Tumor-Infiltrating Lymphocytes in Glioblastoma Are Associated with Mutations in NF1, RB1 and TP53 and Enriched in the Mesenchymal Transcriptional Class
Daniel Brat, Caleb Rutledge, Jun Kong, David Gutman, Lee Cooper, Christina Appin, Candace Chisolm, Yuna Park, Lisa Scarpace, Tom Mikkelsen, Carlos Moreno, Joel Saltz. Emory University School of Medicine, Atlanta, GA; Henry Ford Hospital, Detroit, MI
Background: Tumor-infiltrating lymphocytes have prognostic significance in many human neoplasms and may be an important variable to consider in future immunologic therapies. Their biologic and clinical significance in glioblastoma (GBM) have not been fully defined. We investigated if lymphocytes in GBM were associated with specific molecular alterations, histologies or patient outcome.
Design: Using publicly available molecular, histologic and clinical data from The Cancer Genome Atlas (TCGA), we annotated lymphocytes as absent (0), present (1+), or abundant (2+) in 171 cases. Associations between lymphocytes and other histologic features, copy number alterations, mutations and gene expression class were examined by Chi-square tests. The association of lymphocytes with survival was assessed by log-rank tests.
Results: We detected a positive correlation between lymphocytes and GBMs with gemistocytes, sarcomatous cells, epithelioid cells, and giant cells (all p<0.05). Conversely, lymphocytes were depleted in GBMs characterized by small cells and oligodendroglial cells (both p<0.05). Lymphocytes were also negatively correlated with EGFR-amplification (p<0.05). Lymphocytes were enriched in the mesenchymal transcriptional class (p<0.05), with 71% of cases in this class displaying abundant (2+) lymphocytes. Lymphocytes were also strongly associated with mutations in NF1, TP53, and RB1 (all p<0.05), which are enriched in the mesenchymal transcriptional class and characteristic of gemistocytic, sarcomatous, epithelioid, and giant cell histologic subtypes of GBM. Within the mesenchymal transcriptional class, lymphocytes were associated with NF1 deletions (p<0.05). Lymphocytes were not associated with survival.
Conclusions: We found that tumor-infiltrating lymphocytes in GBM were strongly correlated with the mesenchymal transcriptional class; associated with mutations in NF1, TP53, and RB1; and typical of histologic subtypes of characterized by these mutations including gemistocytic, sarcomatous, epithelioid, and giant cell GBMs. Immunogenic mechanisms underlying these molecular and histologic associations remain to be determined.
Monday, March 4, 2013 9:00 AM
Proffered Papers: Section G1, Monday Morning