Mutational analysis of N-ras, p53, p16INK4a, p14ARF and CDK4 genes in primary human malignant mesotheliomas

Papp, Thilo; Schipper, Holger; Pemsel, Heidi; Bastrop, Ralf; Müller, Klaus‐Michael; Wiethege, Thorsten; Weiss, Dieter G.; Dopp, Elke; Schiffmann, Dietmar; Rahman, Qamar

doi:10.3892/ijo.18.2.425

Cited by 37 publications

(35 citation statements)

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“…In addition, in this tumor type, an association between the mutant p53 gene and the ALT mechanism was recently reported, suggesting that p53 gene deficiency plays a permissive role in the activation of ALT (45). In this context, it is worthy of note that p53 mutations are rarely seen in mesothelioma (46). In contrast, there was no significant difference in survival between ALT+ and ALT-osteosarcoma patients (16,17).…”

Section: Discussionmentioning

confidence: 77%

Multiple Mechanisms of Telomere Maintenance Exist and Differentially Affect Clinical Outcome in Diffuse Malignant Peritoneal Mesothelioma

Villa¹,

Daidone²,

Motta³

et al. 2008

Clinical Cancer Research

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Purpose: This study aims to investigate the prevalence of the two known telomere maintenance mechanisms, telomerase activity (TA) and alternative lengthening of telomeres (ALT), and to assess their prognostic relevance in diffuse malignant peritoneal mesothelioma (DMPM). Experimental Design: In 44 DMPM specimens obtained from 38 patients, TA was determined using the telomeric repeat amplification protocol and ALT was detected by assaying ALT-associated promyelocytic leukemia nuclear bodies. The prognostic significance of telomere maintenance mechanisms was analyzed by Cox regression in the overall series and in a subset of 29 patients who underwent a uniform treatment regimen consisting of cytoreductive surgery and hyperthermic i.p. chemotherapy. Results: Telomere maintenance mechanisms were detectable in 86.4% of DMPM: ALT or TA alone was found in 18.2% or 63.6% of lesions, respectively, whereas two cases (4.6%) were ALT+/TA+. TA and ALT proved to be inversely associated (P = 0.002). In the overall series, TA was prognostic for 4-year relapse (TA+ versus TA-, hazard ratio, 3.30; 95% confidence interval, 1.23-8.86; P = 0.018) and cancer-related death (TA+ versusTA-, hazard ratio, 3.56; 95% confidence interval, 1.03-12.51; P = 0.045), whereas ALT failed to significantly affect clinical outcome. These results held true also in the subset of patients submitted to uniform treatment with cytoreductive surgery and hyperthermic i.p. chemotherapy. Conclusions: Our results indicate that both known telomere maintenance mechanisms,TA and ALT, are present in DMPM and differentially affect patient prognosis.

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Section: Discussionmentioning

confidence: 77%

Multiple Mechanisms of Telomere Maintenance Exist and Differentially Affect Clinical Outcome in Diffuse Malignant Peritoneal Mesothelioma

Villa¹,

Daidone²,

Motta³

et al. 2008

Clinical Cancer Research

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“…The minimal common region at 22q, 22cen ] q12.3, contains the NF2 gene, the inactivation or loss of which has been shown to be a central event in MM, relating to its invasiveness (Pylkkanen et al, 2002;Schipper et al, 2003;Xiao et al, 2005;Poulikakos et al, 2006). The malignant transformation of mesothelial cells can be considered to depend on the inactivation of multiple tumor suppressor genes (Papp et al, 2001;Illei et al, 2003;Pylkkanen et al, 2004), of which CDKN1A , CDKN1B, FHIT, RASSF1A, CDKN2A , CDKN2B , and NF2 can be pinpointed as important (reviewed in Spugnini et al, 2006). This study showed a recurrent pattern of copy number changes, where losses predominated over gains, and furthermore suggests some regions to be important for further investigation.…”

Section: Resultsmentioning

confidence: 99%

Gene copy number analysis in malignant pleural mesothelioma using oligonucleotide array CGH

Lindholm

Salmenkivi

Vauhkonen

et al. 2007

Cytogenet Genome Res

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Conventional cytogenetic analyses and comparative genomic hybridization have revealed a complex and even chaotic nature of chromosomal aberrations in pleural malignant mesothelioma (MM). We set out to describe the complex gene copy number changes and screen for novel genetic aberrations using a high-density oligonucleotide microarray platform for comparative genomic hybridization (aCGH) of a series of 26 well-characterized MM tumor samples. The number of copy number changes varied from zero to 40 per sample. Gene copy number losses predominated over gains, and the most frequent region of loss was 9p21.3 (17/26 cases), the locus of CDKN2A and CDKN2B, both known to be commonly lost in MM. The most recurrent minimal regions of losses were 1p31.1→ p13.2, 3p22.1→p14.2, 6q22.1, 9p21.3, 13cen→q14.12, 14q22.1→qter, and 22qcen→q12.3. Previously unreported gains included 9p13.3, 7p22.3→p22.2, 12q13.3, and 17q21.32→qter. The results suggest that gene copy number losses are a major mechanism of MM carcinogenesis and reveal a recurrent pattern of copy number changes in MM.

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“…However, more recent analyses utilizing novel technologies have reported that N-RAS mutations are frequent events even in some nevi and early-stage melanomas. More specifically, Papp et al (1999) reported that 56% of congenital nevi harbored activating N-RAS point mutations. Bastian et al (2000) in a study of Spitz nevi found H-RAS copy number increases on chromosome 11p, which were highly associated with oncogenic point mutations of H-RAS alleles.…”

Section: Rasmentioning

confidence: 99%

Oncogenes in melanoma

2003

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Transformation of normal melanocytes into melanoma cells is accomplished by the activation of growth stimulatory pathways, typically leading to cellular proliferation, and the inactivation of apoptotic and tumor suppressor pathways. Small molecule inhibitors of proteins in the growth stimulatory pathways are under active investigation, and their application to melanoma patients would represent a new treatement strategy to inhibit cell proliferation or induce cell death. We provide a general overview of the mechanisms of oncogene activation and the functions of oncogenes. Lastly, we review oncogenic events in melanoma.

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Mutational analysis of N-ras, p53, p16INK4a, p14ARF and CDK4 genes in primary human malignant mesotheliomas

Cited by 37 publications

References 0 publications

Multiple Mechanisms of Telomere Maintenance Exist and Differentially Affect Clinical Outcome in Diffuse Malignant Peritoneal Mesothelioma

Multiple Mechanisms of Telomere Maintenance Exist and Differentially Affect Clinical Outcome in Diffuse Malignant Peritoneal Mesothelioma

Gene copy number analysis in malignant pleural mesothelioma using oligonucleotide array CGH

Oncogenes in melanoma

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