Abstract 2259: Evaluation of polymorphisms in myeloid-associated genes and glioma survival

Abstract

Abstract BACKGROUND: Gliomas are highly infiltrated by immune cells including microglia, macrophages, and myeloid-derived suppressor cells (collectively, glioma-associated myeloid cells). These cells have been shown to be induced by the tumor to be immune-suppressive and tumor-supportive, and are a negative prognosticator for survival in mouse models. Here, we examine whether inherited variants in genes important to the function of glioma-associated myeloid cells are associated with survival following low-grade glioma diagnosis. METHODS: Subjects for this study were 484 patients with WHO grade II or grade III glioma treated at The University of Texas MD Anderson Cancer Center in Houston, Texas between 1992 and 2008 and followed up for survival through August, 2016. We selected 100 genes for analysis including transcription factors, cytokines and chemokines, receptors, enzymes, and other genes central to the function of glioma-associated myeloid cells. Genotyping was originally performed using the Illumina Human 610-Quad Bead Chip platform and 2,040 tagging SNPs as determined by Haploview Tagger software were selected for analysis with minor allele frequency (AF) ≥ 1%. Associations between selected SNPs and survival were evaluated by Cox regression analysis under an additive allelic model adjusting for age, sex, extent of surgery (biopsy only/partial resection/gross total resection), radiotherapy (yes/no), and chemotherapy (yes/no). Models were examined to ensure that proportional hazards assumptions were not violated. RESULTS: Median survival among low-grade glioma patients was 6.7 years. Age at diagnosis, extent of surgery, and having received radiotherapy or chemotherapy were each significantly associated with survival. Five SNPs were associated with survival at a significance level of p<0.001, and two remained significantly associated with low-grade glioma survival after adjustment for multiple comparisons (FDR-adjusted p-value (q)<0.10). These results indicated inferior survival for carriers of the C allele (AF=1.4%) at rs147960238 in CD163 (HR=5.47, 95% CI: 2.49-11.99, p=2.23x10-5, q=0.046) and for carriers of the G allele (AF=3.8%) at rs17138945 in MET (HR=2.27, 95% CI: 1.52-3.38, p=5.61x10-5, q=0.057). These SNPs are located in the 10th and 2nd introns of CD163 and MET, respectively. CONCLUSIONS: Here we provide preliminary evidence of an association between polymorphisms in two genes related to glioma-associated myeloid cell function and low-grade glioma survival. CD163 is a receptor that is highly expressed on macrophages and may play a role in macrophage-mediated anti-inflammatory responses, while MET is a receptor tyrosine kinase and well-studied proto-oncogene that is also involved in the expansion of myeloid-derived suppressor cell populations. Further investigation of these associations is warranted, and validation of these findings is planned in an independent population. Citation Format: Daniel I. Jacobs, Yanhong Liu, Konrad Gabrusiewicz, Spiridon Tsavachidis, E. Susan Amirian, Georgina N. Armstrong, Renke Zhou, Jun Wei, Cristina Ivan, George Calin, Michael Scheurer, Anna Dahlin, Terri Rice, Paige M. Bracci, Helen M. Hansen, John K. Wiencke, Margaret R. Wrensch, Beatrice Melin, Amy B. Heimberger, Melissa L. Bondy. Evaluation of polymorphisms in myeloid-associated genes and glioma survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2259. doi:10.1158/1538-7445.AM2017-2259