Abstract 3406: Comprehensive genomic profiling of hematologic malignancies identifies recurrent somatic splicing factor mutations in non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM)
Authors: Albacker Lee A. , Buonamici Silvia , Frampton Garrett M. , Smith Peter , Stephens Philip J. , Warmuth Markus , Zhu Ping , Yu Lihua 
Published: August 2018

Abstract
Somatic mutations of splicing factors have been reported in multiple tumor types and have been recognized as a new hallmark of cancer. Although these mutations have been observed in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML) and chronic lymphocytic leukemia (CLL), the frequency of these mutations in other hematological malignancies is unknown.
We surveyed somatic mutations of several splicing factors (SF3B1, SRSF2, U2AF1, ZRSR2, DDX3X, ZMYM3, PCBP1 and U2AF2) in 6,235 patients across 15 hematological malignancies. 405 genes were analyzed by DNAseq at &gt;500X coverage using FoundationOneHeme. Consistent with prior reports, we found that the hematopoietic malignancies with the most frequent splicing factor mutations were CMML (48.3%), MDS (36.9%), AML (25.3%) and CLL (22.5%). However, we also identified splicing factor mutations in NHL (13.8%) and MM (9%). In addition to mutations found across the different hematopoietic malignancies in SRSF2 (6%), SF3B1 (4.5%), U2AF1 (3.3%) and ZRSR2 (2.2%), we found DDX3X to be the fifth most frequently mutated gene at 1.6%, followed by ZMYM3 (0.8%), PCBP1 (0.5%) and U2AF2 (0.4%), indicating the importance of splicing dysregulation in hematological malignancies.
Within NHL, diffuse large B cell lymphoma (DLBCL) has the highest frequency of splicing factor mutations (18.3%), and these patients exhibited increased tumor mutation burden (TMB, 13.7 vs. 10.0 mutations per Mb, P &lt; 0.05). Among the splicing factors, the RNA helicase DDX3X is the most frequently mutated in NHL (5.2%). DDX3X is a X chromosome gene and its mutations in NHL are associated with male gender (P = 0.006). Consistent with the reported mutations in CLL and natural killer/T-cell lymphoma, the majority of mutations are loss of function or missense mutations clustered in the two helicase domains. This suggests a pathological relevance of DDX3X in lymphoid malignancies.
In MM, SF3B1 and SRSF2 are two most frequently mutated genes at 3.8% and 1.9%, and patients with these mutations are associated with increased TMB (4.2 vs. 2.5, P &lt; 0.001). Moreover, SF3B1 mutations occurred in 5.3% of samples with IGH-CCND1/2/3 or IGH-MAF/MAFB translocations, but &lt;1% of samples with IGH-WHSC1/FGFR3 translocations. Although the most common SF3B1 mutation in hematopoietic malignancies is p.K700E, in MM the most frequent SF3B1 mutation is p.K666 (36.9% vs p.K700E 12.3%).
Here, we identify splicing factor mutations in NHL and MM, including hotspot somatic mutations of SF3B1, U2AF1 and SRSF2 and loss of function or missense mutations in DDX3X. Overall, our results broaden the disease association of splicing factor mutations in hematological malignancies and strengthen their role in disease pathogenesis.
Citation Format: Lee A. Albacker, Silvia Buonamici, Garrett M. Frampton, Peter Smith, Philip J. Stephens, Markus Warmuth,, Ping Zhu, Lihua Yu. Comprehensive genomic profiling of hematologic malignancies identifies recurrent somatic splicing factor mutations in non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3406.