Monoclonal Expansion with Integration of High-Risk Type Human Papillomaviruses Is an Initial Step for Cervical Carcinogenesis: Association of Clonal Status and Human Papillomavirus Infection with Clinical Outcome in Cervical Intraepithelial Neoplasia

Abstract

SUMMARY:To define the natural history of cervical intraepithelial neoplasia (CIN) as related to clonal status, we evaluated 20 cases of CIN1 and 18 cases of CIN2 that had been clinically followed for 7 to 48 months at Osaka University Hospital. These included 10 cases that progressed, 15 cases that persisted, and 13 cases that regressed. We analyzed the clonal status of each case by analysis of the pattern of X-chromosomal inactivation. Human papillomavirus (HPV) infection was detected by PCR-RFLP analysis. CINs that are monoclonal or infected by high-risk HPVs are more likely to progress or persist than cases that are polyclonal or negative for high-risk HPVs (p ϭ 0.009 for monoclonal vs polyclonal, p ϭ 0.024 for high-risk HPV positive vs negative p ϭ 0.024). Eighteen (90%) of 20 monoclonal, high-risk HPV-associated CINs progressed or persisted, whereas 9 (60%) of 15 polyclonal or high-risk HPV-negative CINs regressed. Therefore, the combination of clonality status and high-risk type HPV infection was significantly correlated with clinical outcome (p ϭ 0.003). The physical status of the HPV genome was evaluated in 17 cases of HPV-16 positive CINs by real-time PCR. Of those, the HPV viral genome was present in both episomal and integrated forms in 14 CINs (84%), and 12 of these cases (86%) were monoclonal in composition. By contrast, all three CINs in which the HPV genome was present in episomal form were polyclonal. In one CIN1 that was polyclonal, HPV-16 was originally present in episomal form but after 24 months, the patient developed a monoclonal CIN3 in which the HPV-16 genome was present in mixed form. These results may imply that HPV viral integration into the host genomic DNA is associated with progression from polyclonal to monoclonal status in CIN. These events may play a fundamental role in the progression from low-grade to higher grade dysplasia of the cervical mucosa. (Lab Invest 2003, 83:1517-1527.

Distribution and viral load of eight oncogenic types of human papillomavirus (HPV) and HPV 16 integration status in cervical intraepithelial neoplasia and carcinoma

“…22 The evaluation of HPV 16 integration using qRT-PCR can also be affected by the quantity of the episomal form of the virus in specimens. 22 Nevertheless, Given the fact that the mixed integrated and episomal forms of HPV 16 are the predominant pattern in CINs or even normal cervix, 30,34,42,44,45 the relative ratio of E2/E6, instead of the prevalence of completely integrated HPV 16, may be more specific in predicting CIN progression and may have potential as a predictive marker. However, our small sample size in a cross-sectional study precludes any conclusion about the use of the HPV 16 E2/E6 ratio cutoff to predict CIN progression.…”

P16INK4a expression and progression risk of low-grade intraepithelial neoplasia of the cervix uteri

“…Unfortunately, morphological criteria alone are not useful in distinguishing lesions that will regress from those that will persist or progress. Several studies have already approached this issue and have evaluated the significance of HPV types [3,9], HPV integration [5,10], clonality [4,23] and immunohistochemical markers on cervical lesions [8,13,16,25]. However, at present, none of the techniques used in these studies seems to be able to combine simplicity, low cost and high reliability.…”

Human Papillomavirus Infections: Warts or Cancer?

“…Gain or loss of host chromosomal loci has been reported (Wilting et al 2009, and references therein). Epigenetic changes in certain host genes increase with lesion severity (Wilting et al 2010;Hesselink et al 2011;van der Meide et al 2011). The reprogramming of p16INK4a and Hox has been attributed to viral oncoproteins (McLaughlin-Drubin et al 2011).…”