Exploratory analyses of consensus molecular subtype-dependent associations of TP53 mutations with immunomodulation and prognosis in colorectal cancer.

Autor:	Smeby J; Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.; Department of Oncology, Oslo University Hospital, Oslo, Norway.; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway., Sveen A; Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway., Bergsland CH; Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway., Eilertsen IA; Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway., Danielsen SA; Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway., Eide PW; Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway., Hektoen M; Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway., Guren MG; K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.; Department of Oncology, Oslo University Hospital, Oslo, Norway., Nesbakken A; K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway., Bruun J; Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway., Lothe RA; Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; K.G. Jebsen Colorectal Cancer Research Centre, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Jazyk:	angličtina
Zdroj:	ESMO open [ESMO Open] 2019 Jun 24; Vol. 4 (3), pp. e000523. Date of Electronic Publication: 2019 Jun 24 (Print Publication: 2019).
DOI:	10.1136/esmoopen-2019-000523
Abstrakt:	Background: Accumulating evidence suggests immunomodulatory and context-dependent effects of TP53 mutations in cancer. We performed an exploratory analysis of the transcriptional, immunobiological and prognostic associations of TP53 mutations within the gene expression-based consensus molecular subtypes (CMSs) of colorectal cancer (CRC). Materials and Methods: In a single-hospital series of 401 stage I-IV primary CRCs, we sequenced the whole coding region of TP53 and analysed CMS-dependent transcriptional consequences of the mutations by gene expression profiling. Immunomodulatory associations were validated by multiplex, fluorescence-based immunohistochemistry of immune cell markers. Prognostic associations of TP53 mutations were analysed in an aggregated series of 635 patients classified according to CMS, including publicly available data from a French multicentre cohort (GSE39582). Results: TP53 mutations were found in 60% of the CRCs. However, gene set enrichment analyses indicated that their transcriptional consequences varied among the CMSs and were most pronounced in CMS1-immune and CMS4-mesenchymal. Subtype specificity was primarily seen as an upregulation of gene sets reflecting cell cycle progression in CMS4 and a downregulation of T cell activity in CMS1. The subtype-dependent immunomodulatory associations were reinforced by significant depletion of several immune cell populations in mutated tumours compared with wild-type (wt) tumours exclusively in CMS1, including cytotoxic lymphocytes (adjusted p value in CMS1=0.002 and CMS2-4>0.9, Microenvironment Cell Populations (MCP)-counter algorithm). This was validated by immunohistochemistry-based quantification of tumour infiltrating CD8+ cells. Within CMS1, the immunomodulatory association of TP53 mutations was strongest among microsatellite stable (MSS) tumours, and this translated into a propensity for metastatic disease and poor prognostic value of the mutations specifically in the CMS1/MSS subtype (both series overall survival: TP53 mutation vs wt: HR 5.52, p=0.028). Conclusions: Integration of TP53 mutation status with the CMS framework in primary CRC suggested subtype-dependent immunobiological associations with prognostic and potentially immunotherapeutic implications, warranting independent validation. Competing Interests: Competing interests: None declared.
Databáze:	MEDLINE
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