Genomics of PDGFR-rearranged hypereosinophilic syndrome

Abstract

The World Health Organization and International Consensus Classification classifications of myeloid neoplasms define a category of myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions.1-3 The most frequent neoplasms in this category are associated with FIP1L1::PDGFRA (F/P) fusions, created because of a somatic, acquired interstitial deletion on chromosome 4q12.4-7 Patients with F/P or rearrangements of PDGFRB may present with hypereosinophilic syndrome (HES), defined as >1.5 × 106 eosinophils/mL blood and evidence of eosinophil-mediated end–organ manifestations.8,9 Patients with PDGFR-rearranged HESN (HES related to a primary myeloid neoplasm) are mostly males, and the hypereosinophilia responds robustly to the multikinase inhibitor imatinib, which targets the constitutive PDGF receptor signaling driven by the fusions.3-7 Our goal was to investigate HESN whole genomes to better characterize the disease and its unique features. Unbiased genomics of PDGFR-rearranged HES have not been comprehensively studied at genome scale, with only small, targeted sequencing panel data reported.10 We performed whole-genome sequencing (WGS) on purified eosinophils (tumor) from 11 patients with chronic phase PDGFR–related HESN (supplemental Table 1; supplemental Methods). Paired normal samples were peripheral blood mononuclear cells collected in hematologic and molecular remission after imatinib treatment, in the setting of normal eosinophil counts and no detectable PDGFR rearrangement (Figure 1A; supplemental Figure 1A). The median age at tumor sampling was 43 years (range, 13-60; supplemental Table 1); there were 10 males and 1 female (expected sex bias5). Nine males had evidence of an F/P fusion. The female had a PDGFRB::ETV6 rearrangement, and 1 male had a novel complex rearrangement involving PDGFRB (as described later in the article). The mean sequencing depth was 83 (range, 61-144) for tumor and 91 (range, 67-125) for normal (supplemental Figure 1B; supplemental Table 2). Few segmental DNA copy number alterations were detected, and the interstitial deletion between FIP1L1 and PDGFRA was the only recurrent event (Figure 1B). F/P was also the most frequently identified structural variant (SV) (supplemental Table 1). No evidence of F/P was detected in paired normal samples. All breakpoints in PDGFRA occurred within exon 12 (Figure 1C). The FIP1L1 breakpoints spanned a region of ~45 kb covering introns 8 to 12 (Figure 1D; supplemental Table 1). SV analysis confirmed PDGFRB fusions in 2 tumors with PDGFRB events using fluorescence in situ hybridization (supplemental Table 1). One was a classic ETV6::PDGFRB fusion.12 The other comprises a previously unreported rearrangement involving IQGAP2 and PDGFRB on chromosome 5 and UVRAG on chromosome 11. This SV created an in-frame protein fusion between exon 10 of IQGAP2 and exon 12 of PDGFRB, with the other ends of these breakpoints connecting to the first intron of UVRAG (Figure 1E-F; supplemental Figure 1C).