PUB051 Comprehensive Analysis of Chromosomal Alterations Involving CDKN2A and 22q in Malignant Pleural Mesothelioma

Abstract

The promise of personalized genomic medicine relies on the identification and clinical management of patients on the basis of specific genomic alterations that drive clinically heterogenous malignancies. While recent large cohort studies of malignant pleural mesothelioma (MPM) tumors have confirmed that CDKN2A and NF2 are among the most commonly mutated genes, the clinical and biological significance of these molecular alterations remains incompletely characterized. Herein, we explore whether loss of CDKN2A and/or 22q define molecular subclasses in a large cohort of MPM patients. FISH analysis was performed using the Vysis LSI9p21/CEP9 Dual Color Probe Set (Abbott Molecular, Des Plaines, IL) for the p16 locus at 9p21, CEP9 at the chromosome 9 centromeric region, and Vysis TUPLEI/LSI ARSA Dual color Probe set (Abbott) for TUPLEI at 22q11.2, and ARSA at 22q13. At least 50 nuclei were observed per tumor. Aberrations observed in ≥ 2% of nuclei was considered abnormal, based on normal mesothelial cell controls. Loss of CDKN2A or 22q was explored in relation to demographic, pathological and clinical factors using Fisher’s exact test. Overall survival (OS) was estimated using the Kaplan–Meier method and compared between groups using the logrank test. CDKN2A and 22q FISH data along with patient’s clinical information were collected from 592 MPM patients. Loss of CDKN2A was detected in 329 (56%), and of 22q in 326 (55%) patients. CDKN2A loss was significantly more common among men (p=0.0027) compared to women, and among men older than 60 compared to younger men (p = 0.0005). Loss of CDKN2A was also significantly correlated with self-reported asbestos exposure (p=0.0419), preoperative anemia (p=0.0007), and epitheliod tumor histology (p<0.0001). Loss of 22q was unrelated to most clinical factors explored, being only marginally associated with N2-N3 lymph node status compared to N0-N1 (p=0.0429). Survival analysis showed that patients with CDKN2A loss, with (n=228) or without (n=101) concurrent loss of 22q, demonstrated reduced OS compared to patients with either wild-type copy number of both markers (n=165; p<0.0001) or loss of 22q only (n=98; p < 0.0001). This study demonstrates a previously unappreciated relationship between demographic, clinical, pathological and outcome characteristics of MPM in association with CDKN2A versus 22q loss. The pattern of alteration involving these chromosomal regions may, therefore, suggest the possibility of distinct molecular subgroups. Further analyses are needed to demonstrate its potential role in precision medicine.