Abstract 4463: The coactivator oncogene AF1Q associates with STAT3 activation downstream of MET action in gastro-esophageal cancer patients
Authors: Gruber Elisabeth S. , Birner Peter , Merkel Olaf , Bergmann Michael M. , Schoppmann Sebastian F. , Park Jino , Moriggl Richard , Tse William , Kenner Lukas 
Published: July 2017

AF1Q was initially identified as an oncogene in acute myeloid leukemia. In breast cancer, AF1q mediates tumor progression by boosting STAT3-signalling. In addition, AF1q enhances wnt-signalling resulting in transcriptional activation of CD44 and promotes tumor cell proliferation, migration and chemo-resistance. In gastrointestinal malignancies both pathways are linked to enhanced MET tyrosine kinase receptor action, accelerating tumor progression and metastases. We showed that Af1q overexpression in the gastro-esophageal cancer cell lines SK-GT-4, FLO-1 and OE33 led to increased sphere formation and increased invasive capacity in the case of FLO-1 and OE33. We investigated the role of AF1q in a retrospective collective of 460 resected gastro-esophageal cancer specimens (74.3% adenocarcinomas (AC), 25.7% esophageal squamous cell cancers (SCC)). With respect to topographic location, 40.4% of tumors were esophageal (EC), 20% gastro-esophageal (GEC) and 39.6% gastric cancers (GC). Immunohistochemistry revealed overexpression of AF1q in 205, and of CD44 in 114 patient tumor samples. AF1q overexpression was found more often in EC/GEC as compared to GC (p=0.007) and associated with HER2 (p=0.035), pySTAT3 (p&lt;0.001) and MET (p=0.004) expression as well as neoadjuvant chemotherapy (p&lt;0.001). AF1q and CD44 overexpression correlated in the overall group (p&lt;0.001) and in AC (p&lt;0.001). In SCC CD44 was expressed more frequently compared to AC (p&lt;0.001). Analysis of the matched primary and metastatic tumors revealed that primary AF1q-positive tumor samples were largely overlapping with AF1q-positive tumors lymph node metastases (23/32) and distant metastases (6/7). AF1q overexpression correlated with shorter disease free survival (DFS) (p=0.003) and shorter disease specific survival (DSS) (p=0.036), but overall survival (OS) was similar (p=0.117). In a subgroup analysis a shorter OS was observed in EC/GEC (p=0.03, log rank test). In a Cox regression model AF1q and CD44 expression was associated with shorter DFS (p&lt;0.001 and p=0.025) and DSS (p=0.005 and p=0.035), but OS remained unchanged. Prognostic significance was limited to AF1q (p=0.003 and p=0.04, respectively). We conclude, that AF1q overexpression is associated with progression and metastases in GEC. AF1q and downstream pathway markers such as pySTAT3- as well as CD44 and MET are linked with AF1q expression. Therefore we propose AF1q as a novel prognostic marker for GECs.

Citation Format: Elisabeth S. Gruber, Peter Birner, Olaf Merkel, Michael M. Bergmann, Sebastian F. Schoppmann, Jino Park, Richard Moriggl, William Tse, Lukas Kenner. The coactivator oncogene AF1Q associates with STAT3 activation downstream of MET action in gastro-esophageal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4463. doi:10.1158/1538-7445.AM2017-4463