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

• Published in: Clinical cancer research 2017-03, Vol.23 (5), p.1220-1226
• Main Authors: George, Julie, Saito, Motonobu, Tsuta, Koji, Iwakawa, Reika, Shiraishi, Kouya, Scheel, Andreas H, Uchida, Shinsuke, Watanabe, Shun-Ichi, Nishikawa, Ryo, Noguchi, Masayuki, Peifer, Martin, Jang, Se Jin, Petersen, Iver, Büttner, Reinhard, Harris, Curtis C, Yokota, Jun, Thomas, Roman K, Kohno, Takashi
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Amplification; Apoptosis; B7-H1 Antigen - genetics; Biomarkers, Tumor - genetics; Cancer; Chromosome 9; Chromosomes, Human, Pair 9 - genetics; Copy number; DNA Copy Number Variations - genetics; Experimental design; Female; Gene Amplification - genetics; Gene expression; Gene Expression Regulation, Neoplastic; Gene sequencing; Genetic transformation; Genome, Human; Genomes; Humans; Immune checkpoint; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Levels; Lung cancer; Male; Middle Aged; PD-L1 protein; Polymorphism, Single Nucleotide; Single-nucleotide polymorphism; Small cell lung carcinoma; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-16-1069

Programmed death ligand-1 (PD-L1), encoded by the gene, is a target for immune checkpoint blockade; however, little is known about genomic alterations. A subset of small-cell lung cancer (SCLC) exhibits increased copy number of chromosome 9p24, on which resides; however, most SCLCs show low expression of PD-L1. We therefore examined whether is a target of recurrent genomic alterations. 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. By examining somatic copy number alterations in two cohorts of primary human SCLC specimens, we observed 9p24 copy number gains (where resides) and focal, high-level amplification of We found evidence for genomic targeting of , suggesting selection during oncogenic transformation. amplification was caused by genomic rearrangements not affecting the open reading frame, thus leading to massively increased transcripts and high level expression of PD-L1. A subset (4/210, 1.9%) of human SCLC patient cases exhibits massive expression of PD-L1 caused by focal amplification of Such tumors may be particularly susceptible to immune checkpoint blockade. .