Fig. 5 |. Gene-disruptive germline SVs in COSMIC and cancer predisposition genes (CPGs) in pediatric patients with solid tumors.

(A) We found germline LoF deletions in DNA damage repair genes, such as PALB2 in Ewing sarcoma and BARD1 in neuroblastoma. (B) We also observed germline LoF SVs of known CPGs, like PHOX2B in neuroblastoma and FANCA in Ewing sarcoma, that were carried by affected children but were inherited from unaffected parents. (C) RAS-MAPK genes were impacted by germline SVs, including a singleton de novo complex SV resulting in a two-exon deletion of BRAF in one neuroblastoma case and an ultra-rare polymorphic duplication over RAF1 in three unrelated cases. (D) The germline RAF1 duplication from (C) was associated with high RAF1 expression in a neuroblastoma tumor, and increased expression of TMEM40, the gene upstream of the RAF1 promoter, in neuroblastoma and osteosarcoma tumors. (E) A rare polymorphic duplication predicted to result in CG of ERCC2, a DNA damage repair gene, was found at a three-fold higher frequency in Ewing sarcoma cases than in controls. (F) We discovered a de novo germline MYCN duplication and a likely post-zygotic MYCN duplication in two unrelated neuroblastoma cases. (G) The overall rates of gene-disruptive rare SVs in CPGs and COSMIC cancer genes were not significantly higher in cases relative to controls.