eprintid: 24305
rev_number: 13
eprint_status: archive
userid: 1589
dir: disk0/00/02/43/05
datestamp: 2018-04-25 08:15:10
lastmod: 2024-08-15 01:22:15
status_changed: 2018-04-25 08:15:10
type: article
metadata_visibility: show
creators_name: Budczies, Jan
creators_name: Denkert, Carsten
creators_name: Győrffy, Balázs
creators_name: Schirmacher, Peter
creators_name: Stenzinger, Albrecht
title: Chromosome 9p copy number gains involving PD-L1 are associated with a specific proliferation and immune-modulating gene expression program active across major cancer types
subjects: ddc-610
divisions: i-850300
divisions: i-912000
abstract: Background: Inhibition of the PD-L1/PD-1 immune checkpoint axis represents one of the most promising approaches of immunotherapy for various cancer types. However, immune checkpoint inhibition is successful only in subpopulations of patients emphasizing the need for powerful biomarkers that adequately reflect the complex interaction between the tumor and the immune system. Recently, recurrent copy number gains (CNG) in chromosome 9p involving PD-L1 were detected in many cancer types including lung cancer, melanoma, bladder cancer, head and neck cancer, cervical cancer, soft tissue sarcoma, prostate cancer, gastric cancer, ovarian cancer, and triple-negative breast cancer.

Methods: Here, we applied functional genomics to analyze global mRNA expression changes associated with chromosome 9p gains. Using the TCGA data set, we identified a list of 75 genes that were strongly up-regulated in tumors with chromosome 9p gains across many cancer types.

Results: As expected, the gene set was enriched for chromosome 9p and in particular chromosome 9p24 (36 genes and 23 genes). Furthermore, we found enrichment of two expression programs derived from genes within and beyond 9p: one implicated in cell cycle regulation (22 genes) and the other implicated in modulation of the immune system (16 genes). Among these were specific cytokines and chemokines, e.g. CCL4, CCL8, CXCL10, CXCL11, other immunoregulatory genes such as IFN-G and IDO1 as well as highly expressed proliferation-related kinases and genes including PLK1, TTK, MELK and CDC20 that represent potential drug targets.

Conclusions: Collectively, these data shed light on mechanisms of immune escape and stimulation of proliferation in cancer with PD-L1 CNG and highlight additional vulnerabilities that may be therapeutically exploitable.
date: 2017
publisher: BioMed Central
id_scheme: DOI
ppn_swb: 1655268554
own_urn: urn:nbn:de:bsz:16-heidok-243051
language: eng
bibsort: BUDCZIESJACHROMOSOME2017
full_text_status: public
publication: BMC Medical Genomics
volume: 10
number: 74
place_of_pub: London
pagerange: 1-8
issn: 1755-8794
citation:   Budczies, Jan ; Denkert, Carsten ; Győrffy, Balázs ; Schirmacher, Peter ; Stenzinger, Albrecht  (2017) Chromosome 9p copy number gains involving PD-L1 are associated with a specific proliferation and immune-modulating gene expression program active across major cancer types.  BMC Medical Genomics, 10 (74).  pp. 1-8.  ISSN 1755-8794     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/24305/1/12920_2017_Article_308.pdf