Genomic Amplification of CD274 (PD-L1) in Small-Cell Lung Cancer
Julie George1, Motonobu Saito2,3, Koji Tsuta4
1Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.
Insights
Genomic alterations in the CD274 gene cause high PD-L1 expression in a small subset of small-cell lung cancer. These tumors may respond well to immune checkpoint blockade therapies.
Area of Science:
- Oncology
- Genetics
- Immunology
Background:
- Programmed death ligand-1 (PD-L1) is a key target for immune checkpoint blockade therapies.
- Genomic alterations of the CD274 gene, which encodes PD-L1, are not well understood.
- Small-cell lung cancer (SCLC) often shows low PD-L1 expression despite chromosome 9p24 gains.
Purpose of the Study:
- To investigate recurrent genomic alterations targeting the CD274 gene in small-cell lung cancer.
- To determine the impact of these alterations on PD-L1 expression levels.
- To assess the potential of CD274-amplified SCLC for immune checkpoint blockade therapy.
Main Methods:
- Somatic copy number alterations were analyzed in two SCLC patient cohorts using quantitative real-time PCR and SNP array analysis.
- Whole-genome sequencing was employed to elucidate the genomic structure of focal amplifications.
- PD-L1 expression was evaluated through transcriptome sequencing and immunohistochemical staining.
Main Results:
- Focal, high-level amplification of the CD274 gene was identified in a subset of SCLC cases.
- Genomic rearrangements in CD274 did not affect the open reading frame but led to significantly increased CD274 transcripts.
- Massively increased PD-L1 expression was observed in tumors with CD274 amplification.
Conclusions:
- Approximately 1.9% of SCLC patients exhibit massive PD-L1 expression due to CD274 focal amplification.
- These specific SCLC tumors are potentially highly susceptible to immune checkpoint blockade therapies.
- Genomic targeting of CD274 suggests its selection during SCLC oncogenic transformation.
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, 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. Clin Cancer Res; 23(5); 1220-6. ©2016 AACR.
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