Format

Send to

Choose Destination
Oncotarget. 2017 Jul 18;8(44):76290-76304. doi: 10.18632/oncotarget.19350. eCollection 2017 Sep 29.

Molecular signatures reflecting microenvironmental metabolism and chemotherapy-induced immunogenic cell death in colorectal liver metastases.

Author information

1
Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
2
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
3
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
4
Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
5
Department of Radiology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
6
Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
7
The Intervention Centre, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
8
Department of Pharmacy, University of Tromsø - The Arctic University of Norway, Tromsø, Norway.
9
Department of Oncology, Akershus University Hospital, Lørenskog, Norway.
10
Department of Gastroenterological Surgery, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
#
Contributed equally

Abstract

Background:

Metastatic colorectal cancer (CRC) is associated with highly variable clinical outcome and response to therapy. The recently identified consensus molecular subtypes (CMS1-4) have prognostic and therapeutic implications in primary CRC, but whether these subtypes are valid for metastatic disease is unclear. We performed multi-level analyses of resectable CRC liver metastases (CLM) to identify molecular characteristics of metastatic disease and evaluate the clinical relevance.

Methods:

In this ancillary study to the Oslo-CoMet trial, CLM and tumor-adjacent liver tissue from 46 patients were analyzed by profiling mutations (targeted sequencing), genome-wide copy number alteration (CNAs), and gene expression.

Results:

Somatic mutations and CNAs detected in CLM were similar to reported primary CRC profiles, while CNA profiles of eight metastatic pairs suggested intra-patient divergence. A CMS classifier tool applied to gene expression data, revealed the cohort to be highly enriched for CMS2. Hierarchical clustering of genes with highly variable expression identified two subgroups separated by high or low expression of 55 genes with immune-related and metabolic functions. Importantly, induction of genes and pathways associated with immunogenic cell death (ICD) was identified in metastases exposed to neoadjuvant chemotherapy (NACT).

Conclusions:

The uniform classification of CLM by CMS subtyping may indicate that novel class discovery approaches need to be explored to uncover clinically useful stratification of CLM. Detected gene expression signatures support the role of metabolism and chemotherapy in shaping the immune microenvironment of CLM. Furthermore, the results point to rational exploration of immune modulating strategies in CLM, particularly by exploiting NACT-induced ICD.

KEYWORDS:

colorectal liver metastases; genomic profiling; immunogenic cell death; neoadjuvant chemotherapy

Conflict of interest statement

CONFLICTS OF INTEREST All authors declare no conflicts of interest.

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central Icon for Norwegian BIBSYS system
Loading ...
Support Center