Genomic amplification of CD274 (PD-L1) in small cell lung cancer
Menée sur deux cohortes de 72 et 138 patients atteints d'un cancer du poumon à petites cellules, cette étude met en évidence, pour 4 patients, une surexpression massive de PD-L1 induite par une amplification focale du gène CD274
Background: 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.
Methods: 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.
Clinical Cancer Research , article en libre accès, 2015