HPV16 E6 oncogene variants in women with cervical intraepithelial neoplasia

Abstract

Human papillomaviruses (HPVs) are strongly associated with the development of high grade cervical intraepithelial neoplasia (CIN) and cervical carcinoma, with between 40-80% of patients with cervical carcinoma being attributed to a single HPV type, HPV16 depending on the methods used and geographical location of the particular study [van den Brule et al., 1996]. An HPV16 E6 variant has been described which is strongly associated with high grade CIN [Ellis et al., 1997] and with the human leukocyte antigen (HLA)-B7 genotype in women with cervical carcinoma where HLA-B7 positive patients were demonstrated to have a significantly poorer clinical outcome [Ellis et al., 1995]. To determine whether this HPV16 E6 variant might play a significant role in the pathogenesis of cervical disease, 174 HPV16 positive women were selected from those attending the colposcopy clinics of Guy's and St Thomas' Hospital Trust following polymerase chain reaction (PCR) amplification of HPV16 L1 or E5 DNAs from cervical brush swabs or fixed biopsy tissue. HPV16 E6 DNA was amplified by PCR and the variant sequence was identified by Msp 1 restriction enzyme digestion, as the nucleotide substitution creates an additional unique Msp 1 site. The study group comprised 29 normal controls, 7 women with borderline cytology, 123 women with cervical dysplasia and 12 women with cervical cancer. 101/174 (58%) of these women had amplifiable E6 DNA and restriction enzyme digestion was performed on 95 of these. The variant E6 sequence was identified in 3/95 (3%) individuals, two of whom had normal histology and one had a CIN II lesion. Wild type E6 sequence was identified in the remaining 92/95 (97%) individuals. These data suggest that this particular E6 variant does not play a major role in the pathogenesis of HPV16 related cervical disease in women living in the South London area.

HPV16 E6 gene variations in invasive cervical squamous cell carcinoma and cancer in situ from Russian patients

“…Our results are consistent with many other recent findings that HPV16 E6 'variants' and 'prototype' have an equally malignant potential (Bontkes et al, 1998;Luxton et al, 2000). To finally elucidate the E6 variants-associated disease outcomes, longitudinal cohort studies should be conducted.…”

Cervical lesions are associated with human papillomavirus type 16 intratypic variants that have high transcriptional activity and increased usage of common mammalian codons

“…We investigated whether our E5 RFLP variants co-segregated with the E6 variant described by Ellis et al (1995) . However, only one of 66 subjects analysed had this E6 variant (data not shown) and we therefore conclude that this HPV-16 variant is rare in our locality (Luxton et al , 2000 ). Whilst the reason for the lack of co-segregation of our E5 variants with this E6 variant is not known, it may reflect demographic and lifestyle differences between the populations studied.…”

Risk for High-Grade Cervical Intraepithelial Neoplasia Associated with Variants of Human Papillomavirus Types 16 and 18

“…A classification of the variants on the basis of the presence of a single nucleotide alteration usually yielded inconsistent findings (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Although data from studies comparing European (prototype-like) with non-European (non -prototype-like) variants have been relatively consistent, with non-European variants being associated with an increased risk of cervical lesions (24)(25)(26)(27)(28), a lack of association has also been reported (29)(30)(31).…”