Recurrent somatic mutations affecting B-cell receptor signaling pathway genes in follicular lymphoma

Kilannin Krysiak, Felicia Gomez, Brian S White, Matthew Matlock, Christopher A Miller, Lee Trani, Catrina C Fronick, Robert S Fulton, Friederike Kreisel, Amanda F Cashen, Kenneth R Carson, Melissa M Berrien-Elliott, Nancy L Bartlett, Malachi Griffith, Obi L Griffith, Todd A Fehniger

Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma, yet it remains only partially characterized at the genomic level. In order to improve our understanding of the genetic underpinnings of this incurable and clinically heterogeneous disease, whole exome sequencing was performed on tumor/normal pairs from a discovery cohort of 24 patients with FL. Using these data, and mutations identified in other B-cell malignancies, 1716 genes were sequenced in 113 FL tumor samples, from 105 primarily treatment-naïve individuals. We identified 39 genes mutated significantly above background mutation rates. CREBBP mutations were associated with inferior PFS. In contrast, mutations in previously unreported HVCN1, a voltage-gated proton channel-encoding gene and B-cell receptor signaling modulator, were associated with improved PFS. In total, 47 [44.8%] patients harbor mutations in the interconnected BCR and CXCR4 signaling pathways. Histone gene mutations were more frequent than previously reported (identified in 43.8% of patients) and often co-occurred (17.1% of patients). A novel, recurrent hotspot was identified at a post-translationally modified residue in the histone H2B family. This study expands the number of mutated genes described in several known signaling pathways and complexes involved in lymphoma pathogenesis (BCR, Notch, SWI/SNF, V-ATPases) and identified novel recurrent mutations (EGR1/2, POU2AF1, BTK, ZNF608, HVCN1) that require further investigation in the context of FL biology, prognosis, and treatment.