title: 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.
authors.affiliation: Department of Human Pathology, University of Pavia, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Tenti
authors.forename: S
authors.initials: S
authors.lastname: Romagnoli
authors.forename: E
authors.initials: E
authors.lastname: Silini
authors.forename: N S
authors.initials: NS
authors.lastname: Pellegata
authors.forename: R
authors.initials: R
authors.lastname: Zappatore
authors.forename: A
authors.initials: A
authors.lastname: Spinillo
authors.forename: C
authors.initials: C
authors.lastname: Zara
authors.forename: G N
authors.initials: GN
authors.lastname: Ranzani
authors.forename: L
authors.initials: L
authors.lastname: Carnevali
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000821:virology*; D000328:Adult; D000368:Aged; D001483:Base Sequence; D017931:DNA Primers / Q000737:chemistry; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D011905:Genes, ras; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D027383:Papillomaviridae / Q000235:genetics*; D030361:Papillomavirus Infections / Q000150:complications* / Q000175:diagnosis; D017354:Point Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D016019:Survival Analysis; D014412:Tumor Virus Infections / Q000150:complications* / Q000175:diagnosis; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000821:virology*
chemical_list: D017931:DNA Primers; D004279:DNA, Viral; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)