As one of few viral-positive cancers, nasopharyngeal carcinoma (NPC) is extremely rare across the world but very frequent in several regions of the world, including Southern China (known as the Cantonese cancer). Even though several genomic studies have been conducted for NPC, their sample sizes are relatively small and systematic comparison with other cancer types has not been explored. In this study, we collected four-hundred-thirty-one samples from six previous studies and provided the first integrative analysis of NPC genomes. Combining several statistical methods for detecting driver genes, we identified 25 novel drivers for NPC, including ATG14 and NLRC5. Many of these novel drivers are enriched in several important pathways, such as autophagy and immunity. By comparing NPC with many other cancer types, we found NPC is a unique cancer type in which a high proportion of patients (45.2%) do not have any known driver mutations (termed as "missing driver events") but have a preponderance of deletion events, including chromosome 3p deletion. Through signature analysis, we identified many known and novel signatures, including single-base signatures (n = 12), double-base signatures (n = 1), indel signatures (n = 9) and copy number signatures (n = 8). Many of these new signatures are involved in DNA repair and have unknown etiology and genome instability, implying an unprecedented dynamic mutational process possibly driven by complex interactions between viral and host genomes. By combining clinical, molecular and intra-tumor heterogeneity features, we constructed the first integrative survival model for NPC, providing a strong basis for patient prognosis and stratification. Taken together, we have performed one of the first integrative analyses of NPC genomes and brought unique genomic insights into tumorigenesis of a viral-driven cancer.
Keywords: NPC; copy number variations; driver genes; genome instability; integrative analysis; mutational signatures.