Myeloid neoplasms with isolated isochromosome 17q demonstrate a high frequency of mutations in SETBP1, SRSF2, ASXL1 and NRAS

Rashmi Kanagal-Shamanna,Keyur P Patel,Rajyalakshmi Luthra,Zhuang Zuo,Carlos E Bueso-Ramos,John Lee,Rajesh R Singh,Patricia Fox,Francesco Stingo,Cameron C Yin,Xinyan Lu,Koichi Takahashi,Guillermo Garcia-Manero,Mark J Routbort,Chong Zhao,Farhad Ravandi,L Jeffrey Medeiros

doi:10.18632/oncotarget.7350

Rashmi Kanagal-Shamanna, Keyur P Patel + Show 15 more

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Isolated isochromosome 17q, i(17q), accounts for less than 1% of myeloid neoplasms that are commonly classified as myelodysplastic/myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN). We have shown previously that these cases have distinctive clinicopathologic features, a poor prognosis and absence of TP53 mutations. However, their molecular mutation profile has not been studied. Here, we explored the mutation profile of 32 cases of myeloid neoplasm with isolated i(17q) that included AML, MDS/MPN, MDS and MPN. In addition to the common i(17q), these neoplasms had frequent mutations in SRSF2 (55%), SETBP1 (59%), ASXL1 (55%), and NRAS (31%); TET2 and TP53 mutations were rare. Eight of 28 patients (29%) showed concurrent mutations in ASXL1, SRSF2, SETBP1 and RAS. There was a significant association between mutations in SETBP1 and RAS (p = 0.003). The mutation pattern was independent of the morphologic diagnosis. Sequential analysis of 5 cases showed evolution from a diploid karyotype to i(17q) and that SRSF2 and ASXL1 mutations precede the detection of i(17q) whereas SETBP1 mutations are associated with i(17q).

Highlights

Isochromosome 17q [i(17q)] is a non-random cytogenetic abnormality that involves deletion of the short “p” arm and duplication of the long “q” arm of chromosome 17
Using sequential mutation analysis in 5 cases that showed evolution of i(17q) abnormality from a diploid karyotype, we show that SRSF2 and ASXL1 mutations precede the detection of i(17q), whereas SETBP1 mutations are associated with i(17q)
We performed mutation analysis of 33 genes using a combination of next-generation sequencing based analysis on all 32 cases targeting the coding regions of 28 genes; and Sanger sequencing for splicing factors, CEBPA, MDM4 and SETBP1

Summary

Introduction

Isochromosome 17q [i(17q)] is a non-random cytogenetic abnormality that involves deletion of the short “p” arm and duplication of the long “q” arm of chromosome 17 It is frequently observed in the setting of a complex karyotype in blast phase of chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML). The presence of isolated i(17q) in myeloid neoplasms is associated with certain distinctive clinicopathologic findings as shown in several recent studies [1,2,3]. These neoplasms are often classified as myelodysplastic/myeloproliferative neoplasms (MDS/MPN) or high-grade myelodysplastic syndrome (MDS)/ AML, and show characteristic morphologic findings, in particular pseudo Pelger-Huet neutrophils and small hypolobated megakaryocytes. I(17q) is classified as “intermediate” cytogenetic prognostic subgroup per the revised International Prognostic Scoring System (IPSS) for MDS [4, 5]; and as an “adverse” cytogenetic prognostic subgroup per revised Medical Research Council classification for AML [6]

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