Screening for cervical cancer: trial of molecular combing

Screening for cervical cancer: trial of molecular combing

Twenty years after its invention, the delicate technique of “molecular combing”, supposed to simplify the sequencing of genetic anomalies, will be the subject of a clinical trial in the context of cervical cancer screening.

In September 1997 [1]researchers from the Institut Pasteur detailed in the journal Science a novel protocol for analyzing DNA. In press releases at the time, they described a technique that was “precise, simple, inexpensive and easily automated, [qui] should allow important advances in the field of the diagnosis of genetic diseases”. However, various financial and technical constraints have slowed the development of this technology.

The process patented by the Pasteur Institute, whose commercial exploitation remains reserved for its inventors, is still very confidential. In 2011, “Le magazine de la santé” devoted a report to the application of molecular combing in the detection of a rare form of myopathy, facio-scapulo-humeral dystrophy (or FSHD) [2]. Professor Aaron Bensimon, co-author of the original work, summarized the mechanism of molecular combing.

As with any DNA analysis technique, the first step consists in extracting these molecules from the cell nucleus, using standard methods. The long protein double helices are immersed in a solution, in which a glass plate chemically treated to attract the end of the DNA strands is soon immersed. By very slowly removing the plaque, the ball of DNA stretches in the form of parallel threads, like long hair coming out of the bath (hence the name “molecular combing”). These filaments adhere to the plate, which presents all the assembly instructions of our organism online.

To read the message, it remains to pair certain proteins with phosphorescent markers, and to observe the result under the microscope. Researchers quickly learn to differentiate a normal sequence from another presenting anomalies, and thus reveal the existence of deleterious mutations.

Has viral genetic material been integrated into human DNA?

At the end of December 2015, the company Genomic Visionfounded by the inventors of the process to support its development, has initiated a clinical trial with the University Hospital of Reims to assess theinterest of molecular combing in routine screening for Cervical cancer. This test, called IDAHO [3]will involve 3,500 women, who will be followed for three years by eleven hospitals spread over the territory.

When the papillomavirus infects the cells of the cervix, it transforms their profile and their activity. The greater the number of affected cells, the greater the lesions are significant. Some of these lesions can develop into cancer. “In cases where this cancerous development is proven, the presence of certain strains of papillomavirus, known as “high-risk papillomavirus” (or HPV-HR) is demonstrated in 99.9% of cases”explains Pr Olivier Graesslin, head of the obstetrics department of the CHU de Reims, who will coordinate the trial.

In four out of five cases, the viruses involved are HPV 16 and 18, “who are particularly aggressive”. But currently, the identification of the strains of HPV present in the lesions is not performed routinely. In the current state of scientific knowledge, the interest of this operation could also be limited. “If HPV has infected a cell, it may have introduced its genetic material in the cell medium without it being integrated into the DNA [humain]”, explains Professor Graesslin. “The hypothesis is that the integration of this genetic material into the DNA greatly increases the risk of a cancerous evolution. It is this hypothesis that we are going to verify in the IDAHO study”.

If the study were to confirm this theory, then there would be great interest in using molecular combing routinely to analyze cells recovered from Pap smears of women with advanced lesions. If “high risk” viral DNA is integrated into their DNA, close monitoring would be particularly useful; conversely, there would be reason to be reassured if this integration is not observed.

In a second phase of the study, the researchers plan to follow, for three years, women with less extensive lesions. It will be a question here of determining if the integration of the viral DNA is a predictor of the evolution of the lesions, both in terms ofextent and of proliferation rate than evolution towards cancerous forms.

[1] The work was derived from research implemented on the bacterium Escherichia coli in 1993.

[2] According to the Molecular Combing Commercial Operating Company, the FSHD screening test has been on the market since 2013, and in France used at La Timone Hospital (Marseille) and a North American genetic diagnostic company, Quest Diagnostics.

[3] For “DNA Integration of Oncogenic HPV”

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