The Degree of Segmental Aneuploidy Measured by Total Copy Number Abnormalities Predicts Survival and Recurrence in Superficial Gastroesophageal Adenocarcinoma

Jon M Davison,Maureen A Lyons-Weiler,Katie S Nason,George K Michalopoulos,J Michael Krill-Burger,William A Laframboise,Melissa Yee,Christin M Sciulli,James D Luketich,Lori A Kelly,Svetlana Pack

doi:10.1371/journal.pone.0079079

Abstract

BackgroundPrognostic biomarkers are needed for superficial gastroesophageal adenocarcinoma (EAC) to predict clinical outcomes and select therapy. Although recurrent mutations have been characterized in EAC, little is known about their clinical and prognostic significance. Aneuploidy is predictive of clinical outcome in many malignancies but has not been evaluated in superficial EAC.MethodsWe quantified copy number changes in 41 superficial EAC using Affymetrix SNP 6.0 arrays. We identified recurrent chromosomal gains and losses and calculated the total copy number abnormality (CNA) count for each tumor as a measure of aneuploidy. We correlated CNA count with overall survival and time to first recurrence in univariate and multivariate analyses.ResultsRecurrent segmental gains and losses involved multiple genes, including: HER2, EGFR, MET, CDK6, KRAS (recurrent gains); and FHIT, WWOX, CDKN2A/B, SMAD4, RUNX1 (recurrent losses). There was a 40-fold variation in CNA count across all cases. Tumors with the lowest and highest quartile CNA count had significantly better overall survival (p = 0.032) and time to first recurrence (p = 0.010) compared to those with intermediate CNA counts. These associations persisted when controlling for other prognostic variables.SignificanceSNP arrays facilitate the assessment of recurrent chromosomal gain and loss and allow high resolution, quantitative assessment of segmental aneuploidy (total CNA count). The non-monotonic association of segmental aneuploidy with survival has been described in other tumors. The degree of aneuploidy is a promising prognostic biomarker in a potentially curable form of EAC.

Highlights

The last several decades have witnessed a substantial increase in the incidence of gastroesophageal adenocarcinoma (EAC) in the United States [1,2]
Tumors location was classified as gastroesophageal junction (GEJ) or esophageal based on the 7th edition AJCC criteria
In superficial EAC, we find that extreme low or high copy number abnormality (CNA) burden connotes a relatively favorable prognosis in comparison to intermediate levels

Summary

Introduction

The last several decades have witnessed a substantial increase in the incidence of gastroesophageal adenocarcinoma (EAC) in the United States [1,2]. The outcome and treatment strategy for EAC depends on the extent of local invasion and presence of regional or distant metastases at the time of diagnosis [3,4]. Invasive (EAC), because of the lower predicted risk of metastases relative to more locally advanced EAC, is potentially cured by esophagectomy or endoscopic resection [5,6]. A subset of patients with superficial EAC develops regional and distant metastases and succumbs to their disease [7,8]. Because of the broad range of potential treatment modalities [9] and clinical outcomes, superficial EAC requires accurate prognostication at the time of initial diagnosis when clinically aggressive tumors have the greatest chance of cure. Prognostic biomarkers are needed for superficial gastroesophageal adenocarcinoma (EAC) to predict clinical outcomes and select therapy.

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Conclusion