HPV16 E7 Genetic Conservation Is Critical to Carcinogenesis

Human papillomavirus (HPV)-induced oropharyngeal squamous cell carcinoma (OPSCC) remains increasing worldwide. We aimed to investigate if the HPV-prevalence of OPSCC in the Netherlands is rising as well, also in female patients. In addition, we evaluated the association between HPV-positive OPSCC and suspicious Pap results of the cervix in these female patients. Patients with OPSCC treated in the period 2000-2015 at the VU University Medical Center Amsterdam, were included (n = 926). The presence of an oncogenic HPV infection was determined by p16-immunostaining, followed by a high-risk HPV general primer 5+/6+ DNA PCR on the p16-immunopositive cases. A review of pathology reports in all female patients (n = 305) was undertaken to identify cytological signs of HPV-related (pre)cancer of the cervix. In total 281 of 926 (30.3%) OPSCCs were HPV-positive. Moreover, a significant increase in the prevalence of HPV-positive OPSCCs was observed from 14.0% in 2000 to 48.1% in 2015 (p < 0.001). Among the female patients with an HPV-positive OPSSC (n = 70), the results of cervical smears were available in 56 of 70 patients (80.0%). Of the female patients with HPV-positive OPSCC, 9 of 56 (16.1%) patients had a vaginal cuff Papanicolaou (Pap) test ≥3b in their medical history compared to 7 of 168 (4.2%) in the HPV-negative group (p = 0.003). In conclusion, a continuous increase in the HPV-attributable fraction of OPSCC was demonstrated in the period 2000-2015 in the Amsterdam region. HPV-positive OPSCC has a significant association with a history of suspicious Pap results of the cervix in female patients.

Section: Discussionmentioning

confidence: 73%

Epidemiologic associations of HPV‐positive oropharyngeal cancer and (pre)cancerous cervical lesions

Rietbergen

Bokhoven

Lissenberg‐Witte

et al. 2018

“…Nonetheless, the hypothesis that different genotypes could have different impact in geographical distinct populations should not be discounted. Mirabello et al . convincingly showed a large variability in HPV16 variant lineages, suggesting that each variant could indeed be considered an individual virus, with individual carcinogenic potential and which could give rise to different geographic risk profiles.…”

Section: Discussionmentioning

confidence: 99%

Bayesian analysis of baseline risk of CIN2 and ≥CIN3 by HPV genotype in a European referral cohort

Bonde

Bottari

Parvu

et al. 2019

Whereas HPV16 and HPV18 have been the focus in current risk‐based cervical cancer screening algorithms using HPV genotype information, mounting evidence suggests that oncogenic HPV types such as HPV31, 33, 52 and 58 pose a ≥CIN3 risk equivalent to or greater than that of HPV18, and the combined risk of HPV31 and HPV33 rivals even HPV16 in women above 30 years of age. Here, we evaluate the baseline risk of CIN2 and CIN3 by genotype in a colposcopy referral population from Denmark and Italy. In total, 655 women were enrolled upon a referral to colposcopy after a positive screening sample. All samples were HPV analyzed using Onclarity HPV assay with extended genotyping and combined with the histology outcomes, a Bayesian probability modeling was used to determine the risk per genotype assessed. The combined data for this referral population showed that the ≥CIN2 risk of HPV16 was 69.1%, HPV31 at 63.3%, HPV33/58 at 52.7%, HPV18 at 46.6% and HPV52 at 40.8%. For ≥CIN3, the risks were 44.3%, 38.5%, 36.8%, 30.9% and 16.8% for HPV16, HPV31, HPV18, HPV33/58 and HPV52, respectively, indicating that the baseline risk of disease arising from HPV16 is, not surprisingly, the highest among the oncogenic HPV genotypes. We find that the HPV genotype‐specific ≥CIN2 and ≥CIN3 risk‐patterns are so distinct that, for example, 35/39/68 and 56/59/66 should be considered only for low intensive follow‐up, thereby proposing active use of this information in triage strategies for screening HPV‐positive women.

“…NGS has already generated important information about carcinogenesis and natural history of HPV . For example, it has demonstrated that HPV 16 sublineages confer differential risks for disease as well as different tropisms for morphological lesion‐type . Among 3,215 HPV16‐positive women in the US, the HPV16 A4, D2, and D3 sublineages conferred significantly increased risks for glandular lesions compared to the more common A1/A2 sublineages .…”

Section: ±P16 ± Ki67mentioning

confidence: 99%

Eurogin roadmap 2017: Triage strategies for the management of HPV‐positive women in cervical screening programs

Cuschieri

Ronco²,

Lörincz

et al. 2018

Self Cite

139

150

Cervical cancer screening will rely, increasingly, on HPV testing as a primary screen. The requirement for triage tests which can delineate clinically significant infection is thus prescient. In this EUROGIN 2017 roadmap, justification behind the most evidenced triages is outlined, as are challenges for implementation. Cytology is the triage with the most follow-up data; the existence of an HR-HPV-positive, cytology-negative group presents a challenge and retesting intervals for this group (and choice of retest) require careful consideration. Furthermore, cytology relies on subjective skills and while adjunctive dual-staining with p16/Ki67 can mitigate inter-operator/-site disparities, clinician-taken samples are required. Comparatively, genotyping and methylation markers are objective and are applicable to self-taken samples, offering logistical advantages including in low and middle income settings. However, genotyping may have diminishing returns in immunised populations and type(s) included must balance absolute risk for disease to avoid low specificity. While viral and cellular methylation markers show promise, more prospective data are needed in addition to refinements in automation. Looking forward, systems that detect multiple targets concurrently such as next generation sequencing platforms will inform the development of triage tools. Additionally, multistep triage strategies may be beneficial provided they do not create complex, unmanageable pathways. Inevitably, the balance of risk to cost(s) will be key in decision making, although defining an acceptable risk will likely differ between settings. Finally, given the significant changes to cervical screening and the variety of triage strategies, appropriate education of both health care providers and the public is essential.