title: Activating KRAS mutations are characteristic of oncocytic sinonasal papilloma and associated sinonasal squamous cell carcinoma.
abstract: Oncocytic sinonasal papillomas (OSPs) are benign tumours of the sinonasal tract, a subset of which are associated with synchronous or metachronous sinonasal squamous cell carcinoma (SNSCC). Activating EGFR mutations were recently identified in nearly 90% of inverted sinonasal papillomas (ISPs) - a related tumour with distinct morphology. EGFR mutations were, however, not found in OSP, suggesting that different molecular alterations drive the oncogenesis of these tumours. In this study, tissue from 51 cases of OSP and five cases of OSP-associated SNSCC was obtained retrospectively from six institutions. Tissue was also obtained from 50 cases of ISP, 22 cases of ISP-associated SNSCC, ten cases of exophytic sinonasal papilloma (ESP), and 19 cases of SNSCC with no known papilloma association. Using targeted next-generation and conventional Sanger sequencing, we identified KRAS mutations in 51/51 (100%) OSPs and 5/5 (100%) OSP-associated SNSCCs. The somatic nature of KRAS mutations was confirmed in a subset of cases with matched germline DNA, and four matched pairs of OSP and concurrent associated SNSCC had concordant KRAS genotypes. In contrast, KRAS mutations were present in only one (5%) SNSCC with no known papilloma association and none of the ISPs, ISP-associated SNSCCs, or ESPs. This is the first report of somatic KRAS mutations in OSP and OSP-associated SNSCC. The presence of identical mutations in OSP and concurrent associated SNSCC supports the putative role of OSP as a precursor to SNSCC, and the high frequency and specificity of KRAS mutations suggest that OSP and OSP-associated SNSCC are biologically distinct from other similar sinonasal tumours. The identification of KRAS mutations in all studied OSP cases represents an important development in our understanding of the pathogenesis of this disease and may have implications for diagnosis and therapy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Aaron M
authors.identifier: 0000-0002-8254-5404
authors.initials: AM
authors.lastname: Udager
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: McHugh
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Betz
authors.affiliation: Department of Pathology, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Kathleen T
authors.initials: KT
authors.lastname: Montone
authors.affiliation: Department of Pathology, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Virginia A
authors.initials: VA
authors.lastname: Livolsi
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Raja R
authors.initials: RR
authors.lastname: Seethala
authors.affiliation: Department of Pathology, Brown University, Providence, RI, USA.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Yakirevich
authors.affiliation: Department of Pathology, Ohio State University, Columbus, OH, USA.
authors.forename: O Hans
authors.initials: OH
authors.lastname: Iwenofu
authors.affiliation: Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Bayardo
authors.initials: B
authors.lastname: Perez-Ordonez
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: DuRoss
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Helmut C
authors.initials: HC
authors.lastname: Weigelin
authors.affiliation: Department of Pathology, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Lim
authors.affiliation: Department of Pathology, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Kojo Sj
authors.initials: KS
authors.lastname: Elenitoba-Johnson
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Noah A
authors.initials: NA
authors.lastname: Brown
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D006801:Humans; D009154:Mutation; D010212:Papilloma / Q000235:genetics* / Q000473:pathology; D010255:Paranasal Sinus Neoplasms / Q000235:genetics* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: C117307:KRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KRAS; Schneiderian; oncocytic; papilloma; sinonasal; squamous cell carcinoma