Candidate regions of tumor suppressor locus on chromosome 9q31.1 in gastric cancer

Kakinuma, Naoto; Kohu, Kazuyoshi; Sato, Masaaki; Yamada, Tatsuya; Nakajima, Motowo; Akiyama, Tetsu; Ohwada, Susumu; Shibanaka, Yasuhiko

doi:10.1002/ijc.11674

Cited by 8 publications

(15 citation statements)

References 13 publications

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“…This evidence is also supported by three recent reports: (1) a high frequency of LOH on chromosome 9q31 was found in human gastric cancers 20 ; (2) the KLF4 locus was methylated and deleted in human gastric cancers 31 ; (3) LOH and hypermethylation of the 5=-untranslated region have been associated with altered KLF4 expression and with functions in colorectal cancer. 28 However, alternative mechanisms for KLF4 transcriptional inactivation may occur in the remaining 11% of KLF4 nonexpressing DPCs that don't exhibit genetic loss or promoter methylation.…”

Section: Discussionsupporting

confidence: 84%

“…19 -23 In particular, loss of heterozygosity (LOH) analysis of 9q at 9q13-31 and 9q34 is the most common genetic abnormality in bladder cancer, being present in 56% to 71% of cases 19 and is often observed in 25% to 50% of sporadic colorectal cancers 21 and in 56.5% of gastric cancers. 20 These data strongly suggest the presence of a tumor suppressor gene in this area. In fact, two very interesting genes, KLF4 and RGS3, map to this region and have been implicated in cancer development: KLF4 maps exactly to position 9q31.2, and its expression is associated with growth arrest.…”

mentioning

confidence: 74%

“…DPCs are characterized by high genomic instability, resulting in complex karyotypes with a large number of numerical and structural chromosomal abnormalities. Allelic losses affecting the long arm of chromosome 9 are often encountered in many human malignancies, including bladder (71%), 19 gastric (56.5%), 20 colorectal (25% to 50%), 21 and esophageal carcinomas (67% to 86%). 22 Two main regions have been described; they involve the 9q32 and 9q31 loci.…”

Section: Discussionmentioning

confidence: 99%

“…This hypothesis is further supported by similar findings reported in gastric cancer, where the loss of the 9q31 region has been significantly associated with the early stages of the disease. 20 A second candidate tumor suppressor gene, RGS3, also maps in this region and has also been suggested as a potential tumor suppressor. 38 -40 However, we were unable to detect any significant change in RGS3 expression within our series, thus excluding RGS3 as a major candidate tumor suppressor gene in our model.…”

Section: Discussionmentioning

confidence: 99%

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KLF4 is a Novel Candidate Tumor Suppressor Gene in Pancreatic Ductal Carcinoma

Zammarchi

Morelli

Menicagli

et al. 2011

The American Journal of Pathology

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Ductal pancreatic carcinoma (DPC) is a deadly disease with an incidence of 9 cases in 100,000 people per year and a mortality rate close to 100%. Allelic losses in the long arm of chromosome 9 are commonly encountered in many human malignancies but no data are yet available about DPC. We screened 40 lasermicrodissected DPC samples and 6 pre-invasive lesions for 9 microsatellite mapping markers of region 9q21.3 through 9q34.2. A small overlapping region of deletion, spanning 8 million base pairs, was identified between D9S127 and D9S105. Two genes, RSG3 and KLF4, mapped to 9q31.1 through 9q32, were further investigated. A highly significant association was found between KLF4 gene expression levels and genomic status. Similarly, absence of immunohistochemical expression of KLF4 protein was found in 86.8% cases of DPC (33/ 38). Overexpression of KLF4 in a human pancreatic carcinoma cell line induced a significant decrease in the proliferation associated with up-regulation of p21 and the down-regulation of cyclin D1. In conclusion, we identified a novel oncosuppressor region located at the 9q 31.1-3 locus that is lost in DPC at high frequency. Loss of KLF4 expression is closely related to the genomic loss, and its restoration inhibits cancer cell proliferation, suggesting a key suppressor role in pancreatic tumorigenesis. Pancreatic cancer is the fifth leading cause of cancerrelated death in both men and women in the Western world, being responsible for 5% of all cancer-related deaths.1 The lack of reliable early diagnostic methods and effective therapeutic regimens makes the mortality rates in persons with pancreatic carcinoma virtually the same as the incidence rates. A radical surgical approach is possible in only 10% of cases, and adjuvant therapies are virtually ineffective.2 A better understanding of the molecular mechanisms leading to pancreatic tumorigenesis may provide new markers for early diagnosis and potential targets for therapeutic intervention.Ductal pancreatic carcinoma (DPC) is by far the most common pancreatic tumor type, accounting for about 90% of all pancreatic malignancies. At present, a molecular model of DPC development has been proposed; it involves key genes, such K-ras, HER2neu, p16, p53, and DPC4 (smad4). Activating mutations in the K-ras oncogene and the overexpression of Her-2/neu gene are considered "early" genetic events because they occur in pre-invasive lesions (pancreatic intra-epithelial neoplasias, or PanINs) 3,4 and are followed by homozygous deletions in the p16 tumor suppressor gene locus. 5,6 Later in the tumor's progression, inactivations of p53 and DPC4 tumor suppressor genes are thought to be key events that lead to fully transformed phenotypes (carcinoma in situ, or PanIN-3). 7-11Wide genomic instability characterizes DPC, as has been documented by the large collection of cytogenetic abnormalities reported in the literature. [12][13][14][15][16][17] Among these, 9p (p16 locus), 17p (p53 locus), and 18q (DPC4 locus) have been reported to have been deleted in more than 60%...

