Network-based stratification analysis of 13 major cancer types using mutations in panels of cancer genes

Background: Cancers are complex diseases with heterogeneous genetic causes and clinical outcomes. It is critical to classify patients into subtypes and associate the subtypes with clinical outcomes for better prognosis and treatment. Large-scale studies have comprehensively identified somatic mutations across multiple tumor types, providing rich datasets for classifying patients based on genomic mutations. One challenge associated with this task is that mutations are rarely shared across patients. Network-based stratification (NBS) approaches have been proposed to overcome this challenge and used to classify tumors based on exome-level mutations. In routine research and clinical applications, however, usually only a small panel of pre-selected genes is screened for mutations. It is unknown whether such small panels are effective in classifying patients into clinically meaningful subtypes. Results: In this study, we applied NBS to 13 major cancer types with exome-level mutation data and compared the classification based on the full exome data with those focusing only on small sets of genes. Specifically, we investigated three panels, FoundationOne (240 genes), PanCan (127 genes) and TruSeq (48 genes). We showed that small panels not only are effective in clustering tumors but also often outperform full exome data for most cancer types. We further associated subtypes with clinical data and identified 5 tumor types (CRC-Colorectal carcinoma, HNSC-Head and neck squamous cell carcinoma, KIRC-Kidney renal clear cell carcinoma, LUAD-Lung adenocarcinoma and UCEC-Uterine corpus endometrial carcinoma) whose subtypes are significantly associated with overall survival, all based on small panels. Conclusion: Our analyses indicate that effective patient subtyping can be carried out using mutations detected in smaller gene panels, probably due to the enrichment of clinically important genes in such panels.