Patterns of chromosomal imbalances in muscle invasive bladder cancer.

Simon, Ronald; Bürger, Horst; Semjonow, Axel; Hertle, L.; Terpe, Hans-Joachim; Böcker, W.

doi:10.3892/ijo.17.5.1025

Cited by 41 publications

(48 citation statements)

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“…22 Partial or total gain of 3q has been suggested as early genetic marker for invasion and metastasis of head and neck squamous cell carcinomas, 26 and a negative prognostic factor for patients with invasive bladder cancer. 31 A significant 3q gains has also been reported in Barrett's adenocarcinoma that subsequently developed lymph node metastasis. 32 Positional mapping has refined the 3q region in head and neck carcinomas to a functional candidate gene PIK3CA (3q26), 33 which holds a broad range of cancer-related functions including proliferation, cell adhesion, apoptosis, RAS signaling and oncogenic transformation.…”

Section: Discussionmentioning

confidence: 91%

Regional over-representations on chromosomes 1q, 3q and 7q in the progression of hepatitis B virus-related hepatocellular carcinoma

Wong

Lai

et al. 2005

Modern Pathology

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Hepatocellular carcinoma is a highly malignant tumor that is prevalent in Southeast Asia and China, where hepatitis B viral infection is the main etiologic factor. Despite a high incidence of hepatocellular carcinoma developing in patients with viral hepatitis B-induced liver cirrhosis, the molecular events underlying the malignant liver progression remain largely unclear. In an effort to characterize the genetic abnormalities involved in the hepatitis B-related liver carcinogenesis, we performed genome-wide explorations by the technique of comparative genomic hybridization (CGH) on 100 hepatocellular carcinoma tumors that arose from hepatitis B-induced liver cirrhosis. According to the American Joint Committee on Cancer staging, four cases were classified as stage I, 69 as stage II, 23 as stage III and four as stage IV. CGH analysis indicated chromosomal instability in both early (stages I/II) and advanced (stages III/IV) stage tumors, with common gains on 1q, 8q and 17q23-q25, and losses on 4q22-q35, 8p21-p22, 13q14-q21, 16q and 17p identified in both groups (P40.05). Nevertheless, preferential sites of chromosomal defects in relation to hepatocellular carcinoma progression were also identified. Statistical correlations suggested a higher incidence of regional 1q21-q22, 3q22-q28, 7q21-q22 and 7q34-q36 over-representations in association with the advanced stage tumors (Po0.05). In this study, our novel identification of specific chromosomal aberrations in relation to the advanced stage tumors may represent a first step towards mapping genes linked to the progression of hepatocellular carcinoma. Modern Pathology (2005) 18, 686-692, advance online publication, 17 December 2004; doi:10.1038/modpathol.3800345 Keywords: hepatocellular carcinoma; hepatitis B virus; liver cirrhosis; progression Hepatocellular carcinoma is a primary liver malignancy that is highly malignant and rapidly fatal. The dismal clinical outcome is largely due to the majority of hepatocellular carcinoma tumors being asymptomatic during the natural course of the disease, consequently rendering most patients not being diagnosed in time for curative surgery. 1 By the time of clinical presentation, intra-and extrahepatic metastases are also common, which in turn has limited the scope of curative surgery. 2 In addition, the relatively high incidences of hepatocellular carcinoma recurrence, possibly from micrometastasis prior to surgical treatment, has further lowered the 5-year survival rate for individuals diagnosed with hepatocellular carcinoma. 3 The understanding of molecular events involved in the malignant liver progression thus would hold much value in the prognosis for patients with hepatocellular carcinoma.Studies on the molecular pathogenesis have guided the development of gene-based biomarkers in a number of human cancers including breast, colon, prostate and lung. 4 In hepatocellular carcinoma, although genetic characterizations have indicated frequent chromosomal over-representations on 1q, 6p, 8q, 17q and 20q, and deletions on 1p, 4q, ...

