Cancer  1998 Jul 1;83(1):122-9 

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.

Leis PF, Stevens KR, Baer SC, Kadmon D, Goldberg LH, Wang XJ.

Department of Dermatology, Baylor College of Medicine, Houston, Texas 77030,
USA.

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.

PMID: 9655301 [PubMed - indexed for MEDLINE]