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Tumor suppress genes screening analysis on 4q in sporadic colorectal carcinoma.

ABSTRACT: AIM:To search candidate tumor suppressor genes (TSGs) on chromosome 4q through detecting high loss of heterozygosity (LOH) regions in sporadic colorectal carcinoma in Chinese patients. METHODS:Thirteen fluorescent labeled polymorphic microsatellite markers were analyzed in 83 cases of colorectal carcinoma and matched normal tissue DNA by polymerase chain reaction (PCR). PCR products were electrophoresed on an ABI 377 DNA sequencer. Genescan 3.7 and Genotype 3.7 software were used for LOH scanning and analysis. Comparison between LOH frequency and clinicopathological factors were performed by c2 test. RESULTS:Data were collected on all informative loci. The average LOH frequency on 4q was 28.56%. The D4S2915 locus showed highest LOH frequency (36.17%). Two obvious deletion regions were detected: one between D4S3000 and D4S2915 locus (4q12-21.1), another flanked by D4S407 and D4S2939 locus (4q25-31.1). None case showed complete deletion of 4q, most cases displayed interstitial deletion pattern solely. Furthermore, compared with clinicopathological features, a significant relationship was observed between LOH frequencies on D4S3018 locus. In tumors larger than 5 cm in diameter, LOH frequency was significantly higher than tumors that were less than 5 cm (56% vs 13.79%, P = 0.01). On D4S1534 locus, LOH was significantly associated with liver metastasis (80% vs 17.25%, P = 0.012). No relationship was detected on other locus compared with clinicopathological features. CONCLUSION:By high resolution deletion mapping, two high frequency regions of LOH (4q12-21.1 and 4q25-31.1) were detected, which may contribute to locate TSGs on chromosome 4q involved in carcinogenesis and progression of sporadic colorectal carcinoma.

SUBMITTER: Jiang LX

PROVIDER: S-EPMC2746351 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Tumor suppress genes screening analysis on 4q in sporadic colorectal carcinoma.

Jiang Li-Xin LX Xu Jie J Wang Zhao-Wen ZW Li Da-Peng DP Peng Zhi-Hai ZH Gao Jian-Jun JJ He Lin L Zheng Hai-Tao HT

World journal of gastroenterology 20080901 36

<h4>Aim</h4>To search candidate tumor suppressor genes (TSGs) on chromosome 4q through detecting high loss of heterozygosity (LOH) regions in sporadic colorectal carcinoma in Chinese patients.<h4>Methods</h4>Thirteen fluorescent labeled polymorphic microsatellite markers were analyzed in 83 cases of colorectal carcinoma and matched normal tissue DNA by polymerase chain reaction (PCR). PCR products were electrophoresed on an ABI 377 DNA sequencer. Genescan 3.7 and Genotype 3.7 software were used ...[more]

PMID: 18810782

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Project description:The ErbB signalling network plays a crucial role in the growth and progression of several cancers, including colorectal cancer (CRC), and includes potentially drug-targetable genes. Oncogenic activation of the ErbB pathway by mutations and focal amplifications have emerged recently as an important predictive marker of the prognosis of CRC patients. However, in contrast to genetic events, little is known about epigenetic alternations of ErbB-associated genes and their impact on gene expression. Genome-wide methylation in sporadic CRCs (n = 12) paired with adjacent normal tissues have been previously analysed by Illumina Infinium HumanMethylation27 (HM27) at 27,578 CpG sites. For confirmation of our initial genome-wide analysis, we used a published HM27 dataset (GSE25062). Subsequently, CpG island methylation of selected ErbB pathway-associated genes was assessed on 233 CRC samples using methylation-sensitive polymerase chain reaction (MS-PCR) and analysed along with various genetic factors associated with CRC [epigenotype, BRAF and KRAS mutations, microsatellite instability (MSI)]. Methylation and expression integration was performed using published datasets including 25 pairs of CRC and normal colon tissues (GSE25062 and GSE25070), and confirmed with real-time PCR. Our previous microarray-based genome-wide DNA methylation analysis of 12 CRCs revealed that four ErbB-associated genes (PIK3CD, PKCΒ, ERBB4, ) were differentially methylated in CRCs. This was further confirmed by statistical re-analysis of an HM27 dataset (GSE25062). Frequent methylation at these loci in tumours was subsequently confirmed by MS-PCR (63%, 43%, 43% and 92%, respectively). Hypermethylation of PKCΒ associated with KRAS mutation (p = 0.04), whereas hypermethylation of ERBB4 associated with high-methylation epigenotypes (HME), BRAF mutation and MSI (p = 0.001, 0.002 and 0.0002, respectively). One of the four analysed genes (PKCΒ) was significantly downregulated in CRC tissue, as revealed by real-time PCR and re-analysis of the GSE25062 and GSE25070 datasets. After careful re-analysis of published methylation and expression data, we conclude that methylation of ERBB4, PAK7 and PIK3CD has no functional role in CRC carcinogenesis. In contrast, methylation seems to have a potential impact on the biology of colorectal tumours by negatively modulating the expression of PKCΒ. Importantly, the relationship between DNA methylation of PKCΒ and gene expression may warrant further attention in the context of colon cancer chemoprevention and anti-cancer therapy.

Dataset Information

Tumor suppress genes screening analysis on 4q in sporadic colorectal carcinoma.

Publications

Tumor suppress genes screening analysis on 4q in sporadic colorectal carcinoma.

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