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Section: Discussionmentioning

confidence: 91%

Regional over-representations on chromosomes 1q, 3q and 7q in the progression of hepatitis B virus-related hepatocellular carcinoma

Wong

Lai

et al. 2005

Modern Pathology

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“…However, the portion of pT2-4 tumors with TRIO copy numbers Ն3 was 30%, which is similar to that observed by CGH analysis. 5,34 It is of note that 5p gains detected by CGH were associated with high risk of progression in early invasive (pT1) bladder cancer in one study. 6 This finding was interpreted with caution because only 5 of 54 pT1 tumors analyzed demonstrated 5p gains.…”

Section: Discussionmentioning

confidence: 99%

TRIO Amplification and Abundant mRNA Expression Is Associated with Invasive Tumor Growth and Rapid Tumor Cell Proliferation in Urinary Bladder Cancer

Zheng

Simon

Mirlacher

et al. 2004

The American Journal of Pathology

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Studies by comparative genome hybridization have suggested that 5p amplification is related to tumor progression in urinary bladder cancer. In this study seven genes (TAS2R, ADCY2, DNAH5, CTNND2, TRIO, ANKH, and MYO10) located to 5p15.31-5p15.1 were analyzed by fluorescence in situ hybridization using a tissue microarray containing samples from tumors and cell lines with known 5p amplification by comparative genome hybridization. Amplification frequency was highest for TRIO, which maps to 5p15.2 and encodes a protein with a putative role in cellcycle regulation. To further investigate the role of TRIO amplification in bladder cancer, a tissue microarray containing samples from 2317 bladder tumors was used for fluorescence in situ hybridization analysis. TRIO amplification was strongly associated with invasive tumor phenotype, high tumor grade, and rapid tumor cell proliferation (Ki67 LI) (P < 0.0001 each). Only 7 of 456 pTaG1/G2 tumors (1.5%) but 62 of 485 pT1-4 carcinomas (12.8%) had TRIO amplification. TRIO amplification was not associated with poor prognosis. Using a frozen bladder tumor tissue microarray RNA in situ hybridization confirmed that TRIO is up-regulated in amplified tumors. It is concluded that TRIO up-regulation through amplification has a potential role in bladder cancer progression. Studies by comparative genomic hybridization (CGH) demonstrated gains and amplifications at many different chromosomal loci mainly in invasive bladder cancer. 1 Gene copy number increase is an important mechanism leading to abnormal expression of known oncogenes such as MYC at 8q24, CCND1 at 11q13, or HER2 at 17q21. 2-4 However, most of the chromosomal regions found amplified in bladder cancer 1 do not contain known oncogenes, suggesting that many amplification target genes remain to be identified.Amplifications of the short arm of chromosome 5 are of particular interest. In previous CGH studies 5p amplification was found to be one of the few alterations occurring more frequently in muscle invasive tumors (stage pT2 and higher) than in early invasive cancers (stage pT1). 5 Our hypothesis of a role of 5p amplification for bladder cancer progression was further corroborated by the results of a second CGH study finding a significant association between 5p amplifications and an increased risk for tumor progression in a series of pT1 carcinomas. 6 Because amplifications often cover large areas of 5p in bladder cancer, it is difficult to narrow down the region of amplification using positional cloning approaches. Based on our CGH studies, one of the most common sites of amplification is in the 5p15-p14 region. 5 In an attempt to find oncogene candidates among known genes allocated in this chromosomal area, we became interested in TRIO located at 5p15.2. 7 The TRIO protein contains a serine/threonine kinase domain and two guanine nucleotide exchange factor domains for the family of Rho-like GTPases, specific for Rac1 and RhoA. 8 These functional domains suggest that this enzyme may play a role in signaling pathways contro...

