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

Abstract

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.

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

“…40,41 Despite the differences between peritoneal and pleural mesotheliomas, previous studies have demonstrated homozygous CDKN2A deletions in malignant mesothelioma are a poor prognostic indicator regardless of site. 22,25,32 Consistent with these reports, we found that patients with peritoneal mesothelioma harboring a homozygous CDKN2A deletion had decreased PFS and OS. In addition, patients with a hemizygous NF2 loss also exhibited poor PFS and OS.…”

“…However, the prevalence of homozygous CDKN2A deletions and hemizygous NF2 loss in peritoneal mesotheliomas is less than those reported for pleural mesotheliomas. 16,[21][22][23]26,32 In addition, the most frequent abnormality in peritoneal mesotheliomas was the loss of BAP1 protein expression rather than homozygous CDKN2A deletions. An explanation for the disparities between peritoneal and pleural mesotheliomas remains elusive, but not surprising as both entities are clinically and pathologically distinct.…”

“…22,23,32 CDKN2A was assessed using a Spectrum-Orange labeled, locus-specific probe (Abbott Molecular, Des Plains, IL, USA) with a Spectrum Green-labeled chromosome 9 centromeric (CEP9) probe. 22 Probes for NF2 assessment included a FITC-labeled chromosome 22 centromeric (CEP22q) probe and a Texas Red-labeled, locusspecific NF2 probe (Abnova, Walnut, CA, USA).…”

“…30,31 Analogous to pleural mesotheliomas, homozygous CDKN2A deletions are also present in peritoneal mesotheliomas and confer an unfavorable outcome after CRS and HIPEC. 32 However, the prevalence and prognostic significance of NF2 and BAP1 alterations in peritoneal mesotheliomas remains relatively unknown. We, therefore, evaluated the status of CDKN2A, NF2, and BAP1 within a large cohort of peritoneal mesotheliomas.…”

Guidelines for Pathologic Diagnosis of Malignant Mesothelioma: 2012 Update of the Consensus Statement from the International Mesothelioma Interest Group

“…It has been demonstrated that the presence of p16 homozygous deletion correlates with a shorter survival in patients with malignant mesotheliomas. 85,90,91 There is also a correlation between p16 protein loss, as demonstrated by immunohistochemistry, and a poor prognosis with increased risk of death in peritoneal mesothelioma, but the association is not as strong. 55,90 There are no molecular markers to help distinguish malignant mesotheliomas from carcinomas or sarcomas on formalin-fixed, paraffin embedded tissue.…”