Frequent p16 inactivation by homozygous deletion or methylation is associated with a poor prognosis in Japanese patients with pleural mesothelioma

Kobayashi, Naruyuki; Toyooka, Shinichi; Yanai, Hiroyuki; Soh, Junichi; Fujimoto, Nobukazu; Yamamoto, Hiromasa; Ichihara, Shuji; Kimura, Kentaro; Ichimura, Kouichi; Sano, Yoshifumi; Kishimoto, Takumi; Date, Hiroshi

doi:10.1016/j.lungcan.2008.02.013

Cited by 50 publications

(40 citation statements)

References 25 publications

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“…Similar to our findings, a recent study of pleural mesotheliomas showed that all 21 cases with CDKN2A deletion had loss of p16 expression by IHC, and that two of the three cases with p16 loss without deletion showed CDKN2A gene methylation. 25 This and other studies have shown that, at least in a small percentage of pleural mesotheliomas (11-21%), the CDKN2A gene is inactivated by methylation. [24][25][26] Although we did not test for aberrant methylation of the CDKN2A gene, a similar percentage of our peritoneal mesothelioma cases (19%) showed loss of p16 expression without loss of the CDKN2A gene.…”

Section: Am Krasinskas Et Almentioning

confidence: 70%

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CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival

et al. 2010

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Homozygous deletion of CDKN2A (p16) is one of the most common genetic alterations in pleural mesotheliomas, occurring in up to 74% of cases. MTAP resides in the same gene cluster of the 9p21 region and is co-deleted in the majority of CDKN2A deleted cases. This study examines the genetic alterations in peritoneal mesotheliomas, which may have a different pathogenesis than their pleural counterparts. Twenty-six cases of peritoneal mesotheliomas in a triplicate tissue microarray were studied. Dual-color fluorescence in situ hybridization was performed with CDKN2A and MTAP locus-specific probes. Nine of 26 (35%) peritoneal mesotheliomas had homozygous deletion of CDKN2A; MTAP was co-deleted in every case. All cases with CDKN2A deletions had loss of p16 protein expression; five cases had loss of p16 protein without evidence of CDKN2A deletions. All patients with CDKN2A deletions were men (P, NS) and were significantly older (mean, 63 years) than the patients with no deletions (mean, 52 years) (P ¼ 0.033, t-test). An association with asbestos exposure could not be proved in this study. Similar to pleural mesotheliomas, patients with CDKN2A deletions and loss of p16 protein expression had worse overall and disease-specific survival (P ¼ 0.010 and 0.006, respectively; Kaplan-Meier log rank). Detection of CDKN2A-MTAP co-deletion in peritoneal mesotheliomas, coupled with a p16 immunohistochemical stain as an inexpensive screening tool, can help identify those patients who may have an unfavorable outcome after aggressive cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy and those who may respond to targeted therapy of the MTAP pathway.

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Section: Am Krasinskas Et Almentioning

confidence: 70%

“…23 In pleural mesotheliomas, loss of p16 protein expression is typically associated with CDKN2A deletion, but a subset of cases showed loss of p16 due to inactivation of the gene by methylation. [24][25][26] The correlation between CDKN2A deletion, loss of p16 protein expression and survival has not been made in peritoneal mesotheliomas.…”

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confidence: 99%

CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival

et al. 2010

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“…[21][22][23] In addition, homozygous CDKN2A deletions are a poor prognostic indicator for patients with pleural mesothelioma. 22,24,25 NF2, located on chromosome 22q12, is mutated in 50% of pleural mesotheliomas with corresponding loss of the wild-type allele by deletion of either 22q or all of chromosome 22. 16,26 Hemizygous loss of NF2 is associated with increased mesothelioma proliferation, invasiveness, spreading, and migration.…”

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The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma

et al. 2016

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Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion for patients with malignant peritoneal mesothelioma has resulted in improved disease control and increased survival. Despite these results, there are significant perioperative risks associated with this aggressive procedure that necessitate consideration of prognostic markers during patient selection. The molecular pathogenesis of peritoneal mesothelioma remains relatively unknown, but extrapolation of findings from their pleural counterpart would suggest frequent alterations in CDKN2A, NF2, and BAP1. Homozygous deletions in CDKN2A portend a worse overall survival in peritoneal mesothelioma. However, the prevalence and prognostic significance of NF2 and BAP1 abnormalities has not been studied. Dual-color fluorescence in situ hybridization using CDKN2A and NF2 locus-specific probes and BAP1 immunohistochemistry identified homozygous CDKN2A deletions (n = 25, 29%), hemizygous NF2 loss (n = 30, 35%), and/or loss of BAP1 protein expression (n = 49, 57%) in 68 of 86 (79%) peritoneal mesotheliomas. Homozygous CDKN2A deletions or hemizygous NF2 loss correlated with shorter progressionfree survival (Po 0.02) and poor overall survival (Po 0.03). Moreover, the significance of these findings was cumulative. Patients harboring both homozygous CDKN2A deletions and hemizygous NF2 loss had a 2-year progression-free survival rate of 9% with a median of 6 months (Po 0.01) and overall survival rate of 18% with a median of 8 months (Po 0.01). By multivariate analysis, combined homozygous CDKN2A deletions and hemizygous NF2 loss was a negative prognostic factor for both progression-free survival and overall survival, independent of patient age, peritoneal cancer index, completeness of cytoreduction, and extent of invasion. In contrast, loss of BAP1 was not associated with clinical outcome. In summary, homozygous deletions in CDKN2A and hemizygous loss of NF2 as detected by fluorescence in situ hybridization would confer a poor clinical outcome and may guide future treatment decisions for patients with peritoneal mesothelioma.

