title: p16INK4A, p53, EGFR expression and KRAS mutation status in squamous cell cancers of the anus: correlation with outcomes following chemo-radiotherapy.
abstract: OBJECTIVE
  Squamous cell carcinomas of the anal canal are associated with infection with Human Papilloma Viruses (HPVs). Chemo-radiotherapy (CRT) gives 70% 3-year relapse-free survival. Improved predictive markers and therapeutic options are required.
  
  
  METHODS
  Tumours from 153 patients treated with radical chemo-radiotherapy (50.4 Gy in 28# with concurrent Mitomycin and 5-Fluorouracil between 2004 and 2009) were retrieved and immunohistochemistry performed for p16(INK4A), p53 and EGFR and correlated with outcome. Primary and relapsed samples were analysed for mutations in KRAS.
  
  
  RESULTS
  137/153 (89.5%) stained moderately or strongly for p16(INK4A). p16(INK4A) correlated strongly with outcome. 37/137 patients demonstrating moderate/strong p16(INK4A) expression relapsed (27.0%), as opposed to 10/16 (62.5%) with absent/weak staining (log rank test p<0.001). p16 and p53 expression were inversely correlated. p16(INK4A) negative tumours were more frequent in men. p16(INK4A) negative patients had significantly worse overall survival (p<0.001). No mutations in KRAS were identified in primary tumours or relapses following treatment.
  
  
  CONCLUSIONS
  p16(INK4A) is strongly associated with relapse in SCC of the anus and identifies patients with very poor rates of relapse-free and overall survival. Primary and recurrent anal cancer expresses wild type KRAS, unaffected by treatment, supporting trials targeting EGFR in poor risk/recurrent anal cancer.
authors.affiliation: Sussex Cancer Centre, Brighton and Sussex University Hospitals NHS Trust, United Kingdom; Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom. Electronic address: dcgilbert@doctors.org.uk.
authors.forename: Duncan C
authors.initials: DC
authors.lastname: Gilbert
authors.forename: Anthony
authors.initials: A
authors.lastname: Williams
authors.forename: Kimberley
authors.initials: K
authors.lastname: Allan
authors.forename: Joanna
authors.initials: J
authors.lastname: Stokoe
authors.forename: Tim
authors.initials: T
authors.lastname: Jackson
authors.forename: Suzanne
authors.initials: S
authors.lastname: Linsdall
authors.forename: Charles Mh
authors.initials: CM
authors.lastname: Bailey
authors.forename: Jeff
authors.initials: J
authors.lastname: Summers
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001005:Anus Neoplasms / Q000737:chemistry / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy; D019941:Cyclin-Dependent Kinase Inhibitor p16; D066246:ErbB Receptors / Q000032:analysis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000032:analysis*; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D016159:Tumor Suppressor Protein p53 / Q000032:analysis*; D018631:ras Proteins / Q000235:genetics*
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; C117307:KRAS protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: Anal cancer; Chemo-radiotherapy; HPV; KRAS; p16(INK4A)