title: EWSR1-ATF1 fusion is a novel and consistent finding in hyalinizing clear-cell carcinoma of salivary gland.
abstract: Hyalinizing clear-cell carcinoma (HCCC) is a rare, low-grade salivary gland tumor with distinctive clear-cell morphology and pattern of hyalinization as well as focal mucinous differentiation. However, histological overlap exists with other salivary gland tumors, such as epithelial-myoepithelial carcinoma (EMCa), salivary myoepithelial carcinoma, and mucoepidermoid carcinoma (MEC). The potential relationship between HCCC and its morphological mimics has not been yet investigated at the genetic level. In this study, we conducted a molecular analysis for the presence of rearrangements in MAML2, commonly seen in MECs, and EWSR1, involved in "soft tissue myoepithelial tumors" (SMET) by fusion with POU5F1, PBX1, or ZNF444. Fluorescence in situ hybridization (FISH) was performed on 23 HCCC cases for abnormalities in MAML2, EWSR1, FUS, POU5F1, PBX1, and ZNF444. FISH for MAML2 was negative in all cases (0 of 14), including those with mucinous differentiation (0 of 7). An EWSR1 rearrangement was identified in 18 of 22 HCCCs (82%), while no break-apart signals were seen in FUS, POU5F1, PBX1, or ZNF444. 3'RACE on an EWSR1 rearranged HCCC identified an EWSR1-ATF1 fusion, which was confirmed by RT-PCR. ATF1 involvement was further confirmed by FISH analysis in 13 of 14 EWSR1-rearranged HCCC cases (93%). In contrast, all control cases tested, including among others 5 EMCa and 3 MEC with clear cells, were negative for EWSR1 and ATF1 rearrangements. The presence of EWSR1-ATF1 fusion in most HCCCs reliably separates these tumors from its histological mimics. The distinction from MEC is particularly important, as conventional MEC grading schemes overgrade these indolent HCCCs, potentially impacting on treatment.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. antonesc@mskcc.org
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.forename: Nora
authors.initials: N
authors.lastname: Katabi
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Yun Shao
authors.initials: YS
authors.lastname: Sung
authors.forename: Raja R
authors.initials: RR
authors.lastname: Seethala
authors.forename: Richard C
authors.initials: RC
authors.lastname: Jordan
authors.forename: Bayardo
authors.initials: B
authors.lastname: Perez-Ordoñez
authors.forename: Cherry
authors.initials: C
authors.lastname: Have
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Asa
authors.forename: Iona T
authors.initials: IT
authors.lastname: Leong
authors.forename: Grace
authors.initials: G
authors.lastname: Bradley
authors.forename: Hagen
authors.initials: H
authors.lastname: Klieb
authors.forename: Ilan
authors.initials: I
authors.lastname: Weinreb
mesh_terms: D051697:Activating Transcription Factor 1 / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002148:Calmodulin-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D012468:Salivary Gland Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000235:genetics / Q000378:metabolism
chemical_list: C531110:ATF1 protein, human; D051697:Activating Transcription Factor 1; D002148:Calmodulin-Binding Proteins; C500986:EWSR1 protein, human; C560860:EWSR1-ATF1 fusion protein, human; D015514:Oncogene Proteins, Fusion; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins