Recurrent and novel USP6 fusions in cranial fasciitis identified by targeted RNA sequencing

• Published in: Modern pathology Vol. 33; no. 5; pp. 775 - 780
• Main Authors: Paulson, Vera A., Stojanov, Ivan A., Wasman, Jay K., Restrepo, Tamara, Cano, Samantha, Plunkitt, Joanna, Duraisamy, Sekhar, Harris, Marian H., Chute, Deborah J., Al-Ibraheemi, Alyaa, Church, Alanna J.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-05-2020; Elsevier Limited
• Subjects: 13/51; 45/90; 45/91; 631/67/69; 692/308/2056; Case reports; Child; Child, Preschool; Fasciitis; Fasciitis - genetics; Fasciitis - pathology; Female; Humans; Infant; Laboratory Medicine; Male; Medicine; Medicine & Public Health; Osteonectin; Paraffin; Pathology; Reclassification; Recombinant Fusion Proteins - genetics; Ribonucleic acid; RNA; Scalp; Scalp - pathology; Skull; Skull - pathology; Stellate cells; Translocation; Ubiquitin Thiolesterase - genetics; Wnt protein; β-Catenin
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/s41379-019-0422-6

Cranial fasciitis is a benign myofibroproliferative lesion of the scalp and underlying bones typically occurring in the pediatric population. Histologically, it is characterized by loose fascicles of stellate cells in a fibromyxoid background, findings similar to those described in the closely related variant nodular fasciitis. Previously characterized as a reactive process, the identification of
USP6
translocations in over 90% of nodular fasciitis cases prompted their reclassification as a clonal neoplastic process. Unlike nodular fasciitis, the molecular underpinnings of cranial fasciitis are less clear. While a subset of cranial fasciitis has been associated with Wnt/
β
-catenin pathway dysregulation, recent case reports suggest that this entity may also harbor
USP6
fusions, a finding we sought to further investigate. We identified fifteen archival cases of cranial fasciitis, five females and ten males ranging in age from 3 months to 9 years (median 11 months), composed of formalin-fixed paraffin-embedded and fresh frozen tissues (11 and 4 cases respectively). Samples were evaluated on an RNA-based targeted sequencing panel targeting genes recurrently rearranged in neoplasia, including
USP6
. Five of fifteen cases (33%) were positive for
USP6
rearrangements predicted to result in the fusion of the entire USP6 coding region to the promoter of the 5′ partner, (three of which were novel):  two
SERPINH1-USP6
(novel) and one each of
COL3A1-USP6
(novel),
SPARC-USP6
, and
MYH9-USP6
. These results demonstrate the recurrent nature of
USP6
rearrangements in cranial fasciitis, and highlight the success of targeted RNA sequencing in identifying known and novel fusion partners. The identification of
USP6
promoter-swapping rearrangements is helpful in understanding the underlying biology of cranial fasciitis, and reinforces its biologic relationship to nodular fasciitis. Targeted RNA sequencing is a helpful tool in diagnosing this pseudosarcomatous lesion.