|
Dr Dinesh Gupta
|
There has been unprecedented surge in our knowledge and understanding about cervical cancer during the past three decades, enabling us to charter a successful passage for its total prevention within our lifetime. The group of human papilloma viruses (HPVs), essentially transmitted through the sexual route, has been identified with considerably higher oncogenic potential that discounts almost every other critically known risk factor including multiple sex partners or early age for sex or oral contraceptive use or even smoking. This is a leading cancer in Indian women and the second most common worldwide, dubiously contributing over one third of the global burden, both in terms of annual incidence as well as mortality. Documented evidences indicate that almost 80 per cent of sexually active women acquire genital HPV by 50 years of age. Relying upon annual screening with pap test, the Western world was able to curtail the incidence of cervical cancer considerably in the last five decades but India could not draw any advantage owing to the lack of community screening, commensurate technical expertise, health consciousness, inappropriate national health policies and priorities as well as highly commercialised healthcare industry. Thanks to the rising middle class, the trend has been seen changing during the past decade. People are getting more concerned about their sexual health, which in its basic obligation, is the crux of social health.
Of late, going past the conventional pap test, a number of new-gen armaments have been added to deal with the latent phase of cervical precursor disease. This phase, spanning over few to several years, provides a greatest window of opportunity to plan its successful prevention. This is a clinically detectable phase with predictably identifiable characteristics, most commonly involving uterine cervix but also other organs of lower ano-genitalia of women and men alike. Therefore, most state-of-the-modern-care tools of cervical cancer prevention, such as early detection technologies or prophylactic and therapeutic vaccines are continuously being evolved around ceasing disease progression beyond this phase.
The most advanced ammunition to this armament is HPV E6/E7 mRNA assay, popularly referred to as OncoTect in global references. This clinical assay combines fluorescence in situ hybridisation (FISH) with molecular diagnostics on the very sensitive flow cytometry technology platform. Going past HPV DNA detection that gives us risk assessment of the disease, identifying individual cells undergoing oncogenic activity due to HPV oncogenes gives us a real time status of the precursor disease. This knowledge is then most accurately verifiable through clinical procedures such as colposcopy or histopathology examinations, and helps to plan a successful disease intervention. The positive reports thus indicate a current pre-cancerous disease which would put the woman at increased risk of developing cervical cancer. Conversely, the negative reports may indicate that the woman is healthy and may return to preventive health check-up in next five years, killing the anxiety around cervical cancer!
The high-risk HPVs are known to induce chronic infections leading to oncogenesis without any observable viremia. The virus infects the metaplastic basal keratinocytes of squamous tissue and integrates its DNA with host cell genome. The infected basal cells rapidly divide to carry infection in the upper parabasal layer where viral early oncogenes (E6 and E7) start to express viral particles in low copy numbers, to the order of 50 to 100 copies per cell. Active viral replication to above 1000 viral particles only takes place in the terminally differentiated superficial epithelial layers. Periodically large amounts of infectious virus are either cleared due to the death of terminally differentiated cells or shed for transmission to other naive individuals. Thus there is no viral induced cytolysis or cellular necrosis and no release of pro-inflammatory cytokine which could trigger antigen presenting cells (APC) to become activated. The immunity at this stage is largely reflected by the cytotoxic T cells as a part of host immune defence but is successfully evaded by the virus. Therefore, most HPV infections resolve within 8 to 10 months as a result of a successful cell-mediated immune response directed against early HPV proteins. At the advanced pre-cancer stage (CIN 2 and above) however, the viral clearance is rapidly overtaken by the viral oncogene expressed proteins making the oncogenesis progress in the forward direction irreversibly, leading to cancer development.
Although most ano-genital HPV infections get resolved, about 10 per cent of individuals develop persistent infection who go on develop high-grade cervical intraepithelial (CIN 2 and above). This is essentially characterised by the over-expression of HPV E6 and E7 proteins in dividing cells, exhibited in the form of chromosomal instability and the progressive ability to resist host immunity.
Most clinical guidelines developed during 2012 suggest HPV DNA testing together with pap test for women above 30. Given the higher positive prediction of the disease, HPV mRNA testing offers us with a real time choice! While HPV DNA has an excellent sensitivity for detecting HPV infection for women potentially at risk of precancer disease, HPV mRNA gives us nearly four-fold higher specificity to identify the active disease at an equal sensitivity as that of a DNA test. It’s like, leaving no scope for the virus to escape detection!
Moving forward, a growing number of clinical researchers are reinventing gene therapy with mRNA and finding success in treating cancer as well as other diseases. Though the DNA forms a basis of genetic code, mRNA offers a platform for the genetic activity taking place in the living cells at all the time.
No wonder, then that most future strategies of cancer prevention will be revolving around the mRNA expression, making cervical cancer prevention possible within our lifetime itself.
Contact Detail:
Email: digup100@gmail.com