Abstract

Glomus tumors are benign mesenchymal neoplasms with rare malignant transformation. Prior genomic studies have identified that these tumors harbor frequent activating fusions in NOTCH genes and occasionally alterations in genes that activate the RAS/MAPK pathway. This study characterizes the genetic changes of a series of glomus tumors arising in skin and subcutaneous soft tissue. Our case archive of 11 skin primary glomus samples from medical care facilities in North America underwent comprehensive genomic profiling by a hybrid capture-based DNA sequencing platform (FoundationOne®CDx). The molecular findings, pathology reports, and archived histopathology images were reviewed for each case. Median age was 48 years (range, 17-67 y), 64% were female, and 64% had histologically malignant disease. Specimen sites included primary sites (n=5) and distant metastases (n=6). Seven cases harbored NOTCH2 fusion (n=5) or NOTCH3 fusions (n=2). Three of the remaining four cases harbored novel NOTCH2 and NOTCH3 frameshift truncating mutations (n=2 and n=1, respectively). Other alterations included ATRX mutation (n=2), PDGFRB indel (n=1), and BRAF V600E (n=1). Median tumor mutational burden was low at 0.9 mut/Mb (range, 0-5.2). HPV genomic reads or an ultraviolet mutational signature were not detected in any case. Skin primary glomus tumors show frequent mutations in NOTCH2 and NOTCH3, including gene fusions and novel truncating mutations. The presence of occasional BRAF and PDGFRB alterations raise the possibility of targeted therapies in clinically-advanced cases of this tumor type.