Audit of B-cell cancer genes

Comprehensive genetic analysis of tumors with exome or whole-genome sequencing has enabled the identification of the genes that are recurrently mutated in cancer. This has stimulated a series of exciting advances over the past 15 years, guiding us to new molecular biomarkers and therapeutic targets among the common mature B-cell neoplasms. In particular, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Burkitt lymphoma (BL) have each been the subject of considerable attention in this field. Currently, >850 genes have been reported as targets of protein-coding mutations in at least 1 of these entities. To reduce this to a manageable size, we describe a systematic approach to prioritize and categorize these genes, based on the quality and type of supporting data. For each entity, we provide a list of candidate driver genes categorized into Tier 1 (high-confidence genes), Tier 2 (candidate driver genes), or Tier 3 (lowest-confidence genes). Collectively, this reduces the number of high-confidence genes for these 3 lymphomas to a mere 144. This further affirms the substantial overlap between the genes relevant in DLBCL and each of FL and BL. These highly curated and annotated gene lists will continue to be maintained as a resource to the community. These results emphasize the extent of the knowledge gap regarding the role of each of these genes in lymphomagenesis. We offer our perspective on how to accelerate the experimental confirmation of drivers using a variety of model systems, using these lists as a guide for prioritizing genes.