The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma.
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 progression-free survival (P<0.02) and poor overall survival (P<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 (P<0.01) and overall survival rate of 18% with a median of 8 months (P<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.
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Aatur D
AD
Singhi
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Alyssa M
AM
Krasinskas
Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Haroon A
HA
Choudry
Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
David L
DL
Bartlett
Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
James F
JF
Pingpank
Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Herbert J
HJ
Zeh
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Alyssa
A
Luvison
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Kimberly
K
Fuhrer
Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Nathan
N
Bahary
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Raja R
RR
Seethala
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Sanja
S
Dacic
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D016518:Neurofibromatosis 2 / Q000378:metabolism*; D010534:Peritoneal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D055815:Young Adult
C400134:BAP1 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase