Molecular cytogenetic differences between histological subtypes of malignant mesotheliomas: DNA cytometry and comparative genomic hybridization of 90 cases

Krismann, M.; Müller, Klaus‐Michael; Jaworska, Małgorzata; Johnen, Georg

doi:10.1002/path.1128

Cited by 64 publications

(61 citation statements)

References 22 publications

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“…1A) as previously reported (7)(8)(9)35). The homozygous deletions of 9p21 were detected in all MM samples, and the allele losses of 22q were frequently found in all histological types of cells.…”

Section: Discussionsupporting

confidence: 80%

“…Five purchased MM cell lines were also analyzed to compare with our primary cell cultures. Many molecular cytogenetic studies using karyotyping, CGH and array-based CGH have been performed and they show that the 1p, 3p21, 9p21 and 22q regions are frequently lost in MM (7)(8)(9). Chromosome 9p21 and 22q carry the tumor suppressor genes CDKN2A (cyclindependent kinase inhibitor 2A) and NF2 (neurofibromin 2), respectively, and there are many functional analyses of these genes (10)(11)(12)(13).…”

Section: Frequent Deletion Of 3p211 Region Carrying Semaphorin 3g Anmentioning

confidence: 99%

“…From data for deletions of the 3p21.31 region during early stages of the formation of lung, breast, kidney and other cancers, several candidates of tumor suppressor genes such as SEMA3F (semaphorin 3F) and 3B, RASSF1A [Ras association (RalGDS/AF-6) domain family member 1], HYAL1 (hyaluronoglucosaminidase 1) and TUSC2 (tumor suppressor candidate 2) have been proposed (14)(15)(16). The significance of the 3p21.31 deletion in MM has been under investigation and loss of the same genes that are lost in other cancers may be associated in the oncogenesis of MM (8,9,17). In this report we found a novel homozygous deletion region at 3p21.1 in the epithelioid type of MMs, and this region contained seven genes including SEMA3G.…”

Section: Frequent Deletion Of 3p211 Region Carrying Semaphorin 3g Anmentioning

confidence: 99%

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Frequent deletion of 3p21.1 region carrying semaphorin 3G and aberrant expression of the genes participating in semaphorin signaling in the epithelioid type of malignant mesothelioma cells

Yoshikawa

Sato²,

Tsujimura

et al. 2011

Int J Oncol

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Abstract. Array-based comparative genomic hybridization analysis was performed on 21 malignant mesothelioma (MM) samples (16 primary cell cultures and 5 cell lines) and two reactive mesothelial hyperplasia (RM) primary cell cultures. The RM samples did not have any genomic losses or gains. In MM samples, deletions in 1p, 3p21, 4q, 9p21, 16p13 and 22q were detected frequently. We focused on 3p21 because this deletion was specific to the epithelioid type. Especially, a deletion in 3p21.1 region carrying seven genes including SEMA3G was found in 52% of MM samples (11 of 14 epithelioid samples). The allele loss of 3p21.1 might be a good marker for the epithelioid MM. A homozygous deletion in this region was detected in two MM primary cell cultures. A heterozygous deletion detected in nine samples contained the 3p21.1 region and 3p21.31 one carrying the candidate tumor suppressor genes such as semaphorin 3F (SEMA3F), SEMA3B and Ras association (RalGDS/AF-6) domain family member 1 (RASSF1A). SEMA3B, 3F and 3G are class 3 semaphorins and inhibit growth by competing with vascular endothelial growth factor (VEGF) through binding to neuropilin. All MM samples downregulated the expression of more than one gene for SEMA3B, 3F and 3G when compared with Met5a, a normal pleura-derived cell line. Moreover, in 12 of 14 epithelioid MM samples the expression level of SEMA3A was lower than that in Met5a and the two RM samples. An augmented expression of VEGFA was detected in half of the MM samples. The expression ratio of VEGFA/SEMA3A was significantly higher in the epithelioid MMs than in Met5a, RMs and the non-epithelioid MMs. Our data suggest that the downregulated expression of SEMA3A and several SEMA3s results in a loss of inhibitory activities in tumor angiogenesis and tumor growth of VEGFA; therefore, it may play an important role on the pathogenesis of the epithelioid type of MM.

