A c-ras(Ha) mutation in the metastasis of a human papillomavirus (HPV)- 18 positive penile squamous cell carcinoma suggests a cooperative effect between HPV-18 and c-ras(HA) activation in malignant progression

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-ras(Ha). 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-ras(Ha) 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-ras(Ha), the 7-year metastasis had a missense mutation within c-ras(Ha) codon 61. CONCLUSIONS. To the authors' knowledge, this is the first report of an activating c-ras(Ha) mutation associated with squamous cell carcinoma of the penis. The presence of activated c-ras(Ha) in the second metastasis but not in the first metastasis or the primary lesion suggests that activation of c-ras(Ha) 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-ras(Ha) activation in penile squamous cell carcinoma.