Analysis of ras Point Mutations and Human Papillomavirus 16 and 18 in Cervical Carcinomata and Their Metastases

Willis, Gavin; Jennings, BA; Ball, R. Y.; New, N.E.; Gibson, IR

doi:10.1006/gyno.1993.1140

Cited by 15 publications

(8 citation statements)

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“…35 Although it has been suggested that overexpression of p21ras correlates with the progression of cervical carcinoma, 9,11 the analysis of human cervical carcinoma samples has yielded variable results. Activating mutations are not detected in some sample populations [36][37][38][39] but are present in others. [5][6][7] The p21ras IHC studies in this report revealed detectable p21ras in 79% of patients.…”

Section: Discussionmentioning

confidence: 99%

Expression ofras, c-myc, and p53 proteins in cervical intraepithelial neoplasia

Slagle

Kaufman

Reeves

et al. 1998

Cancer

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Section: Discussionmentioning

confidence: 99%

Expression ofras, c-myc, and p53 proteins in cervical intraepithelial neoplasia

Slagle

Kaufman

Reeves

et al. 1998

Cancer

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“…A possible explanation for this result is that mucinous adenocarcinoma originates from endocervical epithelial reserve cells, which are permissive of HPV infection, while non-mucinous histotypes may have a different histogenesis (Young and Scully, 1990). The presence of HPV 16 and 18 infection did not differ significantly between cases with K-ras mutations and cases with wild-type gene ( p = 0.68).…”

Section: Survival Analysismentioning

confidence: 91%

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

Tenti

Romagnoli

Silini

et al. 1995

Intl Journal of Cancer

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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.

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“…An early study found mutant Ha-ras genes in a significant fraction of late-stage cervical cancers (Riou et al, 1988). However, subsequent studies by other groups failed to confirm these findings (Willis et al, 1993), and this led the International Agency for Carcinogenic Risks (IARC, 1995b) to suggest in 1995 that ras mutations were not an important step in the development of cervical cancers. Nevertheless, more recent histochemical, serological and sequencing analyses suggested that the ras oncogene may indeed contribute to a small (approximately 20%) but significant fraction of HPV-associated neoplasia (Lee et al, 1996;Dokianakis et al, 1999;Golijow et al, 1999;Alonio et al, 2000;Mouron et al, 2000;Pedroza-Saavedra et al, 2000;Stenzel et al, 2001;Prokopakis et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Strong synergy between mutant ras and HPV16 E6/E7 in the development of primary tumors

et al. 2004

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E6/E7 oncogenes of high-risk human papilloma virus (HPV) subtypes are essential for the development of certain types of cancers. However, these oncogenes are insufficient to transform normal cells into an immortalized or malignant state. Mutant Ha-ras cooperates with E6/E7 of HPV subtype 16 in transformation of cells in vitro and may contribute to some HPV-associated cancers in humans. This study investigates whether HPV16 E6/E7 and v-Ha-ras synergize in vivo. FVB/n mice transgenic for v-Ha-ras gene (R þ ) were crossed with transgenic C57BL/ 6 mice that harbor E6/E7 of HPV16 (E þ ). Beginning at about 3 months of age, the bitransgenic E þ R þ (C57BL/ 6 Â FVB/n) F1 mice developed mouth, eye and ear tumors. By 6 months, the prevalence of these types of mouth, eye and ear tumors was 100, 71 and 79% respectively in the E þ R þ mice. Most tumors grew progressively until the mice had to be killed. The median times for the appearance of the first mouth, eye and ear tumor were 3.6, 4.3 and 4.2 months, respectively. For the two singly transgenic groups of mice, the prevalence of mouth, eye and ear tumors was 0, 0 and 6% (E À R þ ) and 0, 0 and 0% (E þ R À ), respectively, and the median time to first tumor was greater than 12 months for singly transgenic mice (E À R þ , E þ R À ). Thus, a remarkable synergy occurred between the v-Ha-ras and HPV16 E6/E7 oncogenes in the development of primary tumors in mice.

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Analysis of ras Point Mutations and Human Papillomavirus 16 and 18 in Cervical Carcinomata and Their Metastases

Cited by 15 publications

References 0 publications

Expression ofras, c-myc, and p53 proteins in cervical intraepithelial neoplasia

Expression ofras, c-myc, and p53 proteins in cervical intraepithelial neoplasia

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

Strong synergy between mutant ras and HPV16 E6/E7 in the development of primary tumors

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