Recurrent BRAF gene rearrangements in myxoinflammatory fibroblastic sarcomas, but not hemosiderotic fibrolipomatous tumors Journal Article
| Authors: | Kao, Y. C.; Ranucci, V.; Zhang, L.; Sung, Y. S.; Athanasian, E. A.; Swanson, D.; Dickson, B. C.; Antonescu, C. R. |
| Article Title: | Recurrent BRAF gene rearrangements in myxoinflammatory fibroblastic sarcomas, but not hemosiderotic fibrolipomatous tumors |
| Abstract: | Myxoinflammatory fibroblastic sarcoma (MIFS) is a low grade soft tissue sarcoma with a predilection for acral sites, being associated with a high rate of local recurrence but very infrequent distant metastases. Although a t(1;10) translocation resulting in TGFBR3-MGEA5 fusion has been reported as a recurrent genetic event in MIFS, this abnormality is seen only in a subset of cases. As no studies to date have investigated the spectrum of alternative genetic alterations in TGFBR3-MGEA5 fusion negative MIFS, we undertook a genetic analysis of this particular cohort for further molecular classification. Triggered by an index case occurring in the finger of a 37-year-old female and harboring a novel TOM1L2-BRAF fusion by targeted RNA sequencing we investigated potential recurrent BRAF abnormalities by screening a large group of 19 TGFBR3-MGEA5 fusion negative MIFS by fluorescence in situ hybridization. There were 6 (32%) additional MIFS with BRAF genetic abnormalities, including 5 gene rearrangements and one showing BRAF amplification. Interestingly, VGLL3 amplification, a recurrent genetic abnormality coexisting with t(1;10) in some MIFS, was also detected by fluorescence in situ hybridization in 4/6 (67%) BRAF-rearranged MIFS, but not in the BRAF-amplified case. Up-regulated VGLL3 mRNA expression was also demonstrated in the index case by RNA sequencing. The 7 BRAF-rearranged/amplified MIFS arose in the fingers (n=3), and 1 each in wrist, forearm, foot, and knee, of adult patients (36 to 74 y; M:F=4:3). The histologic spectrum ranged from predominantly solid growth of plump histiocytoid to epithelioid tumor cells with focal myxoid change to a predominantly myxoid background with scattered tumor cells. Varying degree of inflammatory infiltrates and large tumor cells with virocyte-like macronucleoli were observed in most cases. Immunohistochemical stains of phosphorylated ERK, a downstream effector of BRAF activation, were positive in all 4 cases tested (2 diffuse strong, 2 focal strong). Unlike t(1;10), BRAF rearrangements were only found in MIFS but not in 6 hemosiderotic fibrolipomatous tumor (HFLT) lacking TGFBR3-MGEA5 fusions (including 2 pure HFLT, 2 hybrid HFLT-MIFS, and 2 associated with pleomorphic hyalinizing angiectatic tumors). © 2017 Wolters Kluwer Health, Inc. All rights reserved. |
| Keywords: | immunohistochemistry; mitogen activated protein kinase; adult; aged; middle aged; carrier protein; sequence analysis; case control study; genetics; case-control studies; case report; cancer grading; phenotype; in situ hybridization, fluorescence; genetic predisposition to disease; reverse transcription polymerase chain reaction; gene amplification; transcription factor; enzymology; pathology; phosphorylation; tumor antigen; tumor marker; transcription factors; fluorescence in situ hybridization; gene rearrangement; fibrosarcoma; antigens, neoplasm; messenger rna; reverse transcriptase polymerase chain reaction; rna, messenger; carrier proteins; gene fusion; transforming growth factor beta receptor; receptors, transforming growth factor beta; extracellular signal-regulated map kinases; sequence analysis, rna; genetic predisposition; b raf kinase; braf; mapk; soft tissue neoplasms; soft tissue tumor; proto-oncogene proteins b-raf; braf protein, human; lipoma; hemosiderosis; myxoinflammatory fibroblastic sarcoma; hyaluronoglucosaminidase; proteoglycans; histone acetyltransferase; histone acetyltransferases; proteoglycan; amplifications; neoplasm grading; fusions; humans; human; male; female; biomarkers, tumor; vgll3; mgea5 protein, human; tom1l2 protein, human; transforming growth factor beta receptor 3; vgll3 protein, human |
| Journal Title: | American Journal of Surgical Pathology |
| Volume: | 41 |
| Issue: | 11 |
| ISSN: | 0147-5185 |
| Publisher: | Lippincott Williams & Wilkins |
| Date Published: | 2017-11-01 |
| Start Page: | 1456 |
| End Page: | 1465 |
| Language: | English |
| DOI: | 10.1097/pas.0000000000000899 |
| PUBMED: | 28692601 |
| PROVIDER: | scopus |
| PMCID: | PMC5636656 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 November 2017 -- Source: Scopus |
Altmetric
Citation Impact
Related MSK Work