang, Jason; Kwon, Gye Cheol; Park, Jong Woo; Jeong, Tae Eun; Noh, Seung Mu; Koo, Sun Hoe

doi:10.3346/jkms.2006.21.4.656

Cited by 27 publications

(25 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Gain of 20q12-1q13, where MMP-9 is located, has been reported to be one of the most frequent regions with genomic gains in gastric cancer (15 -18). Moreover, several reports suggested that the gain at 20q was related to lymph node metastasis of gastric cancer (19,20). Whereas the progression of gastric cancer is obviously influenced by the quantitative changes in MMP-9 expression, the effects of qualitative changes (variations in amino acid sequence) are largely unknown.…”

Section: Matrix Metalloproteinases (Mmp) Have Been Well Documentedmentioning

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

View full text Add to dashboard Cite

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...

show abstract

Section: Matrix Metalloproteinases (Mmp) Have Been Well Documentedmentioning

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

View full text Add to dashboard Cite

show abstract

“…Previous studies have revealed a complex portrait of recurring chromosomal amplifications and deletions in GC, including gains and losses at chromosomes 1q, 8q, 17q, and 20q (2)(3)(4). The recurrent nature of these aberrations has been attributed to the presence of genes important for gastric carcinogenesis, such as CD44 at 11p13, CCNE1 at 19q13, and BTAK at 20q13 (5-7).…”

Section: Introductionmentioning

confidence: 99%

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

Hou

Grabsch

et al. 2008

Cancer Research

View full text Add to dashboard Cite

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]

show abstract

“…Cytogenetic and molecular biological studies of human cancers have identified chromosomal abnormalities, including partial deletions of specific loci (Wang et al, 1998;Senchenko et al, 2004). Furthermore, allelotyping studies performed on solid tumors involving loss of heterozygosity (LOH) using cytogenetic techniques, such as fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH), have demonstrated genomic alterations in gastric cancer at specific regions and copy number losses in regions containing tumor suppressor genes (Sakakura et al, 1999;Kang et al, 2006;Takada et al, 2006). These findings suggest that complicated genetic alterations contribute to gastric carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of methylthioadenosin phosphorylase by homozygous deletion in gastric carcinoma

Kim

Min

et al. 2011

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

The methylthioadenosine phosphorylase (MTAP) gene is located on 9p21 telomeric to the CDKN2A tumor suppressor gene. Loss of MTAP gene is frequently associated with CDKN2A homozygous deletion. Although the homozygous deletion of MTAP has been reported in various human cancers, its function in gastric carcinogenesis is unknown. Here, we determined the status of the MTAP gene by using a combination of array-based comparative genomic hybridization and oligonucleotide microarray. It was found that MTAP was deleted and downregulated in 2 of 10 gastric cancer cell lines. Of the 494 primary gastric carcinomas examined, MTAP expression at the protein level was reduced in 59 (11.9%). Furthermore, a lack of MTAP expression was found to be associated with poor survival (P = 0.038). The genomic loss of MTAP and CDKN2A in gastric carcinomas was investigated by quantitative real-time PCR. Among 20 gastric carcinomas, two cases showed deletion of both MTAP and CDKN2A, and three samples showed homozygous deletion of MTAP, but not of CDKN2A. An analysis of gastric carcinomas revealed that reduced MTAP expression correlated significantly with a genomic deletion. Furthermore, functional assays by transfecting the siRNA or the expressional cDNA into gastric cancer cell lines demonstrated that MTAP regulates cell growth and invasion. The present study suggests that MTAP plays an important role in the regulation of gastric carcinogenesis and, in particular, that MTAP loss is implicated in some way with tumor growth via the modulation of cellular properties, which, in turn, suggests that MTAP has therapeutic applications.

show abstract

Genetic Alterations in Primary Gastric Carcinomas Correlated with Clinicopathological Variables by Array Comparative Genomic Hybridization

Cited by 27 publications

References 26 publications

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

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

Downregulation of methylthioadenosin phosphorylase by homozygous deletion in gastric carcinoma

Contact Info

Product

Resources

About