Genomic Amplification of <i>CD274</i> (PD-L1) in Small-Cell Lung Cancer

Abstract

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