Reduced genetic tumor heterogeneity after neoadjuvant chemotherapy is related to favorable outcome in patients with esophageal adenocarcinoma

ABSTRACT: The incidence of oesophageal adenocarcinoma (OeC) has been increasing rapidly in most Western countries during the last few decades. Although multimodal treatment combining pre-operative chemotherapy with radical surgical resection has become the standard of care in the UK for all patients with locally advanced resectable disease, the 5-year survival rate in this patient group is less than 25%. Only 30% of all patients will benefit from pre-operative chemotherapy. Hence, there is an urgent clinical need to identify genomic markers that allow stratification of patients for a more individualised therapy approach. The goal of this study is to use whole genome high-resolution array CGH to examine the DNA copy number profile of a subset of OeC patients recruited into the OE02 trial and establish it’s relationship with clinicopathological variables including pathological tumor regression and patient survival. High-resolution array CGH analysis was conducted on 84 formalin fixed paraffin embedded resection samples obtained from subjects enrolled in the Oe02 trial. We compared the DNA copy number profiles between patients treated with chemotherapy and surgery and those treated with surgery alone. DNA copy number entropy was assessed to identify differences in overall copy number aberrations between the two treatment groups. Furthermore, the association between DNA copy number aberrations and tumor regression grade was investigated. The genetic make-up of OeCs investigated in the current study proved to be highly complex reducing our ability to determine the background normal copy number level in a tumor sample. Using DNA copy number entropy as a measure to compare sample profiles, we identified significant treatment arm specific DNA copy number aberration patterns predominantly in chromosome 1 and 5. High DNA copy number entropy was associated with longer overall survival. Differential DNA copy number entropy was observed between the two treatment groups, and the positions of the driving DNA regions were identified. To our surprise, the differences between the treatment groups went unnoticed when a standard test was applied. We also found that the DNA copy number entropy was strongly correlated with patients’ overall survival and clinicopathological characteristics. To the best of our knowledge, this is the first study in OeC quantitatively showed that the tumor heterogeneity was reduced by chemotherapy. And, the observed tumor heterogeneity was shown to has prognostic value. However, further research is needed to narrow down these regions to a few driving genes/probes that may aid in predicting whether a new patient will benefit from chemotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE56106 | GEO | 2017/02/10

SECONDARY ACCESSION(S): PRJNA242425

REPOSITORIES: GEO