Analysis and clinical implications of k‐ras gene mutations and infection with human papillomavirus types 16 and 18 in primary adenocarcinoma of the uterine cervix

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Abstract
Experimental models indicate that activated ras genes and HPV oncogenic sequences may cooperate in inducing a completely transformed phenotype in epithelial cells. We searched for K‐ras gene mutations and HPV type‐16 and ‐18 sequences in 67 primary adenocarcinomas of the uterine cervix by analyzing DNAs from formalin‐fixed, paraffin‐embedded tissue samples. Target sequences were amplified by PCR and analyzed by denaturing gradient gel electrophoresis (DGGE) and sequencing for the detection of K‐ras gene mutations and by Southern blotting for the detection of HPV infection. We found 16 mutations in 15 cases; 14 were at codon 12 and 2 at codon 13; 11 were base transitions and 5 were transversions. Mutations were more frequent in mucin‐secreting than in non‐mucinous tumors. HPV oncogenic sequences were detected in 58 cases with no significant difference between K‐ras‐mutated and wild‐type tumors. HPV oncogenic sequences were also more frequent in mucin‐secreting than in non‐mucinous tumors. Both molecular events were present simultaneously in 13 out of 58 cases, all of which had histologically grade‐2 and grade‐3 tumors. Clinico‐pathological parameters of the disease and the overall survival, however, were independent of K‐ras mutations and of HPV‐16 and ‐18 infection, as shown by univariate and multivariate analysis. In contrast, stage of disease, lymph‐node metastases, deep infiltration, clear‐cell histology and low grade of differentiation were risk factors for tumor‐related death.