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Clin Cancer Res. 2017 Mar 1;23(5):1220-1226. doi: 10.1158/1078-0432.CCR-16-1069. Epub 2016 Sep 12.

Genomic Amplification of CD274 (PD-L1) in Small-Cell Lung Cancer.

Author information

1
Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.
2
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
3
Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.
4
Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
5
Institute of Pathology, University Hospital Cologne, Cologne, Germany.
6
Division of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan.
7
Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, Japan.
8
Department of Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
9
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
10
Center for Cancer Genome Discovery, Asan Institute for Life Science, Asan Medical Center, Seoul, Korea.
11
Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany.
12
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
13
Cancer Genome Biology Group, Institute of Predictive and Personalized Medicine of Cancer, Barcelona, Spain.
14
Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany. tkkohno@ncc.go.jp roman.thomas@uni-koeln.de.
15
German Cancer Research Center, German Cancer Consortium (DKTK), Heidelberg, Germany.
16
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan. tkkohno@ncc.go.jp roman.thomas@uni-koeln.de.
17
Division of Translational Research Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan.

Abstract

Purpose: Programmed death ligand-1 (PD-L1), encoded by the CD274 gene, is a target for immune checkpoint blockade; however, little is known about genomic CD274 alterations. A subset of small-cell lung cancer (SCLC) exhibits increased copy number of chromosome 9p24, on which CD274 resides; however, most SCLCs show low expression of PD-L1. We therefore examined whether CD274 is a target of recurrent genomic alterations.Experimental Design: We examined somatic copy number alterations in two patient cohorts by quantitative real-time PCR in 72 human SCLC cases (cohort 1) and SNP array analysis in 138 human SCLC cases (cohort 2). Whole-genome sequencing revealed the detailed genomic structure underlying focal amplification. PD-L1 expression in amplified cases from cohorts 1 and 2 was further examined by transcriptome sequencing and immunohistochemical (IHC) staining.Results: By examining somatic copy number alterations in two cohorts of primary human SCLC specimens, we observed 9p24 copy number gains (where CD274 resides) and focal, high-level amplification of CD274 We found evidence for genomic targeting of CD274, suggesting selection during oncogenic transformation. CD274 amplification was caused by genomic rearrangements not affecting the open reading frame, thus leading to massively increased CD274 transcripts and high level expression of PD-L1.Conclusions: A subset (4/210, 1.9%) of human SCLC patient cases exhibits massive expression of PD-L1 caused by focal amplification of CD274 Such tumors may be particularly susceptible to immune checkpoint blockade. Clin Cancer Res; 23(5); 1220-6. ©2016 AACR.

PMID:
27620277
PMCID:
PMC6329376
DOI:
10.1158/1078-0432.CCR-16-1069
[Indexed for MEDLINE]
Free PMC Article

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