Integrated Genomics for Pinpointing Survival Loci within Arm-Level Somatic Copy Number Alterations

• There exists a wide spectrum of arm-level SCNAs of variable prognostic “impact”
• Arm-level dissection via copy number status alone frequently yields false positives
• Only a minority of genetic loci influence powerful arm-level SCNA phenotypes
• Several 9p loci, but not CDKN2A, are linked to survival outcomes in LGG

SummaryThe identification of driver loci underlying arm-level somatic copy number alterations (SCNAs) in cancer has remained challenging and incomplete. Here, we assess the relative impact and present a detailed landscape of arm-level SCNAs in 10,985 patient samples across 33 cancer types from The Cancer Genome Atlas (TCGA). Furthermore, using chromosome 9p loss in lower grade glioma (LGG) as a model, we employ a unique multi-tiered genomic dissection strategy using 540 patients from three independent LGG datasets to identify genetic loci that govern tumor aggressiveness and poor survival. This comprehensive approach uncovered several 9p loss-specific prognostic markers, validated existing ones, and redefined the impact of CDKN2A loss in LGG.