title: A c-rasHa mutation in the metastasis of a human papillomavirus (HPV)-18 positive penile squamous cell carcinoma suggests a cooperative effect between HPV-18 and c-rasHa activation in malignant progression.
abstract: BACKGROUND
  Human papillomaviruses (HPV) have been implicated in the etiology of anogenital squamous epithelial tumors. Of the 65 HPV strains, subtypes HPV-16 and HPV-18 frequently are associated with malignant conditions and are capable of transforming keratinocytes in vitro. However, additional cellular changes are necessary to confer tumorigenicity to HPV-infected cells. Secondary events implicated in the progression to malignancy include loss of tumor suppressor genes such as p53 and/or activation of cellular oncogenes such as c-rasHa.
  
  
  METHODS
  Polymerase chain reaction (PCR) was used to identify HPV-16 or HPV-18 genetic sequence in primary penile squamous cell carcinoma and two inguinal lymph node metastases. p53 and c-rasHa loci were analyzed by sequencing of PCR-amplified genomic DNA.
  
  
  RESULTS
  HPV-18 but not HPV-16 infection was found in the primary carcinoma and in inguinal metastases occurring 5 and 7 years after the initial lesion. Sequence analysis did not identify any p53 mutations in the primary carcinoma or its metastases. However, although the primary lesion and the 5-year metastasis encoded wild-type c-rasHa, the 7-year metastasis had a missense mutation within c-rasHa codon 61.
  
  
  CONCLUSIONS
  To the authors' knowledge, this is the first report of an activating c-rasHa mutation associated with squamous cell carcinoma of the penis. The presence of activated c-rasHa in the second metastasis but not in the first metastasis or the primary lesion suggests that activation of c-rasHa may be a late event in the malignant progression of HPV-18-associated penile squamous cell carcinoma. Analysis of additional samples from primary lesions and their resultant metastases is necessary to elucidate the incidence and significance of c-rasHa activation in penile squamous cell carcinoma.
authors.affiliation: Department of Dermatology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: P F
authors.initials: PF
authors.lastname: Leis
authors.forename: K R
authors.initials: KR
authors.lastname: Stevens
authors.forename: S C
authors.initials: SC
authors.lastname: Baer
authors.forename: D
authors.initials: D
authors.lastname: Kadmon
authors.forename: L H
authors.initials: LH
authors.lastname: Goldberg
authors.forename: X J
authors.initials: XJ
authors.lastname: Wang
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000556:secondary / Q000821:virology; D004279:DNA, Viral / Q000032:analysis; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D007633:Keratins / Q000032:analysis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D027383:Papillomaviridae / Q000235:genetics / Q000302:isolation & purification*; D010412:Penile Neoplasms / Q000235:genetics* / Q000821:virology
chemical_list: D004279:DNA, Viral; D007633:Keratins