Joshua D. Schiffman

Figure S4 from Germline Pathogenic DROSHA Variants Are Linked to Pineoblastoma and Wilms Tumor Predisposition

Supplemental Tables including Representativeness of Study Participants

Elephant populations are threatened by elephant endotheliotropic herpesvirus-hemorrhagic disease (EEHV-HD), a fast-acting infection that often kills very young elephants before they reach maturity. Because it strikes calves at a critical age for survival of the species, EEHV-HD is a major challenge for global conservation. Understanding how the disease causes such severe illness is essential to improving outcomes. In other hemorrhagic diseases, dangerous blood clots form when immune cells release sticky webs of DNA called neutrophil extracellular traps (NETs). We investigate whether this process occurs in elephants with EEHV-HD. Here we show, for the first time, that elephant heterophils (neutrophils) release NETs when stimulated, including by plasma from sick elephants. Tissue samples from fatal cases show large amounts of NETs, suggesting they play a harmful role in disease progression. Encouragingly, known NET inhibitors prevent this response in vitro. Our findings reveal that uncontrolled NET formation likely contributes to EEHV-HD and identify a new potential treatment strategy. Blocking NETs could be combined with existing therapies to improve survival of affected calves, offering a promising way to support elephant health and conservation.

Ewing sarcoma (EwS) is a rare, aggressive pediatric malignancy driven by FET :: ETS family fusions ( EWSR1 :: FLI1 in >85% of cases) with no established environmental risk factors. To investigate germline predisposition, we analyzed 2,014 EwS cases and 10,525 cancer-free controls in a two-stage analysis that combined an international genome-wide association study and a case□parent trio study. The combined meta-analysis identified 18 variants at 14 susceptibility loci (9 novel, 5 replicated) with moderate effect sizes (odds ratios≥1.25). Integrative analyses of the EwS loci revealed enrichment of expanded GGAA microsatellites, with evidence for binding of the EWSR1 :: FLI1 chimeric oncogenic activator. EWSR1::ETS knockdown in EwS cell lines resulted in dysregulated genes at susceptibility loci related to skeletal/muscle development, RNA binding/processing, and chromatin regulation. Our findings provide insights into the inherited component of EwS, highlighting a genetic architecture in which common germline variations with moderate effects interact with somatic EWSR1 :: FLI1 fusions to promote sarcomagenesis by dysregulating local genes.