Prognostic significance of p16/cdkn2a loss in pleural malignant mesotheliomas

Abstract

Homozygous deletion of p16/CDKN2A is the most common genetic abnormality in malignant mesotheliomas. The aim of this study was to determine prognostic significance of p16/CDKN2A loss in malignant pleural mesotheliomas (MPM) as defined by immunohistochemistry and fluorescence in situ hybridization (FISH). High-density tissue microarrays were constructed from archival formalin-fixed paraffin-embedded samples of 48 MPM. Long survival (LS) was defined as survival greater than 3 years from the time of diagnosis, and short survival was defined as less than 3 years from the time of diagnosis. Both loss of p16 protein expression by immunohistochemistry and homozygous deletion of p16 by FISH were associated with adverse prognosis. Female gender, positive p16 immunoexpression, and lack of p16/CDKN2A deletion significantly predicted the survival for the LS group. Statistical analysis showed a very strong correlation of immunohistochemistry and FISH data. Cases positive for p16 immunoexpression and negative for 9p21 deletion showed the best survival time. Our study is the first to demonstrate decreased frequency of homozygous deletion of 9p21 and loss of p16 immunoreactivity in pleural mesotheliomas from patients with long-term survival of greater than 3 years in contrast to patients with rapidly fatal mesotheliomas. A possible implementation of these tests into preoperative prognostication of MPM and therapeutic decisions should be considered.

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

“…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). Staining of tissue microarrays and whole sections were performed as previously described using 4-μm unstained paraffin sections.…”

“…Staining of tissue microarrays and whole sections were performed as previously described using 4-μm unstained paraffin sections. 22,23 Each core on the tissue microarrays was identified and only individual and well-delineated cells were scored; overlapping cells were excluded from the analysis. For both tissue microarrays and whole sections, at least 60 cells were scored for each case and control.…”

“…Each tumor was assessed by the average and the maximum numbers of copies of the either CDKN2A or NF2 per cell and the average ratio of the gene to CEP9 and CEP22q copy numbers, respectively. 22,23,35 Immunohistochemistry Immunohistochemical labeling was performed on 4-μm unstained paraffin sections for both the tissue microarrays and whole sections. Slides were deparaffinized with serial xylene treatments and subjected to antigen retrieval using heated citrate solution (pH 9.0) at 100 o C for 10 min.…”

“…Homozygous deletions in CDKN2A are the most frequent genetic alteration in pleural mesothelioma with a reported deletion rate ranging from 60 to 74% by fluorescence in situ hybridization. [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.…”

“…[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.…”