Abstract LB-169: Multidimensional genomic dissection of chromosome 9p in glioma

Abstract

Abstract Background: Characterization of focal somatic copy number alterations (SCNAs) has led to the identification of many cancer genes, yet similar investigations of arm-level SCNAs remain challenging. The identity of driver genes within these broad SCNAs remains a critical unanswered question in cancer genetics. One of the most frequent arm-level SCNAs is 9p loss, which contains the tumor suppressor gene (TSG) CDKN2A. It is also believed that other TSGs exist on 9p, though their identity has yet to be revealed. Methods: We analyzed every arm-level SCNA in 28 cancer types from The Cancer Genome Atlas (TCGA) to clarify the relative impact of 9p loss across cancer. We also performed a multi-tiered genomic dissection of chromosome 9p in 540 patients from 3 independent lower grade glioma (LGG) datasets (TCGA, REMBRANDT, MSKCC) to pinpoint genetic loci that are tied to tumor aggressiveness and poor survival. Focal and arm-level SCNAs were determined by GISTIC2.0. As per recently proposed criteria, 3 LGG subtypes were clustered by IDH mutation and 1p/19q deletion status. Survival analyses were performed using log-rank tests or Cox regression. Results: We found that chromosome 9p loss is one of the most frequent and prognostic arm-level events across 28 TCGA cancer types. Of these, the strongest 9p survival association was found in LGG. We performed a large-scale associations test of 376 important clinical and molecular variables and revealed that 9p loss was only associated with 6q or 9q loss, and 9p loss alone was sufficient to predict poor prognosis. On subtype-specific analysis, 9p loss predicted worse overall survival (OS) in both IDH mutant LGG subtypes but not IDH wild-type (IDHwt). To identify underlying drivers on 9p, we identified 87 genes most frequently targeted by 9p loss. Additional genetic events were rare except for homozygous deletion (HD) at 9p21.3, which contains CDKN2A. In contrast, mRNA/miRNA expression at all gene loci was much more variable and poorly correlated to copy number status. Therefore, pan-LGG and subtype-specific gene expression analyses were used to identify several drivers of tumor aggressiveness, notably KLHL9, MTAP, PLAA, and PTPRD. Although CDKN2A HD was linked to worse OS in a pan-LGG analysis, this event significantly co-occurred with the LGG IDHwt subtype, a group with GBM-like survival outcomes. Further, CDKN2A copy number status and expression did not predict worse OS in any subtype. Discussion: We characterize the nature of 9p loss in LGG, pinpoint genes involved in worse survival, and redefine the role of the tumor suppressor CDKN2A. These results provide new critical insight into long-standing questions about the nature of chromosome 9p loss and establish a framework for examining other arm-level SCNAs in cancer. Citation Format: David M. Roy, Logan A. Walsh, Alexis Desrichard, Jianjiong Gao, Promita Bose, Jason T. Huse, William Lee, Timothy A. Chan. Multidimensional genomic dissection of chromosome 9p in glioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-169. doi:10.1158/1538-7445.AM2015-LB-169