title: Classic and nonclassic HLA class I expression in penile cancer and relation to HPV status and clinical outcome.
abstract: OBJECTIVE
  Loss of expression of HLA class I is a mechanism of immune evasion in various cancers that is often associated with a worse patient outcome. We analyzed HLA expression in a large cohort with penile cancer in relation to clinical outcome.
  
  
  METHODS
  We used penile cancer tissue blocks from 168 patients who underwent surgical resection between 2000 and 2009 to construct tissue microarrays. Immunohistochemical staining was done with antibodies directed against classic and nonclassic HLA molecules. HLA expression was scored semiquantitatively, divided into 3 expression groups and correlated with clinicopathological variables, including HPV and survival. Survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards models.
  
  
  RESULTS
  Complete and partial loss of total classic HLA class I was observed in 32% and 50% of cases, and up-regulation of HLA-E and G in 16% and 13%, respectively. When corrected for relevant clinical parameters, partial HLA-A loss was significantly associated with decreased survival overall (HR 2.3, 95% CI 1.1-4.6) and in HPV negative patients alone (HR 3.4, 95% CI 1.4-8.4). Abnormal HLA-B/C, E or G expression levels were not associated with survival.
  
  
  CONCLUSIONS
  To our knowledge this is the first study to describe a link between HLA expression and the clinical outcome of penile cancer. HLA down-regulation occurs frequently and partial loss of HLA-A is an independent predictor of poor survival in HPV negative patients. Complete understanding of the mechanisms and relevance of HLA down-regulation and immune evasion in regard to the clinical outcome will contribute to the future design of immunotherapy interventions.
authors.affiliation: Department of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Rosa S
authors.initials: RS
authors.lastname: Djajadiningrat
authors.affiliation: Department of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Simon
authors.initials: S
authors.lastname: Horenblas
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Daniëlle A M
authors.initials: DA
authors.lastname: Heideman
authors.affiliation: Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Joyce
authors.initials: J
authors.lastname: Sanders
authors.affiliation: Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: de Jong
authors.affiliation: Centre for Gynaecologic Oncology Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: e.jordanova@vumc.nl.
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005805:Genes, MHC Class I; D006680:HLA Antigens / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D008875:Middle Aged; D027383:Papillomaviridae / Q000302:isolation & purification*; D010412:Penile Neoplasms / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000821:virology*; D011446:Prospective Studies; D015996:Survival Rate
chemical_list: D006680:HLA Antigens
keywords: HLA antigens; carcinoma; human papillomavirus DNA test; mortality; penile neoplasms; squamous cell