Abstract 1752: Immune-related gene signatures in colorectal liver metastases: Exposing an opportunity for immune modulating therapy
Authors: Nygaard Vigdis , Dagenborg Vegar J. , Østrup Olga , Rødland Einar A. , Skarpeteig Veronica , Silwal-Pandit Laxmi , Grzyb Krzysztof , Berstad Audun E. , Fretland Åsmund A. , Mælandsmo Gunhild M. , Børresen-Dale Anne-Lise , Ree Anne H. , Edwin Bjørn , Flatmark Kjersti 
Published: July 2017

Abstract
Colorectal cancer (CRC) is one of the most common cancers and one of the leading causes of cancer death in the Western world. Up to 50% of patients with CRC develop metastatic disease and the liver is the most common site. The recently identified consensus molecular subtypes (CMS1-4) based on analyses of primary CRC have prognostic and therapeutic implications, but it is unclear whether these molecular subtypes are valid for metastatic disease. In this study, characterisation of CRC liver metastases (CLM) was performed at multiple molecular levels to identify characteristics relevant to metastatic disease. Molecular stratification of a defined metastatic CRC cohort may yield results of clinical relevance and novel treatment opportunities.
Surgically resected CLM and tumor-adjacent liver tissue from 46 patients were analysed for the presence of mutations (targeted deep sequencing), genome-wide copy number alterations (CNA), and transcription profiled. Molecular profiles of CLM and tumor-adjacent liver tissues were analyzed and associations with clinicopathological features and outcome were investigated. We found oncogenic mutations in all except one tumor. Both mutation and CNA profiles were similar to profiles reported for primary CRC. A CMS classifier tool applied to gene expression data, revealed the cohort to be highly enriched for CMS2. Unsupervised clustering based on genes with highly variable expression identified a 55-gene cluster that segregated the samples into two subgroups. The segregation pattern was replicated in relevant publicly available data sets, but the clinical significance of this observation is not evident. The 55 genes were associated with lipid metabolic and immune-related functions, revealing a role of the tumor-host microenvironment. The engagement of the immune system was further underlined by analyzing subgroups defined by neoadjuvant chemotherapy (NACT) administration, which revealed altered expression of inflammatory mediators and immune regulatory genes. The majority of treated patients had received Oxaliplatin based chemotherapy.
The uniform classification of CLM by CMS may reflect the patient composition in our cohort, but may also indicate that novel class discovery approaches need to be explored to uncover clinically useful molecular stratification of CLM. Identified immune-related gene expression signatures associated with molecular and clinical features underline the integration and importance of the immune interactome in resectable CLM. Specifically, the transcriptomic snapshot of NACT exposed CLM revealed altered genes associated with immunogenic cell death but also immune suppression. These results point to rational exploration of immune-modulating strategies in CLM in combination with NACT to increase efficacy and broaden treatment opportunities for this patient group.
Citation Format: Vigdis Nygaard, Vegar J. Dagenborg, Olga Østrup, Einar A. Rødland, Veronica Skarpeteig, Laxmi Silwal-Pandit, Krzysztof Grzyb, Audun E. Berstad, Åsmund A. Fretland, Gunhild M. Mælandsmo, Anne-Lise Børresen-Dale, Anne H. Ree, Bjørn Edwin, Kjersti Flatmark. Immune-related gene signatures in colorectal liver metastases: Exposing an opportunity for immune modulating therapy [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 1752. doi:10.1158/1538-7445.AM2017-1752