Universität zu Köln

George, Julie, Saito, Motonobu ORCID: 0000-0001-5072-3520, Tsuta, Koji, Iwakawa, Reika, Shiraishi, Kouya, Scheel, Andreas H., Uchida, Shinsuke ORCID: 0000-0002-4279-8431, Watanabe, Shun-ichi, Nishikawa, Ryo, Noguchi, Masayuki, Peifer, Martin ORCID: 0000-0002-5243-5503, Jang, Se Jin, Petersen, Iver, Buettner, Reinhard, Harris, Curtis C., Yokota, Jun, Thomas, Roman K. and Kohno, Takashi (2017). Genomic Amplification of CD274 (PD-L1) in Small-Cell Lung Cancer. Clin. Cancer Res., 23 (5). S. 1220 - 1227. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3265

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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, highlevel 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. (C)2016 AACR.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code George, Julie UNSPECIFIED UNSPECIFIED UNSPECIFIED Saito, Motonobu UNSPECIFIED orcid.org/0000-0001-5072-3520 UNSPECIFIED Tsuta, Koji UNSPECIFIED UNSPECIFIED UNSPECIFIED Iwakawa, Reika UNSPECIFIED UNSPECIFIED UNSPECIFIED Shiraishi, Kouya UNSPECIFIED UNSPECIFIED UNSPECIFIED Scheel, Andreas H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Uchida, Shinsuke UNSPECIFIED orcid.org/0000-0002-4279-8431 UNSPECIFIED Watanabe, Shun-ichi UNSPECIFIED UNSPECIFIED UNSPECIFIED Nishikawa, Ryo UNSPECIFIED UNSPECIFIED UNSPECIFIED Noguchi, Masayuki UNSPECIFIED UNSPECIFIED UNSPECIFIED Peifer, Martin UNSPECIFIED orcid.org/0000-0002-5243-5503 UNSPECIFIED Jang, Se Jin UNSPECIFIED UNSPECIFIED UNSPECIFIED Petersen, Iver UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Harris, Curtis C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Yokota, Jun UNSPECIFIED UNSPECIFIED UNSPECIFIED Thomas, Roman K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kohno, Takashi UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-238555
DOI:	10.1158/1078-0432.CCR-16-1069
Journal or Publication Title:	Clin. Cancer Res.
Volume:	23
Number:	5
Page Range:	S. 1220 - 1227
Date:	2017
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1557-3265
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EXPRESSION; BLOCKADE; GENE; IDENTIFICATION; NIVOLUMAB; ANTIBODY; SAFETY Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23855