High-Frequency Targetable EGFR Mutations in Sinonasal Squamous Cell Carcinomas Arising from Inverted Sinonasal Papilloma.
Inverted sinonasal papilloma (ISP) is a locally aggressive neoplasm associated with sinonasal squamous cell carcinoma (SNSCC) in 10% to 25% of cases. To date, no recurrent mutations have been identified in ISP or SNSCC. Using targeted next-generation sequencing and Sanger sequencing, we identified activating EGFR mutations in 88% of ISP and 77% of ISP-associated SNSCC. Identical EGFR genotypes were found in matched pairs of ISP and associated SNSCC, providing the first genetic evidence of a biologic link between these tumors. EGFR mutations were not identified in exophytic or oncocytic papillomas or non-ISP-associated SNSCC, suggesting that the ISP/SNSCC spectrum is biologically distinct among sinonasal squamous tumors. Patients with ISP harboring EGFR mutations also exhibited an increased progression-free survival compared with those with wild-type EGFR. Finally, treatment of ISP-associated carcinoma cells with irreversible EGFR inhibitors resulted in inactivation of EGFR signaling and growth inhibition. These findings implicate a prominent role for activating EGFR mutations in the pathogenesis of ISP and associated SNSCC and rationalize consideration of irreversible EGFR inhibitors in the therapy of these tumors.
Department of Pathology, University of Michigan Health System, Ann Arbor, MI.
Aaron M
AM
Udager
Department of Pathology, University of Michigan Health System, Ann Arbor, MI.
Delphine C M
DCM
Rolland
Department of Pathology, University of Michigan Health System, Ann Arbor, MI.
Jonathan B
JB
McHugh
Department of Pathology, University of Michigan Health System, Ann Arbor, MI.
Bryan L
BL
Betz
Department of Pathology, University of Michigan Health System, Ann Arbor, MI.
Carlos
C
Murga-Zamalloa
Department of Otolaryngology/Head and Neck Surgery, University of Michigan Health System, Ann Arbor, MI.
Thomas E
TE
Carey
Department of Otolaryngology/Head and Neck Surgery, University of Michigan Health System, Ann Arbor, MI.
Lawrence J
LJ
Marentette
Department of Otolaryngology, IUOPA, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.
Mario A
MA
Hermsen
Department of Pathology, University of Michigan Health System, Ann Arbor, MI.
Kathleen E
KE
DuRoss
Department of Pathology, University of Michigan Health System, Ann Arbor, MI.
Megan S
MS
Lim
Department of Pathology, University of Michigan Health System, Ann Arbor, MI.
Kojo S J
KSJ
Elenitoba-Johnson
Department of Pathology, University of Michigan Health System, Ann Arbor, MI.
Noah A
NA
Brown
D000368:Aged; D000595:Amino Acid Sequence; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D018308:Papilloma, Inverted / Q000201:enzymology / Q000235:genetics*; D010255:Paranasal Sinus Neoplasms / Q000201:enzymology / Q000235:genetics*; D017422:Sequence Analysis, DNA; D000077195:Squamous Cell Carcinoma of Head and Neck
C512478:EGFR protein, human; D066246:ErbB Receptors