Recurrent Fusion of the GRB2 Associated Binding Protein 1 (GAB1) Gene With ABL Proto-oncogene 1 (ABL1) in Benign Pediatric Soft Tissue Tumors

Abstract

Background/Aim: Fusions of the ABL protooncogene 1 gene (ABL1 in 9q34) are common in leukemias but rare in solid tumors. The most notable is the t(9;22)(q34;q11)/BCR-ABL1 coding for a chimeric tyrosine kinase. We herein report an ABL1-fusion in a pediatric tumor. Materials and Methods: G-banding, fluorescence in situ hybridization, reverse transcription polymerase chain reaction and Sanger sequencing were performed on a soft tissue perineurioma found in the left musculus erector spinae of a child. Results: A der(4)t(4;9)(q31;q34) and a fusion of the GRB2 associated binding protein 1 (GAB1 in 4q31) gene with ABL1 were found. A literature search revealed 3 more cases with similar genetic and clinicopathological characteristics: a soft tissue perineurioma with t(2;9;4)(p23;q34;q31) and ABL1 rearrangement, a soft tissue angiofibroma with a GAB1-ABL1 chimeric gene, and a solitary fibrous tumor carrying a der(4)t(4;9)(q31.1;q34). Conclusion: GAB1-ABL1 is a recurrent fusion gene in benign pediatric tumors. The ABL proto-oncogene 1 gene (ABL1, previous symbol ABL) in chromosome band 9q34 is ubiquitously expressed and codes for a non-receptor tyrosine kinase which is localized at many subcellular sites including the nucleus, cytoplasm, mitochondria, and endoplasmic reticulum. It is involved in a variety of cellular processes such as cell division, adhesion, differentiation, and response to stress (1-3). ABL1 together with ABL2 (the proto-oncogene 2 gene which encodes a non-receptor tyrosine kinase and maps to chromosome band 1q25) constitute the ABL family of kinase genes (2, 4-6). Both ABL1 and ABL2 fuse with a variety of translocation partner genes in various hematological malignancies (7-10). The most notable fusion is between ABL1 and the 5' end of the breakpoint cluster region gene (BCR), located in 22q11, through the t(9;22)(q34;q11) chromosome translocation that gives rise to the Philadelphia chromosome in chronic myeloid leukemia (CML) (11, 12). The BCR-ABL1 fusion gene codes for a leukemogenic, constitutively active tyrosine kinase (11, 12). The discovery that 2-phenylaminopyrimidines inhibit the ABL protein kinase both in vitro and in vivo, led to the development of imatinib mesylate that now constitutes the first-line treatment of CML, as well as to introduction of other protein kinase inhibitors into cancer therapy (13-19). Rearrangements of the ABL1 and ABL2 genes in solid tumors have also been documented (3-6, 20). Phosphorylation and activation of ABL kinases were reported in various tumors such as breast and lung adenocarcinomas, melanomas, and cancers of the brain (3-6, 20). The mechanisms for activation of ABL1 and ABL2 kinases are in these settings not chromosome translocations/fusion genes but rather genomic amplification, increased expression of mRNA, enhanced protein expression, and increased catalytic activity (3-6, 20). Perineurioma is a tumor composed entirely of neoplastic perineurial cells with ultrastructural and immunohistochemical features similar to those of their normal counterparts (21). A...

Hybrid schwannoma–perineurioma frequently harbors VGLL3 rearrangement

“…Indeed, following a respite from contention, it seems inevitable that next generation sequencing will lead to reinvention in the classification of peripheral nerve tumors. For example, we, and others ( 38 ), have identified a case of perineurioma with a GAB1-ABL1 fusion, as well as other molecular events in related tumor-types. Only through the characterization of larger cohorts, with advanced sequencing, expression analysis, and functional studies will be possible to delineate the relationship and molecular breadth these, and related, neoplasms.…”

GAB1‐ABL1 fusions in tumors that have histologic overlap with NTRK‐rearranged spindle cell tumors

“…The role of ABL in solid tumors has predominantly been through somatic activating mutations which have been described in a small subset (<1%) of epithelial malignancies including breast carcinoma, endometrioid adenocarcinoma, pulmonary adenocarcinoma carcinoma, and in rare cases of melanoma 36‐41 . Only rare examples of ABL as an oncogenic driver in solid mesenchymal tumors have been reported 36‐38,42 …”

“…First, a 7‐year‐old patient with a soft tissue angiofibroma of the foot 11 . Second, two soft tissue perineuriomas; one in a 12‐year‐old boy in the erector spinae muscle 42 and the second in a 14‐year‐old girl within the forearm 49 . While angiofibroma and perineurioma of soft tissues are both distinct, benign diagnostic entities, 10 both may have some histologic and immunophenotypic overlap with NTRK ‐spindle cell tumors, raising the possibility that, as in case 2 presented herein, these prior cases may be worth revisiting in light of recent advances in the understanding of the biology and morphologic diversity of kinase‐driven spindle cell tumors.…”

“…[36][37][38][39][40][41] Only rare examples of ABL as an oncogenic driver in solid mesenchymal tumors have been reported. [36][37][38]42 Specifically, three case reports of GAB1-ABL1 gene fusions have been described in two diagnostic categories of mesenchymal spindle cell tumors within pediatric patients. First, a 7-year-old patient with a soft tissue angiofibroma of the foot.…”

“…47,48 Less frequently perineuriomas have been described with deletions in chr17q11, which includes the NF1 gene locus, 32 or other more rare alterations including the two cases with GAB1-ABL1 gene fusions. 42,49 Further evaluation may help to understand whether these GAB1-ABL1 fusions in other histotypes represent molecular pleiotropy or if spindle cell tumors with GAB1-ABL1 fusions would be better characterized as a single diagnostic category.…”