Abstract 2444: Recurrent mutations and clinical outcomes in patients with follicular lymphoma
Authors: Krysiak Kilannin , Ramirez Cody , Gomez Felicia , Miller Christopher A. , Fulton Robert S. , Kreisel Friederike , Cashen Amanda F. , Bartlett Nancy L. , Ruano Ana , Hsi Eric D. , Griffith Malachi , Griffith Obi L. , Fehniger Todd A. 
Published: July 2017

Abstract
Follicular lymphoma (FL), the most common indolent non-Hodgkin lymphoma (NHL), is associated with a highly heterogeneous clinical course. The genetic landscape of FL is less understood than other B-cell NHLs such as chronic lymphocytic leukemia and diffuse large B-cell lymphoma. With ongoing clinical trials using therapies targeting B cell receptor signaling (e.g., ibrutinib) in FL, recurrent mutations could impact the interpretation of these trial outcomes and the identification of specific patient subpopulations that have increased or decreased clinical benefit.
To identify novel recurrent mutations in FL, we designed a large custom capture lymphoma-related gene panel (WUSM-LP) and queried 113 predominantly treatment-naïve FL samples. To design the WUSM-LP reagent (NimbleGen), we targeted the coding regions of 1716 genes identified in exome sequencing data from a cohort of 24 patients (28 samples) with FL combined with genes recurrently mutated in B-cell non-Hodgkin lymphoma in the literature (Krysiak K et al., Blood, 2016). Previously, we applied the WUSM-LP to the discovery cohort and an additional 81, primarily treatment-naïve, FL samples. Using mutations identified in these 105 individuals, we identified 39 significantly mutated genes (SMGs). These included well-characterized genes in FL (e.g., KMT2D, EZH2, TNFRSF14), and identified novel mutations (BTK, HVCN1, and others) thereby expanding the repertoire of mutations affecting genes in the BCR signaling pathway, SWI/SNF complex and histone family. Including novel BTK mutations, we identified 23 (22%) individuals harboring mutations that likely up-regulate signaling downstream of BTK, potentially affecting response rates to BTK-targeting therapies at the point of FL diagnosis.
We also focused on the subset FL patients (N=59) that were sequenced within 1 year of front-line therapy in order to identify clinical associations between recurrent mutations and clinical outcomes, comparing mutation status of SMGs to progression-free survival (PFS) rates. Improved PFS was observed in patients harboring HVCN1 mutations (p&lt;0.05) in the treated cohort. CREBBP mutations were associated with significantly reduced PFS (p&lt;0.05).
Since our initial analysis, we have completed sequencing of an additional 174 FL samples with clinical data available. Confirming our earlier observations with an independent cohort, we observed 9 TNFAIP3 truncating, 18 CARD11 coiled-coil domain, 4 BCL10 truncating and 8 BTK mutations in these samples. These mutations affect 18.4% of FL patients in this cohort, are likely to up-regulate NFkappaB signaling and may impact ibrutinib sensitivity. With the additional power of 8 HVCN1 and 110 CREBBP mutations we have identified, we will evaluate the previously identified associations. The analyses of recurrent mutations and clinical correlations in this combined cohort of nearly 300 FL patients are ongoing and will be presented.
Citation Format: Kilannin Krysiak, Cody Ramirez, Felicia Gomez, Christopher A. Miller, Robert S. Fulton, Friederike Kreisel, Amanda F. Cashen, Nancy L. Bartlett, Ana Ruano, Eric D. Hsi, Malachi Griffith, Obi L. Griffith, Todd A. Fehniger. Recurrent mutations and clinical outcomes in patients with follicular lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2444. doi:10.1158/1538-7445.AM2017-2444