title: Vulvar Squamous Cell Carcinoma (VSCC) as Two Diseases: HPV Status Identifies Distinct Mutational Profiles Including Oncogenic Fibroblast Growth Factor Receptor 3.
abstract: Purpose:Patients with advanced or recurrent invasive vulvar squamous cell carcinoma (VSCC) have limited treatment options and a grave prognosis. Understanding the genomic landscape may facilitate the identification of new therapies and improve clinical outcomes.Experimental Design:A retrospective chart review and molecular analysis of patients with VSCC from 2000 to 2016 was performed at the Ottawa Hospital Research Institute. The presence of oncogenic human papillomavirus (HPV) was determined by nested PCR and amplified DNA was sequenced using the Ion AmpliSeq Cancer Hotspot v2 Panel. The patients were divided into two groups according to HPV status (HPV-positive versus HPV-negative) and clinical outcome correlated with mutation status using descriptive statistics.Results:In 43 VSCC patients, there was a high mutation rate in both HPV-positive (73%) and HPV-negative (90%) disease with the two subgroups expressing distinct genetic profiles. HPV-positive tumors were characterized by oncogenic mutations inPIK3CA(27%),FGFR3(14%), andPTEN(9%), whereas HPV-negative tumors were found to have mutations inTP53(57%),HRAS(24%),PI3KCA(19%), andCDKN2A(14%). Mutation S249C inFGFR3occurred in 14% of HPV-positive tumors. While there were notable differences in the occurrence ofTP53, HRAS, PTEN, andFGFR3mutations according to HPV status, only the rate ofTP53mutations was statistically significant (P= 0.0004). No significant difference in prognosis was found between patients with HPV-positive and HPV-negative VSCC.Conclusions:HPV-positive VSCC is characterized by oncogenicFGFR3mutations that helps classify this subtype as a separate disease. Inhibitors of FGFR3 merit consideration as a therapeutic strategy in this neglected cancer in women.Clin Cancer Res; 23(15); 4501-10. ©2017 AACR.
authors.affiliation: Division of Gynaecologic Oncology, The Ottawa Hospital, Ottawa, Canada. jweberpals@toh.ca.|Ottawa Hospital Research Institute, Centre for Cancer Therapeutics, Ottawa, Canada.
authors.forename: Johanne I
authors.initials: JI
authors.lastname: Weberpals
authors.affiliation: Ottawa Hospital Research Institute, Centre for Cancer Therapeutics, Ottawa, Canada.|Molecular Oncology Diagnostics Laboratory, The Ottawa Hospital, Ottawa, Ontario.|Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Bryan
authors.initials: B
authors.lastname: Lo
authors.affiliation: Ottawa Hospital Research Institute, Centre for Cancer Therapeutics, Ottawa, Canada.
authors.forename: Marc M
authors.initials: MM
authors.lastname: Duciaume
authors.affiliation: Ottawa Hospital Research Institute, Centre for Cancer Therapeutics, Ottawa, Canada.
authors.forename: Johanna N
authors.initials: JN
authors.lastname: Spaans
authors.affiliation: Department of Obstetrics and Gynaecology, University of Ottawa, Ottawa, Ontario.
authors.forename: Aisling A
authors.initials: AA
authors.lastname: Clancy
authors.affiliation: Ottawa Hospital Research Institute, Centre for Cancer Therapeutics, Ottawa, Canada.
authors.forename: Jim
authors.initials: J
authors.lastname: Dimitroulakos
authors.affiliation: Ottawa Hospital Research Institute, Centre for Cancer Therapeutics, Ottawa, Canada.|Division of Medical Oncology, University of Ottawa, Ottawa, Canada.
authors.forename: Glenwood D
authors.initials: GD
authors.lastname: Goss
authors.affiliation: Ottawa Hospital Research Institute, Centre for Cancer Therapeutics, Ottawa, Canada.|Molecular Oncology Diagnostics Laboratory, The Ottawa Hospital, Ottawa, Ontario.|Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Harman S
authors.initials: HS
authors.lastname: Sekhon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D063646:Carcinogenesis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000145:classification / Q000235:genetics* / Q000473:pathology / Q000821:virology; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D027383:Papillomaviridae / Q000472:pathogenicity; D030361:Papillomavirus Infections / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000821:virology; D011379:Prognosis; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D014846:Vulvar Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology / Q000821:virology
chemical_list: C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3