Go, Ronald S.

ObjectiveErdheim‐Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome‐wide association study.MethodsAfter quality controls, a cohort of 255 patients with ECD and 7,471 healthy donors was included in this study. Afterward, a logistic regression followed by in silico functional annotation was performed.ResultsA signal at the 18q12.3 genomic region was identified as a new susceptibility locus for ECD (P = 2.75 × 10−11; Odds Ratio = 2.09). This association was annotated to the SETBP1 gene, which is involved in clonal haematopoiesis. Functional annotation of this region and of the identified suggestive signals revealed additional genes that could be potentially involved in the pathogenesis of the disease.ConclusionOverall, this work demonstrates that germline genetic variants can impact on the development of ECD and suggests new pathways with a potential pathogenic role.image

Abstract Most patients with solitary bone plasmacytomas (SBP) progress to multiple myeloma (MM) after definitive radiation therapy as their primary treatment. Whether the presence of high-risk (HR) cytogenetic abnormalities by fluorescence in situ hybridization (FISH) in the clonal plasma cells, obtained either directly from the diagnostic SBP tissue or the corresponding bone marrow examination at the time of diagnosis, is associated with a shorter time to progression (TTP) to MM is unknown. This study evaluated all patients diagnosed with SBP at the Mayo Clinic from January 2012 to July 2022. The presence of del(17p), t(14;16), t(4;14), or +1q (gain or amplification) by FISH in clonal plasma cells was defined as HR. A total of 114 patients were included in this cohort, and baseline FISH was available for 55 patients (48%), of which 22 were classified as HR (40%). The median TTP to MM for patients with SBP and HR FISH was 8 months (95% confidence interval [CI], 6.3-26) compared with 42 months (95% CI, 25-not reached [NR]) in patients with SBP without HR FISH (P < .001). In a multivariate analysis, only HR FISH was a significant predictor for shorter TTP to MM, independent of minimal marrow involvement and an abnormal serum free light chain ratio at diagnosis. Deletion (17p) and gain 1q abnormalities were the most common FISH abnormalities responsible for the short TTP to MM. Thus, assessing for HR FISH abnormalities in clonal plasma cells derived from either the diagnostic SBP tissue or the staging bone marrow examination of patients with newly diagnosed SBP is feasible and prognostic for a shorter TTP to MM.

Abstract Objectives Understanding of histiocytic disorders has been revolutionized by demonstration of mitogen-activated protein kinase (MAPK) pathway mutations, most commonly BRAFV600E. The optimal testing strategy to assess BRAFV600E is unknown. We aimed to compare performance of testing modalities, to propose a framework for evaluation of BRAFV600E mutation status in histiocytic disorders. Methods We retrospectively reviewed patients with histiocytic disorders and BRAF mutation testing on a lesional tissue specimen. Results In 120 patients, BRAF assessment included immunohistochemistry (IHC) in 97 (80.2%), polymerase chain reaction (PCR) in 35 (28.9%), and next-generation sequencing (NGS) in 62 (51.2%). Forty-five underwent both NGS and IHC. With NGS as the gold standard, the sensitivity and specificity of IHC were 82.4% and 96.4%. Three false negatives were observed in biopsy specimens with low BRAFV600E variant allele frequency or decalcified tissue. One false-positive IHC was observed in a lung biopsy specimen, likely due to antibody cross-reactivity with respiratory cilia. Among 14 with successful NGS and PCR, a single discordance was observed. Two PCR-to-IHC discrepancies were observed, including one other false-positive IHC. Conclusions Immunohistochemistry was highly specific for detection of BRAFV600E. Main caveats were false negatives and lack of detection of non-BRAFV600E mutations. We propose the use of IHC as initial screening in general practice with reflex molecular testing if negative.

Abstract Objective To retrospectively identify patients with VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome) among male patients with bone marrow vacuolization using a clinically applicable, targeted-screening approach. Methods Bone marrow reports from 1 May 2014 through 18 February 2022 were reviewed for documentation of cytoplasmic vacuolization. Patients with acute leukaemia, lymphoma, metastatic solid tumour, amyloidosis or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome were excluded, as were those without clinical records available for direct chart review. Cases were rated for suspicion of VEXAS syndrome using a 5-point scale based on the presence of laboratory findings, clinical features and treatment response. Patients with available DNA material and moderate (three patients) or high (four to five patients) suspicion were tested for somatic UBA1 variants associated with VEXAS syndrome. Results A total of 315 reports from 292 unique patients included documentation of vacuolization. Following exclusion criteria, 64 patients underwent direct medical chart review to assess likelihood of VEXAS syndrome, for which 21 patients met moderate to high suspicion. Available DNA was present in eight patients, seven (87.5%) of whom had a pathogenic somatic UBA1 variant consistent with VEXAS syndrome. The distribution of cytoplasmic vacuolization in the bone marrow biopsy reports among patients with VEXAS syndrome were erythroid and myeloid precursors (6/7), erythroid precursors only (1/7) and myeloid precursors only (0/7). Conclusion In this study, the utilization of a clinically applicable targeted-screening approach to test bone marrow specimens (with vacuolization) for the presence of previously undiagnosed VEXAS syndrome resulted in a positive detection rate of 87.5%.

VEXAS is caused by somatic mutations in UBA1 (UBA1mut) and characterized by heterogenous systemic auto-inflammation and progressive hematologic manifestations, meeting criteria for myelodysplastic syndrome (MDS) and plasma cell dyscrasias. The landscape of myeloid-related gene mutations leading to typical clonal hematopoiesis (CH) in these patients is unknown. Retrospectively, we screened 80 VEXAS patients for CH in their peripheral blood (PB) and correlated findings with clinical outcomes in 77. UBA1mutwere most common at hotspot p.M41 (median variant allele frequency/VAF = 75%). Typical CH mutations co-occurred with UBA1mut in 60% of patients, mostly in DNMT3A and TET2, and were not associated with inflammatory or hematologic manifestations. In prospective single-cell proteogenomic sequencing (scDNA), UBA1mutwas the dominant clone, present mostly in branched clonal trajectories. Based on integrated bulk and scDNA analyses, clonality in VEXAS followed two major patterns: with either typical CH preceding UBA1mutselection in a clone (Pattern 1), or occurring as an UBA1mutsubclone or in independent clones (Pattern 2). VAF in PB differed markedly between DNMT3A and TET2 clones (median VAF of 25% vs 1%). DNMT3A and TET2 clones associated with hierarchies representing patterns 1 and 2, respectively. Overall survival for all patients was 60% at 10 years. Transfusion-dependent anemia, moderate thrombocytopenia, and typical CH mutations, each correlated with poor outcome. In VEXAS, UBA1mut cells are the primary cause of systemic inflammation and marrow failure, being a new molecularly defined somatic entity associated with MDS. VEXAS-associated MDS is distinct from classical MDS in its presentation and clinical course.