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

Abstract

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).

Somatic SETBP1 mutations in myeloid neoplasms

“…4c) [30,45,57,61]. Isochromosome 17q (i(17q)) is also associated with SETBP1 mutations (54%) [45,48,57,62]. Especially, TP53 and SETBP1 mutations were completely exclusive in cases with i(17q), suggesting that these two major prognostic events are independently involved in poor outcome in myeloid neoplasms [63].…”

TP53 mutation does not confer a poor outcome in adult patients with acute lymphoblastic leukemia who are treated with frontline hyper‐CVAD‐based regimens

“…TP53 mutation analysis was assessed on BM samples by targeted next-generation sequencing (NGS)-based multi-gene profiling 14 (n=124) or Sanger sequencing (SS) (n=40). TP53 mutation analysis by NGS was performed on 250 ng of genomic DNA extracted from bone marrow samples.…”

Next‐generation sequencing reveals unique combination of mutations in cis of CSF3R in atypical chronic myeloid leukemia

“…The Q157 residue is located in the second zinc finger domain, and Q157P is a known pathogenic mutation that alters splicing of many important genes in myeloid disorders, while the prognostic significance has not been fully investigated in aCML. Interestingly, several molecular features in the patient are considered to be related with dysplasia, which is a typical bone marrow finding in aCML SETBP1 mutation is reported to be related with dysplastic morphology in MDS/MPN . The mutation in aCML having dysplasia as one of diagnostic hallmark is frequently found with 24% .…”