Abstract 4683: Co-existence of SRSF2 and EZH2 gene mutations in myeloid malignancies
Authors: Cherukuri Durga P. , Kwok Brian , Lekostaj Jacqueline , Petersen Paris , Bui Peter , Nooraie Farzad , Cheng Li , Fike Francesca , Taylor David A. , Dabbas Bashar , Mcginniss Matthew J. 
Published: July 2017

Abstract
SRSF2 is recurrently mutated in a variety of myeloid malignancies, including chronic myelomonocytic leukemia (CMML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), and acute myeloid leukemia (AML); and most alterations involve the codon proline-95 (P95). In vitro studies have shown that the SRSF2-P95H mutation affects splicing of EZH2 and functionally reduces its protein expression. Inactivating mutations of EZH2, located at 7q36.1, have also been reported in a variety of myeloid malignancies. Studies have shown that SRSF2 and EZH2 gene mutations are mutually exclusive events. In this study, we retrospectively analyzed next-generation sequencing results of 16,767 patient cases with a clinical indication of a possible myeloid malignancy. All exons of the EZH2 gene and exon 1 of SRSF2 gene were sequenced. A total of 33 cases (0.2%) had mutations in both SRSF2 and EZH2 genes; 70% were male (age: 58-&gt;89 years) and 30% were female (age: 64-&gt;89 years). Of the 20 cases with sufficient material for rendering a pathologic diagnosis, 40% were CMML; 10% were MDS/MPN, unclassifiable; 10% were AML with MDS-related changes and monocytic differentiation; 10% were AML with MDS-related changes and no monocytic differentiation; 10% were MDS; 10% were AML, not otherwise specified, with monocytic differentiation; 5% were AML, not otherwise specified, without monocytic differentiation; and 5% were primary myelofibrosis. In total, 60% (12/20) of the cases with co-existing SRSF2 and EZH2 mutations displayed monocytic differentiation. In 97% (32/33) of the cases, SRSF2 mutations occurred in the hot spot codon, proline-95 [P95H (13 cases), P95R (8), P95L (6), P95T (3), P95V (1), and P95 deletion (1)]. In regards to EZH2, a single mutation was detected in 88% (29/33) of the cases. Double mutations were found in four cases with both mutations detected simultaneously in three cases and, acquisition of a second frameshift mutation noted in one case. EZH2 loss-of-function mutations including frameshift, nonsense, and splice-site mutations were detected in 40% (13/33) of the cases. Missense mutations were detected in 48% (16/33) of the cases, and 56% of these mutations were located in the conserved catalytic SET domain of the EZH2 protein. The other mutations included an in-frame insertion involving the SET domain and splice-region mutations. Cytogenetic information was available for 16 cases with 56% showing a normal karyotype. Trisomy 8 was the predominant chromosomal abnormality observed, especially in cases of AML. One case with AML with MDS-related changes showed monosomy 7 and an EZH2-R690H mutation. In conclusion, our data demonstrate that mutations in SRSF2 and EZH2 can infrequently co-exist in different subtypes of myeloid malignancies, and are associated with monocytic differentiation in most cases.
Citation Format: Durga P. Cherukuri, Brian Kwok, Jacqueline Lekostaj, Paris Petersen, Peter Bui, Farzad Nooraie, Li Cheng, Francesca Fike, David A. Taylor, Bashar Dabbas, Matthew J. Mcginniss. Co-existence of SRSF2 and EZH2 gene mutations in myeloid malignancies [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 4683. doi:10.1158/1538-7445.AM2017-4683