Allelic imbalances and homozygous deletion on 8p23.2 for stepwise progression of hepatocarcinogenesis

Abstract

Early hepatocellular carcinoma (eHCC) originates from the hepatocytes of chronic liver disease and develops into classical hepatocellular carcinoma (HCC). To identify sequential genetic changes in multistep hepatocarcinogenesis, we analyzed molecular karyotypes using oligonucleotide genotyping 50K arrays. First, 1q21.3-44 gain and loss of heterozygosity (LOH) on 1p36.21-36.32 and 17p13.1-13.3 were frequently observed in eHCC, but not in chronic liver diseases, suggesting that such chromosomal aberrations are early, possibly causative events in liver cancer. Next, we detected 25 chromosomal loci associated with liver cancer progression in five HCCs with nodule-in-nodule appearance, in which the inner nodule develops within eHCC lesion. Using these chromosomal regions as independent variables, decision tree analysis was applied on 14 early and 25 overt HCCs, and extracted combination of chromosomal gains on 5q11.1-35.3 and 8q11.1-24.3 and LOH on 4q11-34.3 and 8p11.21-23.3 as distinctive attributes, which can classify early and overt HCCs recursively. In these four altered regions identified as late events of hepatocarcinogenesis, two tumors in 32 overt HCCs analyzed in the present study and one in a set of independent samples of 36 overt HCCs in our previous study harbored a homozygous deletion near the CSMD1 locus on 8p23.2. CSMD1 messenger RNA expression was decreased in HCC without 8p23.2 deletion, possibly due to hypermethylation of the CpG islands in its promoter region. Conclusion: 1q gain and 1p and 17p LOH are early molecular events, whereas gains in 5q and 8q and LOH on 4q and 8p only occur in advanced HCC, and inactivation of the putative suppressor gene, CSMD1, may be the key event in progression of liver cancer. (HEPATOLOGY 2009;49:513-522.)

Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells

“…We examined whether DACH1 expression affected TGF-β signaling in glioma cells. Induced DACH1 expression reduced the proliferation of the U-373MG cells, which are widely used as a cell model for analyzing TGF-β signaling (19), and repressed TGF-β3-stimulated (CAGA) 9 -and p800-luciferase activity ( Fig. S5 A-C).…”

“…Genetic alterations of GBMs, including aberration of DNA copy number such as gene amplifications, loss of heterozygosity (LOH), and homozygous deletions, leads to activation of oncogenes and inactivation of tumor suppressor genes (1)(2)(3). DNA copy number analysis by single-nucleotide polymorphism (SNP) genotyping enables the high-resolution analysis of allelic DNA copy number and has been used to obtain a genome-wide view of DNA copy number alterations in human cancers (4)(5)(6)(7)(8)(9)(10). Particularly, pairwise analysis of normal and tumor DNAs is crucial in detecting homozygous deletion in clinical specimens, because infiltrating nontumorous cells are significant in GBMs.…”

Expression profile analysis of microRNAs and downregulated miR-486-5p and miR-30a-5p in non-small cell lung cancer

“…hsa-miR-486-5p is located on chromosome 8p11.21, which is one of the most frequent genomic deletion regions that contain potential tumor-suppressor genes in various types of tumors, such as NSCLC (14,15). hsa-miR-486-5p was first cloned from the fetal liver.…”

Copy number variation in archival melanoma biopsies versus benign melanocytic lesions

“…89 The 4-probes FISH has shown a sensitivity and speci-90 ficity of 86.7% and 95.4% respectively [18]. Recent 91 study has shown an improvement of the FISH assay by 92 incorporating new probes that target 4 different chro-93 mosomes (CDKN2A on 9p21, RREB1 on 6p25, MYC 94 on 8q24 and CCND1 on 11q13) with increased sensi- 95 tivity and specificity to 94% and 98% respectively [7]. 96 Although the FISH assay was introduced as a di-97 agnostic tool in the field of differential diagnosis of 98 melanoma fairly recently, the principle of developing 99 this assay was based on findings that existed over a 100 decade ago.…”

“…A 502 later study that sought to improve the sensitivity and 503 specificity of FISH assay for discriminating melanoma 504 from nevi has confirmed and included the 8q24 re-505 gion as one of four FISH targets with high discrimi-506 natory power to differentiate between melanoma and 507 benign nevi [7]. The most prominent gene in this re-508 gion is MYC, a proto-oncogene that encodes a nu-509 clear phosphoprotein transcription factor that plays a 510 role in different cellular processes, such as prolifer-511 ation, cell cycle progression, metabolism, differentia-512 tion and apoptosis [74] [95], ovary cancer [96], 588 and more common in the head and neck squamous cell 589 carcinoma (HNSCC) and correlates with poor prog-590 nosis [97,98]. In melanoma, a recent study of Tang 591 et al has reported that CSMD1 functions as a tumor 592 suppressor gene in melanoma cells.…”