Favorable outcome of patients with lung adenocarcinoma harboring POLE mutations and expressing high PD-L1

Abstract

Mutations in polymerase ε (POLE) confer favorable prognosis and outcomes in various cancer types, but their role in non-small cell lung cancer (NSCLC) is unknown. Utilizing the data of 513 patients with adenocarcinoma (LUAD) and 497 patients with squamous cell carcinoma (LUSC) from The Cancer Genome Atlas (TCGA) cohort, we tested the prognostic value of POLE mutations and programmed cell death ligand 1 (PD-L1) expression in the two main subtypes of NSCLC. POLE mutation is a favorable biomarker for the improved overall survival (OS) of the LUSC patients (P = 0.033, 28 mutant vs. 469 wildtype patients), but not that of the LUAD patients (P = 0.12, 31 mutant vs. 482 wildtype patients). POLE-mutant LUAD patients with high expression of PD-L1 (Mut-High, n = 6) exhibited improved OS (P = 0.024) when compared to POLE-mutant patients with low PD-L1 expression (Mut-Low, n = 24) and other patients without POLE mutation (n = 476). This benefit was not due to the high content of the tumor infiltrating lymphocytes. Instead, the antitumor immune response was activated in Mut-High patients so that these patients were likely responding more effectively to immuno-oncology (IO) treatments; whereas genes involved with metabolic pathways were enriched in Mut-Low group, which may cause the decreased OS of these patients. Our study sheds light on the molecular basis of NSCLC and adds to our understanding of responses to chemotherapy and IO therapy.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0832-y) contains supplementary material, which is available to authorized users.

ecTMB: a robust method to estimate and classify tumor mutational burden

“…Although multiple studies have observed a better prognosis in MSI-H patients, we showed that TMB-extreme caused by dysfunctional POLE showed even better overall survival outcomes compared to TMB-high (MSI-H). Similar to our result, studies have reported that mutations in POLE proofreading domain are associated with improved prognosis in several cancer types, including high-grade glioma 33 , lung adenocarcinoma 34 , endometrial cancer, and colorectal cancer 35 . This suggests that TMB-extreme might be another promising biomarker to predict patient prognosis or guide cancer treatment.…”

CDC27 Promotes Tumor Progression and Affects PD-L1 Expression in T-Cell Lymphoblastic Lymphoma

“…Therefore, blocking the PD-1/PD-L1 axis is critical for cancer immunotherapy. However, the response rates to PD-1/PD-L1 immune checkpoint blockade therapy are likely to vary widely, ∼10-20% across whole tumor types (12,13). It is urgent to find predictive molecules and relevant pathways for PD-1/PD-L1 checkpoint blockade immunotherapy to develop innovative treatments.…”

Precision Medicine for NSCLC in the Era of Immunotherapy: New Biomarkers to Select the Most Suitable Treatment or the Most Suitable Patient

“…Intriguingly, in POLE mutated lung adenocarcinomas the median TMB was increased by 1.6-fold per Mb (p = 0.026), and both PD-L1 expression and CD8+ tumor infiltrating lymphocytes were higher in this subgroup of NSCLC patients, suggesting POLE mutation as a candidate biomarker to predict the response to immunotherapy [127]. In parallel, Liu et al [128] investigated a cohort of 513 patients with lung adenocarcinoma and 497 with squamous cell carcinoma from The Cancer Genome Atlas (TCGA) to test the prognostic value of POLE mutations and PD-L1 expression. Of patient cohorts, 6% and 5.6% were positive for a POLE mutation in adenocarcinoma and squamous cell carcinoma, respectively.…”

“…POLE mutations have been identified in 7-12% of endometrial and 1-2% of colorectal cancers as well as in other tumors [125,126], including NSCLC [127,128]. Interestingly, endometrial cancers with somatic POLE proofreading domain mutations have an outstanding prognosis, which probably depends on the abundance of antigenic neoepitopes, able to stimulate a strong antitumor immune response [125].…”