Type‐specific human papillomavirus oncogene messenger RNA levels correlate with the severity of cervical neoplasia

Abstract

This study aimed to evaluate whether quantitation of high-risk human papillomavirus (HR-HPV) E6 messenger RNA (mRNA) can be a potential biomarker for detecting the severity of cervical lesions. HPV genotyping was performed using a modified MY11/ GP61 PCR for HPV DNA amplification, followed by HPV genotype-specific hybridization with on a gene chip. E6 type-specific PCR was used to validate multiple infections. Quantitative real-time reverse transcriptase (QRT-PCR) and real-time PCR used to measure mRNA levels and DNA viral loads of 6 HPV oncogenic types (HPV 16,18,31,33, 52 and 58) in 720 liquid-based cytology samples. The HPV DNA and RNA measurements were correlated with cervical lesions diagnosed by histopathologic examination. mRNA transcripts in the 6 types HPV DNA-positive cases was lower in normal women and <CIN 1 (23%), women with CIN 1 (54%), CIN21 (77%) and CIN31 (80%) (p < 0.001). Geometric mean mRNA levels ranged from 24.5 (copies per 50 ng total RNA) in normal women and <CIN 1 to 210.8 in those with CIN 1, 629.0 in CIN21 and 699.0 in CIN31 (p < 0.0001). Trends of increasing viral mRNA with severity of histopathologic diagnosis were significant for HPV 16, 18, 52 and 58 transcripts but not for HPV 31 and 33 transcripts. However, geometric mean DNA viral loads of HPV 16, 18, 52 and 58 DNA did not significantly increase with the severity of cervical dysplasia. Therefore, quantitative HPV E6 mRNA levels of high-risk HPV types are potentially useful biomarkers for distinguishing among HPV infections, cervical precancerous lesions and cancer.The human papillomavirus (HPV) plays an important role in the carcinogenesis of cervical cancer. 1,2 It is a common viral infection among women, particularly in younger age groups, and most infections are transient and asymptomatic. HPV DNA-negative women are at very low risk of cervical precancer or cancer, whereas most of the HPV DNA-positive women will not have or develop precancerous lesions or cancer. Nonetheless, patients with persistent HPV infection have clearly enhanced risk of developing cervical carcinoma. 3 The most important viral oncogenes involved in cellular immortalization are E6 and E7, the expression of which is necessary for cancer cell division. Their continuous expression is required for inducing and maintaining the neoplastic phenotype of cervical cancer cells. 4 Although their expression is necessary for conversion to cancer, few studies have focused on the prevalence of these transcripts among different HPV types in clinical samples.The HPV types 16, 18, 31, 33 and 45 are reportedly the most prevalent types associated with cervical cancer worldwide. 1,5 The most common oncogenic HPV type in preinvasive and cervical cancer is HPV 16, which is detectable in 21% of women with low-grade squamous intraepithelial lesions (LSILs), 6 in more than 50% of women with cervical intraepithelial neoplasia grade 3 (CIN 3) and in women with cervical cancer in America and Europe. 1,5,7 HPV 18 causes 10-15% of CIN 3 and cervical cancers, 1 as well as more than 3...

Characterization of human papillomavirus infection in north Taiwan

“…In women with cervical intraepithelial neoplasia grade 1 and cervical intraepithelial neoplasia grade 2 lesions, the most prevalent HPV genotypes were HPV 52, 58, 16, and 18 in descending order. In women with cervical intraepithelial neoplasia grade 3 lesions, the most prevalent genotypes were HPV 16,52,58,33,18, and 31, again in descending order; however, HPV 16 and 18 were the predominant types in women with cancer [Ho et al, 2010]. The analysis of 51 HPV genotypes showed that HPV types 52, 16, 58, 56, 39, 51, and 18, were found in 56.1% (885/1,577) of patients with HPV in northern Taiwan.…”

“…The four HPV genotypes that were most likely to be associated with cervical intraepithelial neoplasia grade 2 were HPV 16 (41.7%), HPV 35 (33.3%), HPV 31 (28%), and HPV 33 (18.9%); thus, HPV16 is the predominant type associated with cervical intraepithelial neoplasia grade 2 in Taiwan. Ho et al [2010] reported the rates of association between cervical intraepithelial neoplasia and cancer and six HPV genotypes, HPV 16, 18, 31, 33, 52, and 58 in Taiwan. In women with cervical intraepithelial neoplasia grade 1 and cervical intraepithelial neoplasia grade 2 lesions, the most prevalent HPV genotypes were HPV 52, 58, 16, and 18 in descending order.…”

Women’s health and Chinese integrative medicine

“…HPV testing alone may increase the psychological burden and may cause over-referral to colposcopy. It has been reported that HPV E6/E7 mRNA expression level is highly correlated with the severity of cervical lesions (Ho et al, 2010). HPV E6/E7 mRNA may be useful as a marker for potentially progressive HR-HPV infections and may constitute a useful tool for screening and/or patient management.…”

The Effect of Progesterone Only Contraception on the Accuracy of Cervical Cytologic interpretation

“…Ho and colleagues, in their work looking at messenger RNA levels and relationship to severity of cervical neoplasia, suggested that the transcriptional activity of high risk HPV types is varied. 52 Specific high risk HPV types (16, 18, 52, and 58) are the catalyst for host cell chromosomal instability to a variable extent, depending on the amount of high risk HPV E6 messenger RNA. 53 Thus, Ho and colleagues concluded that quantifying levels of HPV E6 mRNA may in fact be a superior method of measuring dysplastic severity.…”

“…53 Thus, Ho and colleagues concluded that quantifying levels of HPV E6 mRNA may in fact be a superior method of measuring dysplastic severity. 52 The genomes of high risk HPV are thought to be confined to the basal cells of the epithelium following infection. 54,55 This is where the HPV oncogenes gain access into the S-phase of cellular mitosis and replication of the virus is activated.…”