Loss of heterozygosity (LOH) at 17q and 14q in human lung cancers

Pataer, Abujiang; Mori, T; Takahashi, Takashi; Tanaka, Fumihiko; Kasyu, Ippei; Hitomï, Shigeki; Hayashi, Hiroshi

doi:10.1038/sj.onc.1202230

Cited by 46 publications

(33 citation statements)

References 6 publications

(6 reference statements)

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“…However, the critical markers in these studies, in contrast to ours, were all located distal to D14S64 (Chang et al, 1995;Bandera et al, 1997). In lung carcinoma the highest frequency of LOH was found with marker D14S261 at 14q11.1-q11.2 (centromeric to D14S72) (Abujiang et al, 1998). We observed deletions at 14q23-q24 by microsatellite markers D14S258, D14S77 and D14S284 in five, five and six tumours respectively.…”

Section: Discussionmentioning

confidence: 60%

Deletions at 14q in malignant mesothelioma detected by microsatellite marker analysis

Wolf

Nordling

et al. 1999

Br J Cancer

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Summary Previous molecular cytogenetic studies by comparative genomic hybridization (CGH) on primary tumours of human malignant mesothelioma have revealed that loss of genetic material at chromosome 14q is one of the most frequently occurring aberrations. Here we further verify the frequency and pattern of deletions at 14q in mesothelioma. A high-resolution deletion mapping analysis of 23 microsatellite markers was performed on 18 primary mesothelioma tumours. Eight of these had previously been analysed by CGH. Loss of heterozygosity or allelic imbalance with at least one marker was detected in ten of 18 tumours (56%). Partial deletions of varying lengths were more common than loss of all informative markers, which occurred in only one tumour. The highest number of tumours with deletions at a specific marker was detected at 14q11.1-q12 with markers D14S283 (five tumours), D14S972 (seven tumours) and D14S64 (five tumours) and at 14q23-q24 with markers D14S258 (five tumours), D14S77 (five tumours) and D14S284 (six tumours). We conclude from these data that genomic deletions at 14q are more common than previously reported in mesothelioma. Furthermore, confirmation of previous CGH results was obtained in all tumours but one. This tumour showed deletions by allelotyping, but did not show any DNA copy number change at 14q by CGH. Although the number of tumours allelotyped was small and the deletion pattern was complex, 14q11.1-q12 and 14q23-q24 were found to be the most involved regions in deletions. These regions provide a good basis for further molecular analyses and may highlight chromosomal locations of tumour suppressor genes that could be important in the tumorigenesis of malignant mesothelioma.

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Section: Discussionmentioning

confidence: 60%

Deletions at 14q in malignant mesothelioma detected by microsatellite marker analysis

Wolf

Nordling

et al. 1999

Br J Cancer

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“…Receptor-interacting serine-threonine kinase (RIPK) 3, which is part of the same family as RIPK1, which contains a death domain, has never been reported to be hypermethylated in any cancers before our report. Interestingly, the locations of HIC1, RIPK3, FABP3, and PRKCDBP were reported to lose heterozygosity in lung cancer (Konishi et al 1998;Abujiang et al 1998;Chizhikov et al 2001;Petersen et al 1997).…”

Section: Resultsmentioning

confidence: 99%

Microarray analysis of promoter methylation in lung cancers

et al. 2006

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Aberrant DNA methylation is an important event in carcinogenesis. Of the various regions of a gene that can be methylated in cancers, the promoter is the most important for the regulation of gene expression. Here, we describe a microarray analysis of DNA methylation in the promoter regions of genes using a newly developed promoter-associated methylated DNA amplification DNA chip (PMAD). For each sample, methylated Hpa II-resistant DNA fragments and Msp Icleaved (unmethylated + methylated) DNA fragments were amplified and labeled with Cy3 and Cy5 respectively, then hybridized to a microarray containing the promoters of 288 cancer-related genes. Signals from Hpa II-resistant (methylated) DNA (Cy3) were normalized to signals from Msp I-cleaved (unmethylated + methylated) DNA fragments (Cy5). Normalized signals from lung cancer cell lines were compared to signals from normal lung cells. About 10.9% of the cancer-related genes were hypermethylated in lung cancer cell lines. Notably, HIC1, IRF7, ASC, RIPK3, RASSF1A, FABP3, PRKCDBP, and PAX3 genes were hypermethylated in most lung cancer cell lines examined. The expression profiles of these genes correlated to the methylation profiles of the genes, indicating that the microarray analysis of DNA methylation in the promoter region of the genes is convenient for epigenetic study. Further analysis of primary tumors indicated that the frequency of hypermethylation was high for ASC (82%) and PAX3 (86%) in all tumor types, and high for RIPK3 in small cell carcinoma (57%). This demonstrates that our PMAD method is effective at finding epigenetic changes during cancer.

