Abstract 2594: A multigene recurrence signature identifies highly proliferative tumors that escape immune surveillance in early stage lung and pancreas adenocarcinoma
Authors: Weygant Nathaniel , Yao Jiannan , Qu Dongfeng , Chandrakesan Parthasarathy , An Guangyu , Houchen Courtney W. 
Published: August 2018

Background: Accurately predicting recurrence in early stage cancer patients may be used to avoid unnecessary therapies with significant side effects or deliver early interventions that can improve outcomes. Both early stage lung (LAc) and pancreatic adenocarcinoma (PDAc) are high-recurrence cancers for which biomarkers that can quantify this risk could benefit patients. In stage I LAc only a small percentage of stage IB patients receive chemotherapy, while more patients may derive additional benefit if identified. In PDAc, patients with the most aggressive stage I-II disease could derive benefit from early aggressive combination chemotherapy if identified.

Methods: Training and test sets (n=10) were selected by random sampling RNA-seq expression data into groups of 65% and 35% respectively. Cox proportional hazards and Kaplan-Meier analysis were used to predict RFS and OS. Maximally selected rank statistics were used to designate low and high-risk signature groups. Subgroup analysis was performed using multivariate Cox methods. Pathway analysis was performed with Webgestalt. RNA-seq expression data for LAc and PDAc was obtained from the cancer genome atlas and gene microarray data from NCBI GEO. All statistical analyses and plots were generated in R v3.2.

Results/Discussion: An unbiased analysis of RNA-seq data identified a 19-gene consensus signature (19-GCS) that is upregulated in tumors and able to predict LAc stage I RFS. Multivariate analysis demonstrated its independence as a prognostic factor and efficiency in independent validation sets. Pathway analysis identified proliferation and immune surveillance as altered pathways in 19-GCS high-risk (sHR) compared to low-risk (sLR) tumors. In confirmation of this finding Cyclin D was downregulated while Cyclin E/A/B were upregulated in sHR tumors. Moreover, the 19-GCS was correlated with proliferation markers Ki-67 and PCNA and showed universal correlation with G2/M phase-specific genes. The expression of MHC Class I and II subunit markers were lost in sHR tumors as were specific MHC-related genes. Moreover, the expression of tumor-infiltrating immune cell-specific markers were largely lost in sHR tumors. The 19-GCS was better able to predict RFS and OS in PDAc than in LAc, and consistent with PDAc's severity, more patients were identified as high-risk. Gene expression analysis identified the same molecular characteristics in sHR PDAc as in sHR LAc. Analysis of clinical outcomes for both LAc and PDAc demonstrated that sHR predicted progressive disease in response to both primary and followup therapy. Overall, the 19-GCS identifies highly proliferative early stage lung and pancreatic tumors with impaired MHC mechanisms that shield them from immune-mediated destruction. This deadly combination leads to recurrence and poor clinical outcomes that might be avoided if identified early.

Citation Format: Nathaniel Weygant, Jiannan Yao, Dongfeng Qu, Parthasarathy Chandrakesan, Guangyu An, Courtney W. Houchen. A multigene recurrence signature identifies highly proliferative tumors that escape immune surveillance in early stage lung and pancreas adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2594.