HPV E6/E7 mRNA test for the detection of high grade cervical intraepithelial neoplasia (CIN2+): a systematic review

According to the Global Cancer Statistics report of the year 2018, cervical cancer ranks 4th for both incidence and mortality with over 570,000 cases and 311,000 deaths worldwide [1]. The global burden of cervical cancer (close to 85%) occurs in developing countries, where it accounts for about 12% of all female cancers [1, 2]; and nine out of ten cervical cancer deaths disproportionately occur in developing countries [3,4,5,6,7,8,9].

About 95-99% of cervical cancer cases are associated with genital infection with High risk (HR)-HPV, which is the most common viral infection of the reproductive tract globally [10, 11] that most women are experiencing soon after they become sexually active [12]. Persistent infection with HR-HPV is the primary cause of cervical cancer and its precursor lesion, called the cervical intraepithelial neoplasia (CIN) [13, 14]. Next to cervical cancer, the HR-HPV has also been linked to a large proportion of other kinds of cancers (anus, vulva, vagina and penis) and a growing number of head and neck tumors [15,16,17,18,19]. So far, > 150 different HPVs have been characterized and completely sequenced. Of all types, about 40 are sexually transmitted and infect the genitalia [17, 20,21,22,23]. HPV types 16 and 18 are notably responsible for > 70% of all cervical cancer cases worldwide [15, 24, 25].

Cervical cancer is curable if detected at its early stage. Premature detection cervical lesion is valuable as it develops slowly preceding cervical cancer which typically takes over a period 10 years [26]. These precursor lesions called the cervical intraepithelial neoplasia (CINs) could be detected by a variety of methods [27]; the most frequently used one is cytology, but there are other alternative methods such as HPV DNA tests and visual inspection with acetic acid (VIA) [15], the latter being practiced primarily in resource limited settings [15]. However, cytology and HPV-DNA based tests are widely available in most developed nations [28, 29]. HPV DNA testing is being introduced in some countries as an adjunct to cytology (‘co-testing’) or as the primary screening test to be followed by a secondary test such as cytology or measurement of HR-HPV E6/E7 gene products [15, 30, 31].

Getting tools with reasonable diagnostic performance remains a challenge in the fight against cervical cancer globally. Given the inadequacy of existent methods, plus limitations in the use of both cytology and HPV DNA test (including but not limited to the sensitivity/specificity issues and the inability to indicate the risk of progression to cancer), there has long been interest in the development of new screening tools in cervical cancer [28, 29]. Many discovery approaches to find HPV associated cervical cancer screening biomarkers are currently underway, of which the HR-HPV E6/E7 mRNA test is a promising non-invasive biomarker for the detection of high grade cervical lesion (CIN2+) enabling detection of the HPV infection and simultaneously predicting the change of cervical lesions [32,33,34,35,36,37,38,39,40]. This is because continuous expression of E6/E7 oncogenes of HR-HPVs is necessary for the development and maintenance of the dysplastic phenotype [41].

It is known that the synergistic effect of the E6 and E7 proteins results in a disturbance of cell cycle regulation, apoptosis prevention, and the transformation and maintenance of neoplastic and dysplastic cells [42]. The overexpression of the E6 and E7 proteins, which inactivate the p53 and pRB respectively, can be detected by testing for the E6/E7 mRNA transcripts which is a potential biomarker (proxy indicator) for an increased risk of disease progression to the level of cancer [43,44,45,46]. The E6/E7 mRNA test can therefore help in avoiding aggressive procedures (biopsies and over-referral of transient HPV infections) as well as lowering patient’s anxiety and the follow-up period as well [34].

The detection of HR-HPV E6/E7 mRNA is being tested as the potential biomarker to elucidate the oncogenic role of HPV in cancer of the cervix and other kind of tumors in general [30, 35, 36, 39, 40, 42]. However, there is quite limited systematically reviewed data on the diagnostic role of different HPV E6/E7 mRNA tests for detection of CIN2+, using histology as a gold standard test. Specifically, the test performance of Aptima, Quantivirus and PreTect Proofer was assessed. The two tests (Aptima, Quantivirus) are able to detect the E6/7 mRNA from the same 14 HPV types, however, one of these tests (Aptima) is FDA approved and has a number of publications in the literature, whereas the other one (Quantivirus) has no clinical population based study published so far and only few entries in the web. The third test (PreTect Proofer) is only able to detect the E6/7 mRNA of five HPV types.

This post was last modified on November 16, 2024 3:46 am