Molecular Landscape of Myeloid Neoplasms with Der(1;7)(q10;p10)

Abstract

Background: Der(1;7)(q10;p10) ((der(1;7)) is a derivative chromosome comprising 7p and 1q, accounting for approximately 1.5-6% of patients with MDS and AML. It is generated by an unbalanced translocation between chrs. 1 and 7, which results in +1q and -7q. Compared to other cases with -7/del(7q) which do not accompany +1q, der(1;7)(+) cases are reported to have a higher frequency of RUNX1 mutations and fewer TP53 mutations, and showed a better prognosis. However, the small number of cases enrolled and the lack of comprehensive analysis of driver mutations and transcriptome analysis in previous studies have prevented more detailed molecular characterization of der(1;7)(+) MDS/AML. Methods: We enrolled 148 cases with der(1;7) and analyzed their genetic profile using whole exome and/or targeted-capture sequencing as well as RNA-sequencing (N=10) and ATAC-sequencing (n=3). To establish the distinct characteristics of der(1;7)(+) we enrolled an additional 3,238 der(1;7)(-) myeloid neoplasm cases. Results: Highly skewed to male, der(1;7) was widely observed across different subtypes of myeloid neoplasms but it was more prevalent in MDS (107/1106, 9.7%) than AML (35/1466, 2.4%) or MDS/MPN (5/130, 3.8%) cases, while rarely found in MPN cases. Der(1;7)(+) AML cases were more frequently derived from MDS or therapy-related than those with -7/del(7q). Targeted-capture sequencing revealed that the profile of driver mutations and copy number alterations (CNAs) substantially differed between cases with der(1;7), -7/del(7q), +1q, and other cases, even after corrected for diagnosis. RUNX1 (37.8%), EZH2 (18.9%) and ETNK1 (18.2%) were more frequently mutated in der(1;7)(+) than other cases (OR=6.13-22.2), whereas TP53 mutations were less common in der(1;7)(+) cases compared to -7/del(7q). +8 and del(20q) were very common in der(1;7)(+) cases (18.9% and 37.4% respectively), compared to those with -7/der(7q),+1q, or other cases. Prognosis of der(1;7)(+) cases was slightly better than that of -7/del(7q) cases (HR=0.71, p=0.098), but worse than +1q cases (HR=1.36, p=0.11) and others cases (HR=1.8, p<0.001). The most frequent cause of deaths in der(1;7)(+) cases was infection (45.5%), followed by disease progression (36.4%), showing a sharp contrast to the cases with -7/del(7q) (13.9% and 72.3%, respectively) and other cases (10.8% and 76.9%, respectively). RNA-sequencing analysis revealed 1,463 differentially expressed genes in der(1;7) MDS cases compared to non-der(1;7) MDS cases. In GSEA analysis, significantly down-regulated pathways were related to cell cycles, innate immunity and TNFα signaling via NFκB. ATAC-seq analysis identified a total of 53,248 peaks, of which 2,243 were significantly upregulated in der(1;7)(+) samples. GATA family motifs were most significantly enriched in upregulated peaks, compared to other motifs. Footprint analysis further revealed that GATA transcription factors were predicted to bound to more peaks in der(1;7)(+) than der(1;7)(-). Consistent with this, expression of GATA2 downstream genes were significantly upregulated in der(1;7)(+) cases, suggesting the role of deregulated GATA2 downstream transcription in the pathogenesis of der(1;7)(+) MDS. Conclusion: Der(1;7)(+) defines a distinct subset of myeloid neoplasms characterized by a unique co-mutation patter, gene expression, and clinical features. Deregulated ETNK1 and GATA2 signaling might play a role in the pathogenesis of der(1;7)(+) myeloid neoplasms. Infections and other non-leukemic complications are the major cause of mortality in der(1;7)(+) cases and should be carefully monitored during their clinical course. Taken together, our findings provide new insight into the understanding of der(1;7)(+) myeloid neoplasms.