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“…Among the examined molecules, the P16 INK4a gene, which is located at chromosome 9p21, is frequently deleted in MPM, and it has been demonstrated that its deletion results in the dysregulation of cell-cycle control through the Rb pathway and malignant transformation (18,19). In addition, the present authors have previously reported that DNA methylation of P16 is another mechanism that leads to the loss of p16 expression (7). In the present study, P16 deletion was observed in YUMC44 and YUMC64 cells, and P16 was methylated completely in YUMC8, YUMC44, and YUMC64 cells and partially in YUMC63 cells.…”

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confidence: 71%

“…In the current study, 4 MPM cell lines were established from Japanese patients and the methylation status, presence of mutations, copy number and protein expression of representative genes, including NF2, P16, and RASSF1A, which have Establishment and molecular characterization of cell lines from Japanese patients with malignant pleural mesothelioma KEN been reported to be frequently altered in MPM, were characterized (5)(6)(7). In addition, the status of the microRNA (miR) 34 family, which we have previously reported to be important in the pathogenesis of MPM, were analyzed (8).…”

Section: Introductionmentioning

confidence: 99%

Establishment and molecular characterization of cell lines from Japanese patients with malignant pleural mesothelioma

et al. 2015

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Abstract. Malignant pleural mesothelioma (MPM) is an aggressive disease that is resistant to conventional therapies. Cell lines are useful models for studying the biological characteristics of tumors; therefore, the establishment of MPM cell lines is valuable for exploring novel therapeutic strategies for MPM. In the present study, 4 MPM cell lines (YUMC8, YUMC44, YUMC63, and YUMC64) were established, which consisted of 2 epithelioid and 2 sarcomatoid mesothelioma histological subtypes, from Japanese patients with MPM. The DNA methylation status, mutations, copy number gains, protein expression of representative genes, and the sensitivity to several drugs were examined in these 4 cell lines. Methylation of P16 was demonstrated in 3/4 cell lines, in which the protein expression of p16 was lost. Methylation of RASSF1A was observed in 3/4 cell lines. Copy number gains of EGFR, HER2 or MET were not detected in the 4 cell lines. Mutations in various genes, including EGFR, KRAS, HER2, BRAF, and PIK3CA, which are frequently detected in non-small cell lung cancer, were not detected in the 4 cell lines. microRNA-34b/c is a direct transcriptional target of p53 and is often silenced in MPM by promoter methylation. In the present study, miR-34b/c was heavily methylated in 2/4 established MPM cell lines. For cell adhesion molecules, E-cadherin expression was detected in the 2 epithelioid MPM cell lines, whereas N-cadherin expression was detected in all 4 established cell lines by western blotting. Vimentin was strongly expressed in the 2 sarcomatoid MPM cell lines. None of the established MPM cell lines demonstrated significant responses to the drugs tested, including NVP-AUY922, 17-DMAG, Trichostatin A, and Vorinostat. Although novel molecular findings were not observed in the current characterization of these MPM cell lines, these lines will be useful for future extensive analyses of the biological behavior of MPM and the development of novel therapeutic strategies. IntroductionMalignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis, arising from mesothelial cells in the pleural cavity (1). Exposure to asbestos is closely associated with the development of MPM (2). MPM is historically a rare disease; however, the incidence of MPM is predicted to increase due to the use of asbestos worldwide and the long latency period for the development of MPM following exposure (3). Multimodality therapy that is centered on surgical resection is indicated for the treatment of MPM in the early stage (4). However, MPM is often diagnosed at an advanced stage, and it is known to be refractory to conventional therapies, such as surgery, chemotherapy, and radiotherapy (1). Therefore, novel strategies for the diagnosis and treatment of MPM are needed. However, much less information is available for MPM compared with other solid neoplasms. Thus, it is of great importance to investigate the biological behaviors of MPM.In the current study, 4 MPM cell lines were established from Japanese patients and the methylation statu...

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Frequent p16 inactivation by homozygous deletion or methylation is associated with a poor prognosis in Japanese patients with pleural mesothelioma

Cited by 50 publications

References 25 publications

CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival

CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival

The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma

Establishment and molecular characterization of cell lines from Japanese patients with malignant pleural mesothelioma

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