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Section: Discussionsupporting

confidence: 80%

Section: Frequent Deletion Of 3p211 Region Carrying Semaphorin 3g Anmentioning

confidence: 99%

Section: Frequent Deletion Of 3p211 Region Carrying Semaphorin 3g Anmentioning

confidence: 99%

See 1 more Smart Citation

Frequent deletion of 3p21.1 region carrying semaphorin 3G and aberrant expression of the genes participating in semaphorin signaling in the epithelioid type of malignant mesothelioma cells

Yoshikawa

Sato²,

Tsujimura

et al. 2011

Int J Oncol

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“…A comparative genomic hybridization (CGH) technique has recently been introduced to search for additional genes that are potentially involved in MM biology. New alteration regions have been identified, including 1q, 4q, 5p, 6p, 7p, 8p, 8q, 10p13-pter, 13q, 14q, 15q, 17p12-pter, 17q, and 20, in which new cancer-associated genes of MM may be harbored [27,28]. A recent study of array-based CGH analysis with MMs from a total of 22 individuals identified high-copy gain at 1p32, which includes the JUN protooncogene [12].…”

Section: Searching For New Key Genes In Malignant Mesotheliomamentioning

confidence: 99%

Molecular biology of malignant mesothelioma

Sekido

2008

Environ Health Prev Med

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Human malignancies develop via a multi-step that involves the accumulation of several key gene alterations with associated genetic and epigenetic events. Although malignant mesothelioma (MM) has been demonstrated to be clearly correlated with asbestos exposure, it remains poorly understood how asbestos fibers confer key gene alterations and induce cellular transformation in normal mesothelial cells, which results in the acquisition of malignant phenotypes, including deregulated cell proliferation and invasion. Malignant mesothelioma presents with the frequent inactivation of tumor suppressor genes of p16 INK4a /p14 ARF on chromosome 9p21 and neurofibromatosis type 2 (NF2) on chromosome 22q12, with the latter being responsible for the NF2 familial cancer syndrome. In contrast, MM shows infrequent mutation of the p53 gene, which is one of the most frequently mutated tumor suppressor genes in human malignancies. Genetic abnormalities of oncogenes have also been studied in MM, but no frequent mutations have been identified, including the epidermal growth factor receptor (EGFR) and K-RAS genes. Recent studies have suggested the activation of other receptor tyrosine kinases, including Met, and the deregulations of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)-AKT signaling cascades, although the alterations responsible for their activation are still not clear. Thus, further genome-wide studies of genetic and epigenetic alterations as well as detailed analyses of deregulated signaling cascades in MM are necessary to determine the molecular mechanisms of MM, which would also provide some clues for establishing a new molecular target therapy for MM.

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“…Many studies have been conducted to determine the key underlying genetic and epigenetic events responsible for the development of MM. Karyotyping, allele typing and comparative genomic hybridization analysis have demonstrated that most cases of MM have multiple chromosomal alterations, which include chromosome 9p21 and 22q (7)(8)(9)(10)(11)(12)(13)(14). Inactivation of the p16 INK4a /p14 ARF locus at the 9p21 locus is found in over 70% of MM samples (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Activation of the PI3K-AKT pathway in human malignant mesothelioma cells

Suzuki

Murakami²,

Kawaguchi³

et al. 2009

Mol Med Rep

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Abstract. Malignant mesothelioma (MM) is a highly aggressive neoplasm, which is associated with asbestos exposure. The dysregulated phosphatidylinositol 3-kinase (PI3K)-AKT pathway plays an important role in cell proliferation, survival and motility in various cancers. In this study, we analyzed the activation status and underlying mechanisms of this pathway in MM cells using 21 cell lines. AKT activation was observed in 13 (62%) of the 21 MM cell lines under serum-starved conditions. Two cell lines, ACC-MESO-1 and Y-MESO-25, showed no expression of PTEN protein, while 7 other cell lines showed low expression of PTEN mRNA and protein compared to expression levels in an immortalized normal mesothelial cell line, MeT-5A. We found that PTEN inactivation in the ACC-MESO-1 and Y-MESO-25 lines was due to a 39.4-kb deletion including PTEN exon 2, and to a 7.7-kb deletion including exon 1, respectively. Re-expression of PTEN in these cells reduced the activity of colony formation in vitro. In contrast, no mutation of PIK3CA or LKB1 was found in any of the MM cell lines. These findings suggest that AKT is frequently activated in MM cells, in part due to the downregulation of PTEN. Thus, the PI3K-AKT signaling pathway is a potential therapeutic target for MM.

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Molecular cytogenetic differences between histological subtypes of malignant mesotheliomas: DNA cytometry and comparative genomic hybridization of 90 cases

Cited by 64 publications

References 22 publications

Frequent deletion of 3p21.1 region carrying semaphorin 3G and aberrant expression of the genes participating in semaphorin signaling in the epithelioid type of malignant mesothelioma cells

Frequent deletion of 3p21.1 region carrying semaphorin 3G and aberrant expression of the genes participating in semaphorin signaling in the epithelioid type of malignant mesothelioma cells

Molecular biology of malignant mesothelioma

Activation of the PI3K-AKT pathway in human malignant mesothelioma cells

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