Genomic Amplification ofCD274(PD-L1) in Small-Cell Lung Cancer.
Purpose:Programmed death ligand-1 (PD-L1), encoded by theCD274gene, is a target for immune checkpoint blockade; however, little is known about genomicCD274alterations. A subset of small-cell lung cancer (SCLC) exhibits increased copy number of chromosome 9p24, on whichCD274resides; however, most SCLCs show low expression of PD-L1. We therefore examined whetherCD274is 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 (whereCD274resides) and focal, high-level amplification ofCD274We found evidence for genomic targeting ofCD274, suggesting selection during oncogenic transformation.CD274amplification was caused by genomic rearrangements not affecting the open reading frame, thus leading to massively increasedCD274transcripts 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 ofCD274Such tumors may be particularly susceptible to immune checkpoint blockade.Clin Cancer Res; 23(5); 1220-6. ©2016 AACR.
Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.
Julie
J
George
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.|Department of Organ Regulatory Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.
Motonobu
M
Saito
Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
Koji
K
Tsuta
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
Reika
R
Iwakawa
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
Kouya
K
Shiraishi
Institute of Pathology, University Hospital Cologne, Cologne, Germany.
Andreas H
AH
Scheel
Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
Shinsuke
S
Uchida
Division of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan.
Shun-Ichi
SI
Watanabe
Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, Japan.
Ryo
R
Nishikawa
Department of Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
Masayuki
M
Noguchi
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
Martin
M
Peifer
Center for Cancer Genome Discovery, Asan Institute for Life Science, Asan Medical Center, Seoul, Korea.
Se Jin
SJ
Jang
Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany.
Iver
I
Petersen
Institute of Pathology, University Hospital Cologne, Cologne, Germany.
Reinhard
R
Büttner
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
Curtis C
CC
Harris
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.|Cancer Genome Biology Group, Institute of Predictive and Personalized Medicine of Cancer, Barcelona, Spain.
Jun
J
Yokota
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.|Institute of Pathology, University Hospital Cologne, Cologne, Germany.|German Cancer Research Center, German Cancer Consortium (DKTK), Heidelberg, Germany.
Roman K
RK
Thomas
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan. tkkohno@ncc.go.jp roman.thomas@uni-koeln.de.|Division of Translational Research Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan.
Takashi
T
Kohno
D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D005784:Gene Amplification / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human