A Gene Signature to Determine Metastatic Behavior in Thymomas

Yesim Gökmen-Polar,Sunil Badve,Derek Maetzold,Robert W Cook,Patrick J Loehrer,Ioan Tudor Vladislav,Kristen M Oelschlager,John F Stone,Jeff Wilkinson,Kristen L Shirar,Kenneth A Kesler,Chirayu Pankaj Goswami,Xin-Yuan Guan

doi:10.1371/journal.pone.0066047

Abstract

PurposeThymoma represents one of the rarest of all malignancies. Stage and completeness of resection have been used to ascertain postoperative therapeutic strategies albeit with limited prognostic accuracy. A molecular classifier would be useful to improve the assessment of metastatic behaviour and optimize patient management.MethodsqRT-PCR assay for 23 genes (19 test and four reference genes) was performed on multi-institutional archival primary thymomas (n = 36). Gene expression levels were used to compute a signature, classifying tumors into classes 1 and 2, corresponding to low or high likelihood for metastases. The signature was validated in an independent multi-institutional cohort of patients (n = 75).ResultsA nine-gene signature that can predict metastatic behavior of thymomas was developed and validated. Using radial basis machine modeling in the training set, 5-year and 10-year metastasis-free survival rates were 77% and 26% for predicted low (class 1) and high (class 2) risk of metastasis (P = 0.0047, log-rank), respectively. For the validation set, 5-year metastasis-free survival rates were 97% and 30% for predicted low- and high-risk patients (P = 0.0004, log-rank), respectively. The 5-year metastasis-free survival rates for the validation set were 49% and 41% for Masaoka stages I/II and III/IV (P = 0.0537, log-rank), respectively. In univariate and multivariate Cox models evaluating common prognostic factors for thymoma metastasis, the nine-gene signature was the only independent indicator of metastases (P = 0.036).ConclusionA nine-gene signature was established and validated which predicts the likelihood of metastasis more accurately than traditional staging. This further underscores the biologic determinants of the clinical course of thymoma and may improve patient management.

Highlights

Thymomas and thymic carcinomas are rare epithelial tumors arising from the thymus gland in the anterior mediastinum
We report the development and validation of a nine-gene qRT-PCR assay that predicts the likelihood of metastasis using a relatively large multi-institutional series of thymomas
Selection of training set samples was primarily based on shortest time to metastasis and, for nonmetastatic cases, longest followup (.5 yrs; median followup, 8.4 yrs.)

Summary

Introduction

Thymomas and thymic carcinomas are rare epithelial tumors arising from the thymus gland in the anterior mediastinum. Our prior gene expression microarray analysis identified a number of genes that could predict metastatic behavior in thymomas [8] Of note, these genes were not part of the proliferation metagene but had functions related to invasion [9,10]. We report the development and validation of a nine-gene qRT-PCR assay that predicts the likelihood of metastasis using a relatively large multi-institutional series of thymomas. This assay categorizes patients into low (class 1) and high (class 2) risk and enables a novel biologic-based clinical approach for decision making in patients with this rare malignancy

Methods

Results

Discussion

Conclusion