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).

Keywords: ASXL1; SETBP1; SRSF2; isochromosome 17q; myeloid neoplasms.

Figure 1. Mutational analysis of 32 cases of myeloid neoplasm with isolated i(17q) (red, mutation; gray, wild-type; white, not tested)

Genes are segregated based on the biologic functional categories on the left. The upper panels denote the case number, diagnostic categories per 2008 WHO classification and clonal cytogenetic abnormalities. Case #31 could not be sub-classified. Isochromosome (17q) was detected on a post-allogeneic stem cell transplant sample that showed relapsed AML. The pre-transplant cytogenetic studies were diploid, and molecular studies were unavailable. The patient also had a history of breast carcinoma treated with chemotherapy. Cases 7, 9 and 31 (highlighted in lavender) also underwent whole-exome sequencing. *represents a non-R882 DNMT3A mutation. aCML, atypical chronic myeloid leukemia; AML, acute myeloid leukemia; AML MRC, AML with myelodysplasia-related changes; CMML, chronic myelomonocytic leukemia; ET, Essential thrombocythemia; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; MDS/MPN, myelodysplastic/myeloproliferative neoplasm; MDS/MPN-U, myelodysplastic/myeloproliferative neoplasm unclassifiable; MF, myelofibrosis; RAEB, refractory anemia with excess blasts; sAML, secondary AML; SCT, stem cell transplant.

Figure 2. Sequential mutation analysis of myeloid neoplasms during the evolution from a diploid karyotype to the development of isolated i(17q) abnormality

In case #5, i(17q) was observed after allogeneic stem cell transplant. In case #6, i(17q) abnormality was transient (noted for only a duration of 6 months).