Myeloid neoplasms with germline DDX41 mutations have been incorporated into the 2017 WHO classification. Limited studies describing the clinicopathologic features and mutation profile are available. We searched for myeloid neoplasms with a DDX41 gene mutation tested by an 81-gene next-generation sequencing panel over a 7-month period. We identified 34 patients with myeloid neoplasms with DDX41 abnormalities; 26 (76%) men and 8 women (24%) [median age, 70 years], 20 acute myeloid leukemia (AML), 10 myelodysplastic syndrome (MDS), 1 chronic myelomonocytic leukemia (CMML) and 3 myeloproliferative neoplasms (MPN). Fiftynine DDX41 variants were detected: 27 (46%) appeared somatic and 32 (54%) were presumably germline mutations. The majority of presumed germline mutations were upstream of the Helicase 2 domain (93%) and involved loss of the start codon (30%).The majority of somatic mutations were within the Helicase 2 domain (78%), with the missense mutation p.R525H being most common (67%). There was a significant difference in the location of germline or somatic mutations (P < .0001). Concomitant mutations were detected involving 19 genes, but only TP53 (n = 11, 32%), ASXL1 (n = 8, 24%), and JAK2 (n = 4, 12%) were recurrent. Twenty (59%) patients showed diploid cytogenetics. Twenty-three (68%) patients presented with AML or MDS-EB-2, suggesting an association with high-grade myeloid neoplasm. Patients with myeloid neoplasms carrying DDX41 mutations show male predominance (3:1), higher age at presentation, association with TP53 mutations, and association with high-grade myeloid neoplasms in our cohort at a referral cancer center setting. These findings support the recognition of myeloid neoplasms with DDX41 mutation as unique, need for germline confirmation, and further assessment of family members.
Mutant TP53 is an adverse risk factor in acute myeloid leukemia (AML), but large-scale integrated genomic-proteomic analyses of p53 alterations in AML patients remain limited. We analyzed TP53 mutational status, copy number (CN), and protein expression data in AML (N=528) and provide a compilation of mutation sites and types across disease subgroups among treated and untreated patients. Our analysis shows differential hotspots in subsets of AML and uncovered novel pathogenic variants involving TP53 splice sites. In addition, we identified TP53 CN loss in 70.2% of TP53-mutated AML, which had more deleterious TP53 mutations and copy neutral loss of heterozygosity in 5/32 (15.6%) AML patients who had intact TP53 CN. Importantly, we demonstrate that mutant p53 protein expression patterns by immunohistochemistry evaluated using digital image-assisted analysis provide a robust readout that integrates TP53 mutation and allelic states in patients with AML (sensitivity=94.49%, specificity=90.48%). Protein expression of p53 by immunohistochemistry informed mutation status irrespective of TP53 CN status. Genomic analysis of co-mutations in TP53-mutant AML showed a muted landscape that encompassed primarily mutations in genes involved in epigenetic regulation (DNMT3A and TET2), RAS/MAPK signaling (NF1, KRAS/NRAS, PTPN11), and RNA splicing (SRSF2). In summary, our data provides a rationale to refine risk stratification of AML patients on the basis of integrated molecular and protein-level TP53 analyses.
Chromosome banding analysis (CBA) remains the standard-of-care for structural variant (SV) assessment in MDS. Optical genome mapping (OGM) is a novel, non-sequencing-based technique for high-resolution genome-wide SV profiling (SVP). We explored the clinical value of SVP by OGM in 101 consecutive, newly diagnosed MDS patients from a single-center, who underwent standard-of-care cytogenetic and targeted NGS studies. OGM detected 383 clinically significant, recurrent and novel SVs. Of these, 224 (51%) SVs, seen across 34% of patients, were cryptic by CBA (included rearrangements involving MECOM, NUP98::PRRX2, KMT2A partial tandem duplications among others). SVP decreased the proportion of normal karyotype by 16%, identified complex genomes (17%), chromothripsis (6%) and generated informative results in both patients with insufficient metaphases. Precise gene/exon-level mapping allowed assessment of clinically relevant biomarkers (TP53 allele status, KMT2A-PTD) without additional testing. SV data was complementary to NGS. When applied in retrospect, OGM results changed the comprehensive cytogenetic scoring system (CCSS) and R-IPSS risk-groups in 21% and 17% patients respectively with an improved prediction of prognosis. By multivariate analysis, CCSS by OGM only (not CBA), TP53 mutation and BM blasts independently predicted survival. This is the first and largest study reporting the value of combined SVP and NGS for MDS prognostication.
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