title: Alterations in the tumor suppressor gene p16(INK4A) are associated with aggressive behavior of penile carcinomas.
abstract: Alterations in the p16/cyclinD1/Rb and ARF/Mdm2/p53 pathways are frequent events in the pathogenesis of squamous cell carcinomas. Different mechanisms of p16 regulation have been described for penile carcinomas so far. Therefore, expression of p16 and p53 was immunohistochemically detected with monoclonal antibodies in 52 primary invasive penile squamous cell carcinomas. The carcinomas were analyzed for allelic loss (LOH) in p16(INK4A) and p53, as well as for mutations in the p16(INK4A) and the p53 gene. In addition, we examined the promoter status of p16(INK4A) by methylation-specific PCR. The presence of human papilloma virus (HPV) 6/11, HPV 16 and HPV 18 DNA was analyzed by PCR. Data were compared to clinical data. Concerning p16, 26 (50%) tumors showed positive immunohistochemistry, 32 (62%) tumors showed allelic loss and 22 tumors (42%) showed promoter hypermethylation. All tumors with negative p16 immunohistochemistry showed LOH near the p16(INK4A) locus and/or hypermethylation of the p16(INK4A) promoter. HPV 16 DNA was detected in 17 tumors, ten of them with positive p16 immunostaining. The remaining seven tumors with negative p16 staining showed allelic loss and/or promoter hypermethylation. Evidence of lymph node metastasis was significantly associated with negative p16 immunohistochemistry as well as with combined LOH and promoter hypermethylation (p = 0.003 and p = 0.018, respectively). Allelic loss around p53 was found in 22 tumors (42%), and seven mutations of the p53 gene could be demonstrated in our tumors. No correlations could be found between any p53 alteration and clinical parameters.
authors.affiliation: Institute of Legal Medicine, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany. micaela.poetsch@uk-essen.de
authors.forename: Micaela
authors.initials: M
authors.lastname: Poetsch
authors.forename: Martin
authors.initials: M
authors.lastname: Hemmerich
authors.forename: Christoph
authors.initials: C
authors.lastname: Kakies
authors.forename: Britta
authors.initials: B
authors.lastname: Kleist
authors.forename: Eduard
authors.initials: E
authors.lastname: Wolf
authors.forename: Frank
authors.initials: F
authors.lastname: vom Dorp
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Hakenberg
authors.forename: Chris
authors.initials: C
authors.lastname: Protzel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology* / Q000821:virology; D019175:DNA Methylation; D004279:DNA, Viral / Q000032:analysis; D019942:Genes, p16; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000150:complications; D010412:Penile Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000821:virology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D004279:DNA, Viral