Abstract 481: Distinct and overlapping patterns of B-cell growth pathway mutations in CD5-negative B-cell lymphoproliferative disorders

Abstract

Low-grade CD5-negative B-cell lymphoproliferative disorders (CD5- LG B-LPD) encompass several entities that often show mutations in different growth regulatory pathways. These include MYD88 (TLR signaling), CD79A/B (BCR complex), CARD11 (CBM signalosome), CXCR4 (chemokine receptor), and NOTCH1/2 and are complemented by KLF2 mutations and BCL6 and MALT1 overexpression. Using targeted, next-generation sequencing (NGS) for 50 B-cell associated growth regulators and epigenetic modifiers (>1000X depth) and cytogenetic/FISH data, we sought to delineate the complementary mutation and gene amplification patterns in 45 consecutive cases of CD5- LG B-LPD. In mutation-negative cases, a 572-gene NGS panel was used to interrogate these pathways more completely. WHO diagnostic criteria were used, without reliance on molecular data, emphasizing morphology features, paraprotein level and type to distinguish lymphoplasmacytic lymphoma (LPL) from marginal zone lymphoma (MZL). As expected, MYD88 L265P mutations were seen in the majority of LPL (11/17, 65%), but also in CD5- chronic lymphocytic leukemia (CLL) (3/9, 33%) and splenic (S) MZL (1/6, 17%) but not in nodal MZL. In 4 LPL cases lacking MYD88 L265P, extra copies of chromosome 3 (BCL6), 6 (IRF4), 12 and/or 18 (MALT1) were seen, with CARD11 mutations in the other 2. NOTCH1/2 mutations were mostly associated with SLL/CLL (3/9, 33%). Mutations in epigenetic regulators (see Table) were seen in the majority of nodal MZL (8/13, 62%) but only few LPL (2/17, 12%) and SMZL (1/6, 17%). CXCR4 inactivating mutations were seen with MYD88 and CD79B mutations and +3/BCL6 alteration. CARD11 mutations were seen with KLF2, MYD88 and NOTCH1/2 mutations. Less common mutations targets included PTPRC and PLCG2 (pre-ibrutinib treatment). The higher rate of mutation in epigenetic regulators (along with loss of KLF2-mediated BCR signaling) supports a distinct pathogenesis for nodal MZL in contrast to other CD5- B-LPD. Calls per gene in MYD88 negative cases; *TP53, TET2, ASXL1, DNMT3A, BCORCD79BCARD11NOTCH1/2CXCR4KLF2Epigenetic gene set*LPL023000010000000010CD5- CLL000002001001001000001000000001sMZL011010010000000001nMZL000002000022000001010011000101000001000001000001012010000200 Citation Format: Sophia Shaddy, Weiqiang Zhao, Huolin Tu, Brianna Sisson, Rongqin Ren, Sean Caruthers, Susan Long, Peng Ru, Narendranath Epperla, Lynne Abruzzo, Kami Maddocks, Dan Jones. Distinct and overlapping patterns of B-cell growth pathway mutations in CD5-negative B-cell lymphoproliferative disorders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 481.