Abstract LB-326: Identification of novel recurrent mutations in follicular lymphoma
Authors: Krysiak Kilannin , Gomez Felicia , White Brian S. , Matlock Matthew , Miller Chris A. , Fulton Robert S. , Kreisel Friederike , Cashen Amanda F. , Carson Kenneth R. , Berrien-Elliott Melissa M. , Bartlett Nancy L. , Wilson Richard K. , Mardis Elaine R. , Griffith Malachi , Griffith Obi L. , Fehniger Todd A. 
Published: July 2016

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma and although often responsive to treatment remains incurable with conventional therapies. Approximately 30% of patients will undergo transformation to a more aggressive, clonally related malignancy (t-FL). Our understanding of the genomic landscape of FL is limited when compared to other hematologic malignancies such as acute myeloid leukemia or diffuse large B-cell lymphoma.

To better understand the FL genomic landscape and identify novel recurrent mutations, we performed exome sequencing on fresh frozen samples from a discovery cohort of 24 patients with FL prior to treatment (12), FL relapsed after prior therapy (6) or t-FL (6) with paired normal skin samples. From this analysis, we identified 898 genes harboring mutations. We combined these results with a list of 819 recurrently mutated genes from 10 sequencing studies of other B-cell malignancies to develop a custom capture reagent targeting the coding regions and UTRs of 1717 genes. We applied this reagent to the initial discovery samples and an additional 81 FFPE tumor samples from patients with FL (80) or t-FL (1), achieving &gt;20x coverage for &gt;75% of the targeted region.

Through this approach, we confirmed previously described mutations in chromatin/epigenetic modifiers (MLL2 [60%], CREBBP [55%], EP300 [19%], EZH2 [17%], MEF2B [7.6%]), histones linkers (HIST1H1C/E [21%]), transcription factors (IRF8 [13%], STAT6 [12%]), and the BCR signaling pathway (CD79B [5.7%], CARD11 [11.4%], BCL10 [2.8%], TNFAIP3 [2.8%]). Additionally, we identified mutations in novel genes within the previously implicated BCR pathway (CD22 [3.8%], BTK [8.6%], HVCN1 [7.6%]) and multiple hits in complexes not previously described in association with FL such as the Swi/Snf nucleosome remodeling complex (ARID1A/B [8.6%], SMARCA4 [4.8%], SMARCB1 [1.9%], BCL7A [21%], BCL11A [1.9%], PBRM1 [1.9%], DPF1 [1%], ACTB [1%]), hotspot mutations in vacuolar ATPases (ATP6V1B2 [8.6%], VMA21 [4.8%]) and others (EGR1/2 [6.7%], POU2AF1 [6.7%]). Though many of these mutations have been independently reported in patients, those studies lacked sufficient size to evaluate their statistical significance. In contrast, the strength of our approach is illustrated in our finding of 54 genes significantly mutated above background mutation rates (FDR&lt;0.15). Clinical outcomes and treatment regimen data were available for 100 patients, and as expected, the FLIPI score was predictive of PFS. Notably, improved PFS was observed in treated patients harboring novel HVCN1 mutations (p&lt;0.05). In contrast, CREBBP mutations were associated with reduced PFS (p&lt;0.05). Although larger cohort sizes are required to more robustly associate clinical outcomes and mutation profiles, we have identified novel recurrent mutations and pathways in FL. Such discoveries are key to understanding the etiology of and the development of novel therapeutic approaches for FL.

Citation Format: Kilannin Krysiak, Felicia Gomez, Brian S. White, Matthew Matlock, Chris A. Miller, Robert S. Fulton, Friederike Kreisel, Amanda F. Cashen, Kenneth R. Carson, Melissa M. Berrien-Elliott, Nancy L. Bartlett, Richard K. Wilson, Elaine R. Mardis, Malachi Griffith, Obi L. Griffith, Todd A. Fehniger. Identification of novel recurrent mutations in follicular lymphoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-326.