Molecular Discordance between Myeloid Sarcomas and Concurrent Bone Marrows Occurs in Actionable Genes and Is Associated with Worse Overall Survival.

Myeloid sarcoma is a rare, architecture-effacing proliferation of myeloid blasts localized to an extramedullary site, with or without concurrent bone marrow involvement. Clonal heterogeneity results from acquisition of somatic mutations within different subclones of leukemic cells. It was hypothesized that clonal heterogeneity between myeloid sarcomas and concurrent bone marrow biopsies might be present, given their differing biological features and microenvironment. High-throughput sequencing of the largest series (n = 24) of paired myeloid sarcomas and bone marrow biopsies was performed. One third of myeloid sarcomas (8/24) showed discordant molecular profiles, and 75% (n = 6) of these cases had discordant mutations in genes with prognostic significance or molecularly targeted therapies. Patients with molecularly discordant myeloid sarcoma had significantly worse overall survival (median survival, 195 days versus not reached, hazard ratio, 3.3, P < 0.05). Further investigation into molecular discordance between myeloid sarcoma and concurrent bone marrow biopsies may help in understanding clonal evolution of myeloid neoplasms and mechanisms regulating extramedullary blast localization.

Pathogenic Anti-Müllerian Hormone Variants in Polycystic Ovary Syndrome.

Context: Polycystic ovary syndrome (PCOS), a common endocrine condition, is the leading cause of anovulatory infertility. Objective: Given that common disease-susceptibility variants account for only a small percentage of the estimated PCOS heritability, we tested the hypothesis that rare variants contribute to this deficit in heritability. Design, Setting, and Participants: Unbiased whole-genome sequencing (WGS) of 80 patients with PCOS and 24 reproductively normal control subjects identified potentially deleterious variants in AMH, the gene encoding anti-Müllerian hormone (AMH). Targeted sequencing of AMH of 643 patients with PCOS and 153 control patients was used to replicate WGS findings. Main Outcome Measures: Dual luciferase reporter assays measured the impact of the variants on downstream AMH signaling. Results: We found 24 rare (minor allele frequency < 0.01) AMH variants in patients with PCOS and control subjects; 18 variants were specific to women with PCOS. Seventeen of 18 (94%) PCOS-specific variants had significantly reduced AMH signaling, whereas none of 6 variants observed in control subjects showed significant defects in signaling. Thus, we identified rare AMH coding variants that reduced AMH-mediated signaling in a subset of patients with PCOS. Conclusion: To our knowledge, this study is the first to identify rare genetic variants associated with a common PCOS phenotype. Our findings suggest decreased AMH signaling as a mechanism for the pathogenesis of PCOS. AMH decreases androgen biosynthesis by inhibiting CYP17 activity; a potential mechanism of action for AMH variants in PCOS, therefore, is to increase androgen biosynthesis due to decreased AMH-mediated inhibition of CYP17 activity.