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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
Author(s) -
Leis Paula F.,
Stevens Kristin R.,
Baer Susan C.,
Kadmon Dov,
Goldberg Leonard H.,
Wang XiaoJing
Publication year - 1998
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/(sici)1097-0142(19980701)83:1<122::aid-cncr16>3.0.co;2-z
Subject(s) - metastasis , medicine , cancer research , mutation , carcinoma , pathology , cancer , gene , oncology , biology , genetics
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. Cancer 1998;83:122‐129. © 1998 American Cancer Society.