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“…The reported 14q deletion in lung non-small cell carcinoma occurred only in 4% of cases (21), which is much less frequent than 50% in the present study. However, much more frequent LOH at shorter portions in 14q have been reported (40,41), although LOH of 14q32 has not been examined for lung carcinoma. LOH of 14q32 was found in 32-44% of colorectal cancers (22,42), and is associated with metastatic recurrence (42).…”

Section: Discussionmentioning

confidence: 99%

Activation of ERK/IER3/PP2A-B56γ-positive feedback loop in lung adenocarcinoma by allelic deletion of B56γ gene

et al. 2016

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Abstract. In order to investigate the involvement of the IER3/ PP2A-B56γ/ERK-positive feedback loop, which leads to sustained phosphorylation/activation of ERK in carcinogenesis, we immunohistochemically examined the expression of IER3 and phosphorylated ERK in lung tumor tissues. IER3 was overexpressed in all cases of adenocarcinomas examined, but was not overexpressed in squamous cell carcinomas. Phosphorylated ERK (pERK) was also overexpressed in almost all adenocarcinomas. EGFR and RAS, whose gene product is located upstream of ERK, were sequenced. Activating mutation of EGFR, which is a possible cause of overexpression of IER3 and pERK, was found only in 5 adenocarcinomas (42%). No mutation of RAS was found. We further examined the sequences of all exons of B56γ gene (PPP2R5C) and IER3, but no mutation was found. Using a single nucleotide insertion in intron 1 of PPP2R5C, which was found in the process of sequencing, allelic deletion of PPP2R5C was examined. Eight cases were informative (67%), and the deletion was found in 4 of them (50%). Three cases having deletion of PPP2R5C did not have EGFR mutation. Finally, PPP2R5C deletion or EGFR mutation that could be responsible for IER3/pERK overexpression was found in at least 8 cases (67% or more). This is the first report of a high incidence of deletion of PPP2R5C in human carcinomas. IntroductionIER3 (immediate early response gene 3) was first identified in fibroblasts from mouse in 1993 (1), and human IER3, formerly referred to as the immediate early gene X-1 (IEX-1), was first identified in human squamous cell carcinomas. The human IER3 gene is located on the short arm of chromosome 6 (6p21.3) and has 2 exons. The gene encodes 156 amino acids (2). IER3 protein is rapidly and transiently induced by a variety of stimuli, including ionizing radiation, inflammatory cytokines, viral infection, anti-cancer drugs and growth factors (2,3), and is associated with apoptosis and cell proliferation (3,4). As it is involved in cell growth, IER3 expression has been examined in several human tumors, including pancreatic carcinoma, ovarian carcinoma, breast cancer, and myelodysplastic syndrome (5-8). However, there has been no study of IER3 expression in human lung carcinoma.Protein phosphatase 2A (PP2A), which consists of structural subunit A, regulatory subunits B, and catalytic subunit C, has a broad spectrum of functions due to the variety of regulatory subunits, of which there are more than 20 kinds (9). PP2A can act as a tumor suppressor (10,11). B56 regulatory subunits are involved in cell proliferation signaling (11,12). Among them, PP2A-B56γ1 dephosphorylates Thr 202 of phosphorylated extracellular signal-regulated kinase (pERK), leading to inactivation of ERK (13). Furthermore, Garcia et al (14) found that the regulation of cell growth by IER3 is mediated by ERK, which also plays a central role in regulation of a variety of cellular events, including cell proliferation, differentiation, migration, and apoptosis (15,16). IER3 regulates ERK activity through its i...

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Loss of heterozygosity (LOH) at 17q and 14q in human lung cancers

Cited by 46 publications

References 6 publications

Deletions at 14q in malignant mesothelioma detected by microsatellite marker analysis

Deletions at 14q in malignant mesothelioma detected by microsatellite marker analysis

Microarray analysis of promoter methylation in lung cancers

Activation of ERK/IER3/PP2A-B56γ-positive feedback loop in lung adenocarcinoma by allelic deletion of B56γ gene

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