Relevance of PD-L1 Non-Coding Polymorphisms on the Prognosis of a Genetically Admixed NSCLC Cohort

Abstract

Purpose Although non-small cell lung cancer (NSCLC) remains a deadly disease, new predictive biomarkers have emerged to assist in managing the disease, of which one of the most promising is the programmed death‐ligand 1 (PD-L1). Each, PD-L1 variant seem to modulate the function of immune checkpoints differently and affect response to adjuvant treatment and outcome in NSCLC patients. We thus investigated the influence of these PD-L1 genetic variations in genetically admixed NSCLC tissue samples, and correlated these values with clinicopathological characteristics, including prognosis. Materials and Methods We evaluated PD-L1 non-coding genetic variants and protein expression in lung adenocarcinomas (ADC), squamous cell carcinomas (SqCC), and large cell carcinomas (LCC) in silico. Microarray paraffin blocks from 70 samples of ADC (N=33), SqCC (N=24), and LCC (N=13) were used to create PD-L1 multiplex immunofluorescence assays with a Cell Signaling E1L3N clone. Fifteen polymorphisms of the PD-L1 gene were investigated by targeted sequencing and evaluated in silico using dedicated tools. Results Although PD-L1 polymorphisms seemed not to interfere with protein expression, PD-L1 expression varied among different histological subtypes, as did clinical outcomes, with the rs4742098A>G, rs4143815G>C, and rs7041009G>A variants being associated with relapse ( P =0.01; P =0.05; P =0.02, respectively). The rs7041009 GG genotype showed a significant correlation with younger and alive patients compared to carriers of the A allele ( P =0.02 and P< 0.01, respectively). The Cox regression model showed that the rs7041009 GG genotype may influence OS ( P <0.01) as a co-dependent factor associated with radiotherapy and recurrence in NSCLC patients. Furthermore, the Kaplan–Meier survival curves showed that rs7041009 and rs4742098 might impact PPS in relapsed patients. In silico approaches identified the variants as benign. Conclusion PD-L1 non-coding variants play an important role in modulating immune checkpoint function and may be explored as immunotherapy biomarkers. We highlight the rs7041009 variant, which impacts OS and PPS in NSCLC patients.

Programmed death-ligand 1 (PD-L1) polymorphisms as predictive biomarkers for the development of liver cirrhosis and hepatocellular carcinoma in HCV Egyptian patients

“…Yeo and his colleagues reported that the PD‐L1 rs4143815 GG genotype may be beneficial for predicting poor prognosis in lung adenocarcinoma as patients with this genotype had lower overall survival and disease-free survival compared to patients with other genotypes of PD-L1 rs4143815 [ 27 ]. As well, prior studies stated that the PD‐L1 rs4143815C > G was significantly associated with a worse survival outcome and relapse with NSCLC and breast cancer [ 10 , 28 , 29 ]. Furthermore, Lee et al [ 30 ] investigated whether the PD-L1 gene polymorphisms could predict the clinical outcome of patients with advanced NSCLC after paclitaxel-cisplatin chemotherapy and they found that the rs4143815 CG SNP was significantly associated with a better response under additive model for the G-allele.…”

“…rs2297136 is found in the 3′-UTR of PD-L1 gene and serves as a binding site for miRNA-324-5p, miRNA‐632, and miRNA-296-5p. An A to G change, at this location, has been shown to enhance the binding power between PD-L1 mRNA and its regulatory miRNAs resulting in a decline of PD-L1 gene transcription and protein expression [ 10 , 20 ]. The results of the current study indicated that rs2297136 (A > G) AA genotype was significantly associated with the development of liver cirrhosis but not with HCC development.…”

“…The PD-L1 gene is polymorphic and many studies have investigated the association between the genetic variants of the PD-L1 gene and the susceptibility to different types of cancer in distinct ethnic populations, but the findings are still equivocal [ 9 , 10 ]. As a result, this study was designed to detect the relationship between the genetic variations of PD-L1 (rs4143815 and rs2297136) and the risk of developing liver cirrhosis and HCC in the Egyptian population suffering from chronic hepatitis C virus (HCV) illness.…”

Clinical outcome of Brazilian patients with non-small cell lung cancer in early stage harboring rare mutations in epidermal growth factor receptor

“…Previous studies from the present case series have shown that Brazilian patients represent a genetically admixed NSCLC cohort with clinical implications. In fact, we found that patients with adenocarcinoma harboring somatic mutations of EGFR , CTLA4 , PDCD1LG2 , or ZEB2 that only underwent surgical treatment and developed brain metastases may have the worst prognosis ( 8 , 9 ). EGFR somatic mutations were detected in approximately 13% of NSCLC Brazilian patients with clinical significance to be defined.…”

“…Previous studies performed by our group using frozen tissue specimens and next-generation sequencing (NGS) from a cohort of 70 patients have shown that Brazilian patients represent a genetically admixed NSCLC cohort with important predictive and prognostic implications ( 8 , 9 ). In the same case series and the array used (QIAamp DNA Mini Kit Qiagen), we detected some Brazilian patients with NSCLC harboring rare EGFR variants with clinical significance to be defined.…”