title: NAB2-STAT6 fusion types account for clinicopathological variations in solitary fibrous tumors.
abstract: Solitary fibrous tumor (SFT) is characterized by the inv12(q13q13)-derived NAB2-STAT6 fusion, which exhibits variable breakpoints and drives STAT6 nuclear expression. The implications of NAB2-STAT6 fusion variants in pathological features and clinical behavior remain to be characterized in a large cohort of SFTs. We investigated the clinicopathological correlates of this genetic hallmark and analyzed STAT6 immunoexpression in 28 intrathoracic, 37 extrathoracic, and 23 meningeal SFTs. These 88 tumors were designated as histologically nonmalignant in 75 cases and malignant in 13, including 1 dedifferentiated SFT. Eighty cases had formalin-fixed and/or fresh samples to extract assessable RNAs for RT-PCR assay, which revealed NAB2-STAT6 fusion variants comprising 12 types of junction breakpoints in 73 fusion-positive cases, with 65 (89%) falling into 3 major types. The predominant NAB2ex4-STAT6ex2 (n=33) showed constant breakpoints at the ends of involved exons, whereas the NAB2ex6-STAT6ex16 (n=16) and NAB2ex6-STAT6ex17 (n=16) might exhibit variable breakpoints and incorporate NAB2 or STAT6 intronic sequence. Including 73 fusion-positive and 7 CD34-negative SFTs, STAT6 distinctively labeled 87 (99%) SFTs in nuclei, exhibited diffuse reactivity in 73, but did not decorate 98 mimics tested. In seven fusion-negative cases, 6 were STAT6-positive, suggesting rare fusion variants not covered by RT-PCR assay. Regardless of histological subtypes, intrathoracic SFTs affected older patients (P=0.035) and tended to be larger in size (P=0.073). Compared with other variants, NAB2ex4-STAT6ex2/4 fusions were significantly predominant in the SFTs characterised by intrathoracic location (P<0.001), older age (P=0.005), decreased mitoses (P=0.0028), and multifocal or diffuse STAT6 staining (P=0.013), but not found to correlate with disease-free survival. Conclusively, STAT6 nuclear expression was distinctive in the vast majority of SFTs, including all fusion-positive tumors, and exploitable as a robust diagnostics of CD34-negative cases. Despite the associations of NAB2-STAT6 fusion variants with several clincopathological factors, their prognostic relevance should be further validated in large-scale prospective studies of SFTs.
authors.affiliation: Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Hui-Chun
authors.initials: HC
authors.lastname: Tai
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: I-Chieh
authors.initials: IC
authors.lastname: Chuang
authors.affiliation: Department of Anatomical Pathology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Tse-Ching
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan.
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
authors.affiliation: Department of Anatomical Pathology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Shih-Chiang
authors.initials: SC
authors.lastname: Huang
authors.affiliation: Department of Pathology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Chien
authors.initials: YC
authors.lastname: Kao
authors.affiliation: Department of Orthopedics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Po-Chun
authors.initials: PC
authors.lastname: Lin
authors.affiliation: Department of Anatomic Pathology, E-Da Hospital, Kaohsiung, Taiwan.
authors.forename: Jen-Wei
authors.initials: JW
authors.lastname: Tsai
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Jui
authors.initials: J
authors.lastname: Lan
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Shih-Chen
authors.initials: SC
authors.lastname: Yu
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Shao-Lun
authors.initials: SL
authors.lastname: Yen
authors.affiliation: Department of Anatomical Pathology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Jung
authors.affiliation: Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Kuan-Cho
authors.initials: KC
authors.lastname: Liao
authors.affiliation: Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Fu-Min
authors.initials: FM
authors.lastname: Fang
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Hsuan-Ying
authors.initials: HY
authors.lastname: Huang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics*; D050800:STAT6 Transcription Factor / Q000235:genetics*; D054364:Solitary Fibrous Tumors / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D055815:Young Adult
chemical_list: C491000:NAB2 protein, human; D015514:Oncogene Proteins, Fusion; D012097:Repressor Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human