Gorham-Stout case report: a multi-omic analysis reveals recurrent fusions as new potential drivers of the disease

Abstract

Background Gorham-Stout disease is a rare condition characterized by vascular proliferation and the massive destruction of bone tissue. With less than 400 cases in the literature of Gorham-Stout syndrome, we performed a unique study combining whole-genome sequencing and RNA-Seq to probe the genomic features and differentially expressed pathways of a presented case, revealing new possible drivers and biomarkers of the disease. Case presentation We present a case report of a white 45-year-old female patient with marked bone loss of the left humerus associated with vascular proliferation, diagnosed with Gorham-Stout disease. The analysis of whole-genome sequencing showed a dominance of large structural DNA rearrangements. Particularly, rearrangements in chromosomes seven, twelve, and twenty could contribute to the development of the disease, especially a gene fusion involving ATG101 that could affect macroautophagy. The study of RNA-sequencing data from the patient uncovered the PI3K/AKT/mTOR pathway as the most affected signaling cascade in the Gorham-Stout lesional tissue. Furthermore, M2 macrophage infiltration was detected using immunohistochemical staining and confirmed by deconvolution of the RNA-seq expression data. Conclusions The way that DNA and RNA aberrations lead to Gorham-Stout disease is poorly understood due to the limited number of studies focusing on this rare disease. Our study provides the first glimpse into this facet of the disease, exposing new possible therapeutic targets and facilitating the clinicopathological diagnosis of Gorham-Stout disease.

EML4::ALK Fusions In Complex Lymphatic Malformations

“…19 A recent multi-omic analysis of a patient with GSD reported large chromosomal events resulting in multiple gene fusions. 20 None of the fusions involved known oncogenes, however this result supports the idea that structural rearrangements and gene fusions may be more common in CLMs than previously appreciated. In addition, the commonality of the EML4::ALK fusion in GLA and GSD suggests that they may share common pathogenesis, and may even be part of a disease spectrum rather than truly distinct entities.…”

EML4::ALK fusions in complex lymphatic malformations

“…21 A recent multi-omic analysis of a patient with GSD reported large chromosomal events resulting in multiple gene fusions. 22 No fusions involved known oncogenes; however, this result supports the idea that structural rearrangements and gene fusions may be more common in CLMs than previously appreciated. This idea is further supported by reports of kinase fusions in other benign diseases of abnormal cellular growth, such as the recent report of BRAF fusions in spitz nevi (a melanocytic lesion of epithelioid and spindle cell overgrowth).…”

“…Alternatively, RNA‐based fusion panels can be used to capture more fusions 21 . A recent multi‐omic analysis of a patient with GSD reported large chromosomal events resulting in multiple gene fusions 22 . No fusions involved known oncogenes; however, this result supports the idea that structural rearrangements and gene fusions may be more common in CLMs than previously appreciated.…”

The molecular mechanism of Gorham syndrome: an update

“…PI3K directly interacts with receptors or connectors in its SH2 domain, such as phosphate tyrosine residues on P85, to open catalytic subunits. Phosphatidylinositol-4diphosphate (PIP2) is converted to phosphatidylinositol-3pyrrosine-4-trisphosphate (PIP3), which recruits pleckstrin homology (PH) domain-containing proteins, protein kinase B (PKB), and AKT (49) to the membrane to form a complex that can directly regulate the cell cycle and continue to activate the signal transduction target of rapamycin (mTOR) in mammals. PI3K/Akt/ mTOR signal transduction is negatively regulated by the phosphatase PTEN.…”