Abstract IA02: The role of aneuploidy during tumorigenesis

Abstract

Abstract Since Boveri’s postulates in 1914, aneuploidy has been recognized as a hallmark of human cancer; however, no comprehensive theory exists to explain its patterns and its role in tumor evolution. We have developed Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method for the prediction of tumor suppressor genes (TSG) and oncogenes (OG) through the analysis of the pattern of somatic mutations in cancer. By integrating our prediction of TSGs and OGs with information of copy number alterations, we found that the distribution on chromosomes and the potency of TSGs and OGs can predict the frequency of arm-level and chromosome-level deletions and amplification (Davoli et al., 2013). We propose that it is the decrease or increase in the gene dosage of TSG and OG genes in deletion and amplification to determine the recurrent patterns of aneuploidy selected during tumor evolution. More recently, we have performed gene expression analysis on tumor samples, comparing tumors with different levels of aneuploidy (Davoli et al., 2017). We have found that tumors with high levels of aneuploidy show increased markers of proliferation as well as a strong decrease in infiltrating immune cells, especially CD8+ T cells. Notably, we show that aneuploidy predicts patients’ survival in two clinical trails of immunotherapy in cancer patients. Compared to neoantigen load, aneuploidy represents an independent and stronger predictor of survival. A combined score including aneuploidy and neoantigen load allows superior prediction of survival after immunotherapy. We are now investigating the mechanism by which aneuploidy affects cancer immune evasion. I will present novel data suggesting that aneuploidy may play a role in inhibiting and dysregulating antigen processing and presentation in tumor cells. Overall, our data indicate that aneuploidy is a driver event in human tumorigenesis. Citation Format: Teresa Davo4li. The role of aneuploidy during tumorigenesis [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA02.