title: Elevated PDGFRB gene copy number gain is prognostic for improved survival outcomes in resected malignant pleural mesothelioma.
abstract: PDGF/PDGFR pathway has been implicated in malignant pleural mesothelioma (MPM) carcinogenesis, and evidence suggests autocrine mechanisms of proliferation. We sought to evaluate the incidence of PDGFRB gene copy number gain (CNG) by fluorescence in situ hybridization and PDGFR pathway protein expression by immunohistochemistry (IHC) and correlate it to patient clinical outcome. Eighty-eight archived tumor blocks from resected MPM with full clinical information were used to perform IHC biomarkers (PDGFRα, PDGFRβ, p-PDGFRβ) and fluorescence in situ hybridization analysis of PDGFRB gene CNG. Spearman rank correlation, Wilcoxon rank-sum test, Kruskal-Wallis test, BLiP plots, and Kaplan-Meier method were used to analyze the biomarkers and correlation to clinical outcome. Several correlations between the IHC biomarkers were seen; however, none correlated to clinically relevant patient demographics or histology. In the CNG analysis, PDGFRB gene CNG in >10% of tumor cells had lower cytoplasmic p-PDGFRβ (P=.029), while PDGFRB gene CNG in >40% of tumor cells had a higher cytoplasmic PDGFRβ (P=.04). PDGFRB gene CNG status did not associate with patient demographics or tumor characteristics. PDGFR pathway IHC biomarkers did not associate with survival outcomes. However, patients with PDGFRB CNG >40% of tumor cells had improved relapse-free survival (HR 0.25 [95% CI 0.09-0.72], P=.0096) and improved overall survival (HR 0.32 [95% CI 0.11-0.89], P=.029). PDGFRB CNG >40% of MPM tumor cells is a potential prognostic biomarker for surgery and may identify a unique population of mesothelioma patients. Future validation of this biomarker in prospective trials is needed. From a retrospective review of archived tissue specimens from patients with resected malignant pleural mesothelioma tumors, we show that patients with PDGFRB CNG >40% of tumor cells had improved relapse-free survival (HR 0.25 [95% CI 0.09-0.72], P=.0096) and improved overall survival (HR 0.32 [95% CI 0.11-0.89], P=.029). PDGFRB CNG >40% of MPM tumor cells is a potential prognostic biomarker for surgery and may identify a unique population of mesothelioma patients.
authors.affiliation: Department of Thoracic and Head & Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX. Electronic address: astsao@mdanderson.org.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Tsao
authors.affiliation: Department of Biostatistics, University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Nusrat
authors.initials: N
authors.lastname: Harun
authors.affiliation: Department of Thoracic and Head & Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX; Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Junya
authors.initials: J
authors.lastname: Fujimoto
authors.affiliation: Department of Thoracic and Head & Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Vikki
authors.initials: V
authors.lastname: Devito
authors.affiliation: Department of Biostatistics, University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Kuhn
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Reza
authors.initials: R
authors.lastname: Mehran
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: David
authors.initials: D
authors.lastname: Rice
authors.affiliation: Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Cesar
authors.initials: C
authors.lastname: Moran
authors.affiliation: Department of Thoracic and Head & Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
authors.affiliation: Department of Bioinformatics & Computed Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Thoracic and Head & Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Milind
authors.initials: M
authors.lastname: Suraokar
authors.affiliation: Department of Thoracic and Head & Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX; Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Wistuba
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000235:genetics* / Q000401:mortality* / Q000601:surgery; D008875:Middle Aged; D010997:Pleural Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000601:surgery; D011379:Prognosis; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: Copy number gain; PDGFRB; Pleural mesothelioma; Prognostic biomarker
references.citation: J Clin Oncol. 2009 Apr 20;27(12):2081-90
references.pmid: 19255316
references.citation: J Clin Invest. 2007 Aug;117(8):2114-22
references.pmid: 17641778
references.citation: Thorax. 2008 Apr;63(4):345-51
references.pmid: 18086752
references.citation: J Clin Oncol. 2009 Jun 20;27(18):3007-13
references.pmid: 19364962
references.citation: Mod Pathol. 2009 Jun;22(6):744-52
references.pmid: 19377443
references.citation: Lancet Oncol. 2011 Aug;12(8):763-72
references.pmid: 21723781
references.citation: Clin Exp Metastasis. 1998 Aug;16(6):529-39
references.pmid: 9872600
references.citation: J Pathol. 1996 Feb;178(2):151-60
references.pmid: 8683381
references.citation: J Pathol. 1992 May;167(1):1-4
references.pmid: 1320670
references.citation: Clin Cancer Res. 2010 Jan 1;16(1):34-44
references.pmid: 20028769
references.citation: Carcinogenesis. 2009 Jul;30(7):1097-105
references.pmid: 19380521
references.citation: PLoS One. 2008;3(11):e3794
references.pmid: 19030102
references.citation: J Thorac Oncol. 2010 Oct;5(10):1649-54
references.pmid: 20871264
references.citation: J Thorac Cardiovasc Surg. 2008 Mar;135(3):620-6, 626.e1-3
references.pmid: 18329481
references.citation: Proc Natl Acad Sci U S A. 1984 Apr;81(8):2396-400
references.pmid: 6326125
references.citation: Eur J Biochem. 1992 Sep 15;208(3):589-96
references.pmid: 1396665
references.citation: Acta Cytol. 1995 Jul-Aug;39(4):613-22
references.pmid: 7543232
references.citation: Tumour Biol. 2005 Sep-Oct;26(5):221-6
references.pmid: 16103743
references.citation: Eur J Cancer. 2010 Oct;46(15):2837-48
references.pmid: 20692828
references.citation: J Clin Pathol. 2009 Nov;62(11):970-7
references.pmid: 19861557
references.citation: J Thorac Oncol. 2007 Oct;2(10):957-65
references.pmid: 17909360
references.citation: Cancer Chemother Rep. 1966 Mar;50(3):163-70
references.pmid: 5910392
references.citation: J Natl Cancer Inst. 2009 May 6;101(9):678-86
references.pmid: 19401544
references.citation: Am J Respir Cell Mol Biol. 2001 Jun;24(6):694-702
references.pmid: 11415934
references.citation: Mol Pharmacol. 1994 Sep;46(3):437-44
references.pmid: 7935323
references.citation: Clin Lung Cancer. 2009 Jan;10(1):36-41
references.pmid: 19289370
references.citation: Oncogene. 1991 Nov;6(11):2005-11
references.pmid: 1658707