title: Novel PRKD gene rearrangements and variant fusions in cribriform adenocarcinoma of salivary gland origin.
abstract: Polymorphous low-grade adenocarcinoma (PLGA) and cribriform adenocarcinoma of minor salivary gland (CAMSG) are low-grade carcinomas arising most often in oral cavity and oropharynx, respectively. Controversy exists as to whether these tumors represent separate entities or variants of one spectrum, as they appear to have significant overlap, but also clinicopathologic differences. As many salivary carcinomas harbor recurrent translocations, paired-end RNA sequencing and FusionSeq data analysis was applied for novel fusion discovery on two CAMSGs and two PLGAs. Validated rearrangements were then screened by fluorescence in situ hybridization (FISH) in 60 cases. Histologic classification was performed without knowledge of fusion status and included: 21 CAMSG, 18 classic PLGA, and 21 with "mixed/indeterminate" features. The RNAseq of 2 CAMSGs showed ARID1A-PRKD1 and DDX3X-PRKD1 fusions, respectively, while no fusion candidates were identified in two PLGAs. FISH for PRKD1 rearrangements identified 11 additional cases (22%), two more showing ARID1A-PRKD1 fusions. As PRKD2 and PRKD3 share similar functions with PRKD1 in the diacylglycerol and protein kinase C signal transduction pathway, we expanded the investigation for these genes by FISH. Six additional cases each showed PRKD2 and PRKD3 rearrangements. Of the 26 (43%) fusion-positive tumors, there were 16 (80%) CAMSGs and 9 (45%) indeterminate cases. A PRKD2 rearrangement was detected in one PLGA (6%). We describe novel and recurrent gene rearrangements in PRKD1-3 primarily in CAMSG, suggesting a possible pathogenetic dichotomy from "classic" PLGA. However, the presence of similar genetic findings in half of the indeterminate cases and a single PLGA suggests a possible shared pathogenesis for these tumor types.
authors.affiliation: Department of Pathology, University Health Network, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Ilan
authors.initials: I
authors.lastname: Weinreb
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Laxmi M S
authors.initials: LM
authors.lastname: Tirunagari
authors.forename: Yun-Shao
authors.initials: YS
authors.lastname: Sung
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Chen
authors.forename: Bayardo
authors.initials: B
authors.lastname: Perez-Ordonez
authors.forename: Blaise A
authors.initials: BA
authors.lastname: Clarke
authors.forename: Alena
authors.initials: A
authors.lastname: Skalova
authors.forename: Simion I
authors.initials: SI
authors.lastname: Chiosea
authors.forename: Raja R
authors.initials: RR
authors.lastname: Seethala
authors.forename: Daryl
authors.initials: D
authors.lastname: Waggott
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
authors.forename: Christine
authors.initials: C
authors.lastname: How
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Liu
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Irish
authors.forename: David P
authors.initials: DP
authors.lastname: Goldstein
authors.forename: Ralph
authors.initials: R
authors.lastname: Gilbert
authors.forename: Nasir
authors.initials: N
authors.lastname: Ud Din
authors.forename: Adel
authors.initials: A
authors.lastname: Assaad
authors.forename: Jason L
authors.initials: JL
authors.lastname: Hornick
authors.forename: Lester D R
authors.initials: LD
authors.lastname: Thompson
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002460:Cell Line; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D005260:Female; D050939:Gene Fusion; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism; D012468:Salivary Gland Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012469:Salivary Glands / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: C112476:ARID1A protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D014157:Transcription Factors; C089212:protein kinase D; D011493:Protein Kinase C; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases