Abstract 3693: Immunologic and clinical implications of polymerase δ (POLD) and Polymerase ϵ (POLE) gene mutations in non-small cell lung cancer (NSCLC)
Authors: Chae Young Kwang , Rhee Kyunghoon , Park Lee Chun , Cho Anderson , Chang Sangmin , Ko Taeyeong , Davis Andrew , Bhave Manali , Cruz Marcello , Iams Wadw 
Published: August 2018

Abstract
POLD1 plays a role in proofreading the polymerase δ complex while POLE encodes the major catalytic and proofreading subunit of the polymerase ϵ complex. Mutations in POLD1 and POLE increase spontaneous somatic mutation rates which have been linked with favorable response to PD-1 inhibitor in NSCLC. However, little is known about its impact on the immune landscape and prognosis.
We analyzed genomic, transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) database using cBioPortal of patients with lung adenocarcinoma (ADC, 522 samples) and squamous cell carcinoma (SQCC, 504 samples). We compared patient samples with at least one mutation (M group) in POLD/E family genes (POLD1, POLD2, POLD3, POLD4, POLE, POLE2, POLE3, POLE4) with patient samples without any mutations in above mentioned gene set (N group). The tumor immune landscape was analyzed from RNA-seq z-scores of 812 ‘immune metagene' signatures (Angelova, M. et al, 2015) which were used to predict immune infiltration of 31 distinct immune cells for each tumor sample.
POLD family gene mutation frequency was 0.5% (5/1026 samples) while POLE family gene mutation frequency was 2.0% (21/1026 samples). M group showed significantly higher tumor mutational burden (TMB) in both ADC (median mutation count M:475 N:149, t-test p=0.003) and SQCC (median mutation count M: 318 N:218, t-test p=0.01). In ADC, infiltration of activated CD8 T-cells (M:46% N:26%, chi square test p=0.11) and activated CD4 T-cells (M:46% N:29%, chi square test p=0.19) were not significant. In SQCC, M group showed significantly higher infiltration of activated CD8 T-cells (M:54% N:27%, chi square test p=0.03) while infiltration of activated CD4 T-cells (M:46% N:36%, chi square test p=0.44) was not significant. In terms of survival, in ADC, there was significantly worse survival in M group compared to N group (median M:21 N:50 months, log-rank test p&lt;0.001), while in SQCC, there was no significant difference (median M:66 N:62 months, log-rank test p=0.70).
This is the first comprehensive report describing the immunologic and clinical implication of POLD/E family gene mutation status in NSCLC. In summary, POLD/E family gene mutation was linked with higher TMB in NSCLC. In adenocarcinoma, mutational status of POLD/E was associated with an unfavorable survival outcome suggesting potential prognostic implications.
Citation Format: Young Kwang Chae, Kyunghoon Rhee, Lee Chun Park, Anderson Cho, Sangmin Chang, Taeyeong Ko, Andrew Davis, Manali Bhave, Marcello Cruz, Wadw Iams. Immunologic and clinical implications of polymerase δ (POLD) and Polymerase ϵ (POLE) gene mutations in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3693.