Molecular karyotyping of human hepatocellular carcinoma using single-nucleotide polymorphism arrays

Midorikawa, Yutaka; Yamamoto, Shozo; Ishikawa, Shumpei; Kamimura, Naoko; Igarashi, Hisaki; Sugimura, Haruhiko; Makuuchi, Masatoshi; Aburatani, Hiroyuki

doi:10.1038/sj.onc.1209537

Cited by 99 publications

(85 citation statements)

References 48 publications

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“…For all 6q23-25 markers tested, including the ZAC1/LOT1-specific markers, LOH or allelic imbalance was observed in 50% of the PCCs. Similarly, another report has concluded that in human hepatocellular carcinomas LOT1/PLAGL1 is often silenced by allelic loss, possibly the unmethylated allele (Midorikawa et al, 2006). Together with its functional properties and chromosomal localization, these findings substantiated ZAC1/LOT1 as a suitable candidate for the tumor suppressor gene on 6q24-q25.…”

Section: Chromosomal Deletion and Rearrangementmentioning

confidence: 49%

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

Abdollahi

2006

Journal Cellular Physiology

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Lost-on-transformation 1 (LOT1) (PLAGL1/ZAC1) is a member of the novel subfamily of zinc-finger transcription factors, designated as PLAG family. The other members in this group include PLAG1 and PLAGL2, which share high homology with each other and with LOT1, particularly in their zinc-finger amino-terminal region. They are structurally similar but functionally different. For example, the LOT1 gene encodes a growth suppressor protein and is localized on human chromosome 6q24-25, a chromosomal region that is frequently deleted in many types of human cancers. The gene is maternally imprinted and is linked to developmental disorders such as growth retardation and transient neonatal diabetes mellitus (TNDM). LOT1 is a target of growth factor signaling pathway(s) and silenced by epigenetic mechanisms, as well as by the loss of heterozygosity in different tumor tissues. PLAG1 is a protooncogene that is localized on chromosome 8q12 and was found to be a target of several types of chromosomal rearrangement including the one identified in pleomorphic adenomas of the salivary gland. Since the discovery of the PLAG family members in 1997, much has been learned about their structure and function, as are summarized in this review. While the available data suggest that these proteins may play important roles in regulating normal physiological functions in the mammals, a great deal more about their signaling pathway(s), potential role in the complex pathologies such as cancer and developmental disorders, and functional relationship between different family members and splice variants still remains to be uncovered.

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Section: Chromosomal Deletion and Rearrangementmentioning

confidence: 49%

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

Abdollahi

2006

Journal Cellular Physiology

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“…2,3,12,13 Loss of 16q was also frequently detected in other solid tumors including breast, 14 lung, 15 and gastric cancers, 16 suggesting that 16q may harbor one or more TSGs and its inactivation plays a key role in the pathogenesis of many malignancies including HCC. In this study we characterized one candidate TSG, TAT, at 16q22.1.…”

Section: Discussionmentioning

confidence: 99%

Down-Regulation of Tyrosine Aminotransferase at A Frequently Deleted Region 16Q22 Contributes to the Pathogenesis of Hepatocellular Carcinoma

Dong²,

Xie³

et al. 2010

Hepatology

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Loss of 16q is one of the most frequent alterations in many malignancies including hepatocellular carcinomas (HCC), suggesting the existence of a tumor suppressor gene (TSG) within the frequently deleted region. In this report we describe the identification and characterization of one candidate TSG, tyrosine aminotransferase gene (TAT), at 16q22.1. Loss of one TAT allele was detected in 27/50 (54%) of primary HCCs by quantitative real-time polymerase chain reaction. In addition, homo-deletion of TAT alleles was detected in two cases. Down-regulation of TAT was detected in 28/50 (56%) of HCCs, which was significantly associated with the loss of TAT allele and hypermethylation of TAT 5 0 CpG island (CGI) region (P < 0.001). Functional studies found that TAT has a strong tumor suppressive ability. Introduction of the TAT gene into HCC cell lines could effectively inhibit colony formation in soft agar, foci formation, and tumor formation in nude mice. Further study found that the tumor suppressive mechanism of TAT was associated with its proapoptotic role in a mitochondrial-dependent manner by promoting cytochrome-c release and activating caspase-9 and PARP. Conclusion: Taken together, our findings suggest that TAT plays an important suppressive role in the development and progression of HCC.

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“…The median age at transformation was 52 (range 27-73) years. Presentation lymph nodes were analysed in 10/26 patients ( Patients 6,7,9,12,17,19,[20][21][22][23][24][25]. The t(14;18)(q32;q21) cell lines DoHH2, RL2261 and SCI-1 were also included for analysis.…”

Section: Tissue Samplesmentioning

confidence: 99%

“…The application of this approach to other malignancies has not only revealed copy number changes but has also uncovered the presence of large regions of homozygosity in the absence of copy number change. [14][15][16][17][18] Such regions, which have been termed acquired uniparental disomy (aUPD) or isodisomy, appear to be due to mitotic recombination between the two chromosomal homologues 19 and are undetectable by CGH array technology. These events can result in the selection of daughter cells made homozygous for a pre-existing mutation.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide detection of recurring sites of uniparental disomy in follicular and transformed follicular lymphoma

et al. 2007

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Single-nucleotide polymorphism (SNP) array analysis was performed using the 10K GeneChip array on a series of 26 paired follicular lymphoma (FL) and transformed-FL (t-FL) biopsies and the lymphoma cell lines SCI-1, DoHH2 and RL2261. Regions of acquired homozygosity were detected in 43/52 (83%) primary specimens with a mean of 1.7 and 3.0 aberrations in the FL and t-FL, respectively. A notable feature was the occurrence of recurring sites of acquired uniparental disomy (aUDP) on 6p, 9p, 12q and 17p in cell lines and primary samples. Homozygosity of 9p and 17p arose predominantly in t-FL and in three cases rendered the cell homozygous for a preexisting mutation of either CDKN2A or TP53. These data suggest that mutation precedes mitotic recombination, which leads to the removal of the remaining wild-type allele. In all, 18 cases exhibited abnormalities in both FL and t-FL samples. In 10 cases blocks of homozygosity were detected in FL that were absent in the subsequent t-FL sample. These differences support the notion that FL and t-FL may arise in a proportion of patients by divergence from a common malignant ancestor cell rather than by clonal evolution from an antecedent FL.

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Molecular karyotyping of human hepatocellular carcinoma using single-nucleotide polymorphism arrays

Cited by 99 publications

References 48 publications

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

LOT1 (ZAC1/PLAGL1) and its family members: Mechanisms and functions

Down-Regulation of Tyrosine Aminotransferase at A Frequently Deleted Region 16Q22 Contributes to the Pathogenesis of Hepatocellular Carcinoma

Genome-wide detection of recurring sites of uniparental disomy in follicular and transformed follicular lymphoma

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