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Section: Discussionsupporting

confidence: 84%

mentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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KLF4 is a Novel Candidate Tumor Suppressor Gene in Pancreatic Ductal Carcinoma

Zammarchi

Morelli

Menicagli

et al. 2011

The American Journal of Pathology

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“…This notion is also supported by two recent reports. First, a high frequent loss of heterozygosity on chromosome 9q31 (where KLF4 is located) was found in human gastric cancer (42). Second, loss of heterozygosity, hypermethylation of the 5V-untranslated region, and several point mutations of KLF4 are associated with altered KLF4 expression and function in colorectal cancer (16).…”

Section: Discussionmentioning

confidence: 99%

Drastic Down-regulation of Krüppel-Like Factor 4 Expression Is Critical in Human Gastric Cancer Development and Progression

Wei¹,

Gong²,

Kanai³

et al. 2005

Cancer Research

264

268

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Krüppel-like factor 4 (KLF4) is highly expressed in epithelial tissues such as the gut and skin. However, the role of KLF4 in human gastric cancer development and progression is unknown. Here we show that KLF4 protein expression was decreased or lost in primary tumors and, in particular, lymph node metastases when compared with that in normal gastric mucosa. Moreover, loss of KLF4 expression in the primary tumors was significantly associated with poor survival, and also an independent prognostic marker in a multivariate analysis. Consistently, most human gastric cancer cell lines exhibited loss of or a substantial decrease in KLF4 expression at both RNA and protein levels. Enforced restoration of KLF4 expression resulted in marked cell growth inhibition in vitro and significantly attenuated tumor growth and total abrogation of metastasis in an orthotopic animal model of gastric cancer. Mechanism studies indicated that promoter hypermethylation and hemizygous deletion contributed to the down-regulation of KLF4 expression and the induction of apoptosis contributed to the antitumor activity of KLF4. Collectively, our data provide first clinical and casual evidence and potential mechanism that the alteration of KLF4 expression plays a critical role in gastric cancer development and progression. (Cancer Res 2005; 65(7): 2746-54)

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Genome‐wide loss of heterozygosity analysis of WT1–wild‐type and WT1‐mutant Wilms tumors

Ruteshouser¹,

Hendrickson²,

Colella³

et al. 2005

Genes Chromosomes & Cancer

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Wilms tumor (WT) is genetically heterogeneous, and the one known WT gene, WT1 at 11p13, is altered in only a subset of WTs. Previous loss of heterozygosity (LOH) analyses have revealed the existence of additional putative WT genes at 11p15, 16q, and 1p, but these analyses examined only one or a handful of chromosomes or looked at LOH at only a few markers per chromosome. We conducted a genome-wide scan for LOH in WT by using 420 markers spaced at an average of 10 cM throughout the genome and analyzed the data for two genetically defined subsets of WTs: those with mutations in WT1 and those with no detectable WT1 alteration. Our findings indicated that the incidence of LOH throughout the genome was significantly lower in our group of WTs with WT1 mutations. In WT1-wild-type tumors, we observed the expected LOH at 11p, 16q, and 1p, and, in addition, we localized a previously unobserved region of LOH at 9q. Using additional 9q markers within this region of interest, we sublocalized the region of 9q LOH to the 12.2 Mb between D9S283 and a simple tandem repeat in BAC RP11-177I8, a region containing several potential tumor-suppressor genes. As a result, we have established for the first time that WT1-mutant and WT1-wild-type WTs differ significantly in their patterns of LOH throughout the genome, suggesting that the genomic regions showing LOH in WT1-wild-type tumors harbor genes whose expression is regulated by the pleiotropic effects of WT1. Our results implicate 9q22.2-q31.1 as a region containing such a gene.

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Candidate regions of tumor suppressor locus on chromosome 9q31.1 in gastric cancer

Cited by 8 publications

References 13 publications

KLF4 is a Novel Candidate Tumor Suppressor Gene in Pancreatic Ductal Carcinoma

KLF4 is a Novel Candidate Tumor Suppressor Gene in Pancreatic Ductal Carcinoma

Drastic Down-regulation of Krüppel-Like Factor 4 Expression Is Critical in Human Gastric Cancer Development and Progression

Genome‐wide loss of heterozygosity analysis of WT1–wild‐type and WT1‐mutant Wilms tumors

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