title: Oncogenic mutations in cervical cancer: genomic differences between adenocarcinomas and squamous cell carcinomas of the cervix.
abstract: BACKGROUND
  Cervical cancer is the second leading cause of cancer deaths among women worldwide. The objective of this study was to describe the most common oncogenic mutations in cervical cancers and to explore genomic differences between the 2 most common histologic subtypes: adenocarcinoma and squamous cell carcinoma.
  
  
  METHODS
  A high-throughput genotyping platform, termed Oncomap, was used to interrogate 80 cervical tumors for 1250 known mutations in 139 cancer genes. Samples were analyzed using a mass spectrometry-based genotyping platform and were validated using orthogonal chemistry. Epidermal growth factor receptor (EGFR) mutations were further validated by massive parallel sequencing. Human papilloma virus (HPV) genotyping also was performed.
  
  
  RESULTS
  Validated mutations were detected in 48 of 80 tumors (60%) examined. The highest mutation rates were in the genes phosphatidylinositol 3-kinase, catalytic subunit α (PIK3CA) (31.3%); Kirsten rat sarcoma viral oncogene homolog (KRAS) (8.8%); and EGFR (3.8%). PIK3CA mutation rates did not differ significantly between adenocarcinomas and squamous cell carcinomas (25% vs 37.5%, respectively; P = .33). In contrast, KRAS mutations were identified only in adenocarcinomas (17.5% vs 0%; P = .01), and a novel EGFR mutation was detected only in squamous cell carcinomas (0% vs 7.5%; P = .24). There were no associations between HPV-16 or HPV-18 and somatic mutations or overall survival. In adjusted analyses, PIK3CA mutations were associated with shorter survival (67.1 months vs 90.3 months; hazard ratio, 9.1; 95% confidence interval, 2.8-29.5 months; P < .001).
  
  
  CONCLUSIONS
  Cervical cancers harbor high rates of potentially targetable oncogenic mutations. In addition, cervical squamous cell carcinoma and adenocarcinoma have distinct molecular profiles, suggesting that clinical outcomes may be improved with the use of more tailored treatment strategies, including PI3K and MEK inhibitors.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Centers for Outcomes and Policy Research and Psychosocial Epidemiology and Outcomes Research, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Alexi A
authors.initials: AA
authors.lastname: Wright
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Howitt
authors.forename: Andrea P
authors.initials: AP
authors.lastname: Myers
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Dahlberg
authors.forename: Emanuele
authors.initials: E
authors.lastname: Palescandolo
authors.forename: Paul
authors.initials: P
authors.lastname: Van Hummelen
authors.forename: Laura E
authors.initials: LE
authors.lastname: MacConaill
authors.forename: Melina
authors.initials: M
authors.lastname: Shoni
authors.forename: Nikhil
authors.initials: N
authors.lastname: Wagle
authors.forename: Robert T
authors.initials: RT
authors.lastname: Jones
authors.forename: Charles M
authors.initials: CM
authors.lastname: Quick
authors.forename: Anna
authors.initials: A
authors.lastname: Laury
authors.forename: Ingrid T
authors.initials: IT
authors.lastname: Katz
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.forename: Ursula A
authors.initials: UA
authors.lastname: Matulonis
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Hirsch
mesh_terms: D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality / Q000821:virology; D000328:Adult; D002294:Carcinoma, Squamous Cell / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality / Q000821:virology; D058534:Class I Phosphatidylinositol 3-Kinases; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000706:statistics & numerical data; D005260:Female; D005787:Gene Frequency; D018773:Genes, erbB-1 / Q000235:genetics; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009857:Oncogenes / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D018426:SEER Program / Q000706:statistics & numerical data; D002583:Uterine Cervical Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality / Q000821:virology
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human
keywords: DNA mutational analysis; EGFR; KRAS; PIK3CA; adenocarcinoma; cervical cancer; human papillomavirus; mutation; somatic mutations; squamous cell carcinoma
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