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“…Later, several studies showed that allelic changes at specific chromosomal regions and alterations of tumor suppressor genes, such as PTEN, RB, and TP53, correlate with stage and grade of bladder cancers (for review see Knowles, 1999). Comparative genomic hybridization (CGH) studies also suggested quantitative differences of genetic changes, including DNA losses at chromosome 2q22-33, 2q32-qter, and 2q34-qter regions, between the noninvasive and invasive bladder cancers (Richter et al, 1997Simon et al, 1998Simon et al, , 2000. Loss of heterozygosity (LOH) at chromosome 2q is also associated with aggressive growth of head and neck and non-small cell lung carcinomas (Ransom et al, 1998;Shiseki et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Alteration of the LRP1B Gene Region Is Associated with High Grade of Urothelial Cancer

Langbein

Szakács

Wilhelm

et al. 2002

Laboratory Investigation

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SUMMARY:We have delineated regions of interest at chromosome 2q21.2, 2q36.3, and 2q37.1 by deletion mapping of 114 urothelial cancers (UC). Altogether, 17%, 18%, and 63% of the G1, G2, and G3 tumors displayed loss of heterozygosity at chromosome 2q, respectively, The region at 2q21.2 was narrowed down to the LRP1B gene (NT_005129.6). Hemi-and homozygous deletion at the LRP1B gene region was seen in 31 of 114 UCs. Only 8% of the UCs with G1 and none with G2 tumors showed loss of heterozygosity at the LRP1B gene, whereas 49% of the G3 UCs had allelic loss at this region. RT-PCR analysis of the LRP1B gene showed the lack of expression of several exons in 2 of 9 cases analyzed. Our analysis suggests that the LRP1B gene is a candidate tumor suppressor gene in UCs. (Lab Invest 2002, 82:639 -643).C ancer of the urinary bladder is one of the most common tumors in the Western world. The majority of urothelial cancers (UC) are diagnosed as noninvasive tumors (Ta), whereas 20% to 25% of the cases show an invasive growth (T1-4) at the time of first presentation. From the clinical point of view, the question arises whether these two major groups of tumors are distinct entities or correspond to different stages of progression of a single tumor entity. Pioneering cytogenetic analyses before the chromosome banding era have suggested that the number of gross karyotype alterations predicts the clinical course of UCs, for example, recurrency and progression (Falor and Ward, 1978;Lamb, 1967). Later, several studies showed that allelic changes at specific chromosomal regions and alterations of tumor suppressor genes, such as PTEN, RB, and TP53, correlate with stage and grade of bladder cancers (for review see Knowles, 1999). Comparative genomic hybridization (CGH) studies also suggested quantitative differences of genetic changes, including DNA losses at chromosome 2q22-33, 2q32-qter, and 2q34-qter regions, between the noninvasive and invasive bladder cancers (Richter et al, 1997Simon et al, 1998Simon et al, , 2000. Loss of heterozygosity (LOH) at chromosome 2q is also associated with aggressive growth of head and neck and non-small cell lung carcinomas (Ransom et al, 1998;Shiseki et al, 1994). Recently, Liu et al (2000) identified a putative tumor suppressor gene LRP1B from the chromosome 2q21.2 region that was found to be homozygously deleted in several cancer cell lines, including the bladder cancer cell line VM-CUB-2. To delineate putative tumor suppressor gene regions, we analyzed 114 UCs for 20 microsatellite loci at the chromosome 2q including those from the LRP1B region. We identified three distinct regions of LOH in 40% of tumors and found a correlation between LOH at chromosome 2q and tumor grade. Results Three Target Regions of Allelic Loss at Chromosome 2qCGH analysis of 18 Grade 3 (G3) UCs of this series revealed a gain at chromosome 2p in 7 cases and loss of DNA at chromosome 2q in 11 cases (one example is shown in Fig. 2). Therefore, we evaluated score 2 at chromosome 2p as a duplication of one allele, but at chromoso...

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Patterns of chromosomal imbalances in muscle invasive bladder cancer.

Cited by 41 publications

References 0 publications

Regional over-representations on chromosomes 1q, 3q and 7q in the progression of hepatitis B virus-related hepatocellular carcinoma

Regional over-representations on chromosomes 1q, 3q and 7q in the progression of hepatitis B virus-related hepatocellular carcinoma

TRIO Amplification and Abundant mRNA Expression Is Associated with Invasive Tumor Growth and Rapid Tumor Cell Proliferation in Urinary Bladder Cancer

Alteration of the LRP1B Gene Region Is Associated with High Grade of Urothelial Cancer

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