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

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.

Human Papillomavirus Types 16 and 18 Infection in Infiltrating Adenocarcinoma of the Cervix:PCR Analysis of 138 Cases and Correlation With Histologic Type and Grade

“…24 In conclusion, our study extends an partly confirms the result of previous investigators supporting the hypothesis that HPV infection may be of importance in the development of adenocarcinoma in the uterine cervix. However, its precise role in the development of the lesion remains to be clarified.…”

“…Mutations of Kras, or of p53 genes, do not seem to play a key role in this context, as their occurrence is not prevalent in any particular histotype, according to our previous researches. 24 '…”

Human papillomavirus and mutated H‐ras oncogene in cervical carcinomas and pathological negative pelvic lymph nodes: A retrospective follow‐up

“…All mutated cases were HPV 16 positive and presented poorly or moderately differentiated squamous carcinomas (Table V). The results are in line with other publications which suggest that ras activations are present in less differentiated carcinomas [Tenti et al, 1995;Stenzel et al, 2001] and associated to worse prognosis [Soh et al, 2002].…”

Mutations in the STK11 Gene Characterize Minimal Deviation Adenocarcinoma of the Uterine Cervix

“…In contrast, we did not detect mutations in K-ras or p53 in mucinous MDAs. Mutations in K-ras or p53 are also reported to be rare in common endocervical adenocarcinoma (Tenti et al, 1998). These findings indicate that STK11 mutation is involved specifically in the development of mucinous MDA.…”