Coloured scanning electron micrograph (SEM) of an ovarian cancer cell. Credit: Steve Gschmeissner/Science Photo Library.
A new genomic test could detect high-grade serous ovarian cancer (HGSOC) in its early stages through the analysis of DNA taken in Pap tests used for the screening of cervical cancer.
In 2020, 314,000 women worldwide were diagnosed with ovarian cancer. HGSOC is the most common type and has a 5-year survival rate under 30%. It is typically diagnosed late, when it is already at stage III or IV, but early detection at stage I boosts survival to around 90%.
Studies have shown that most HGSOC cases start as tumours at the end of the fallopian tubes, shedding cancerous cells from the tubes towards the uterus. Additionally, HGSOC cells accumulate or lose genomic material, a phenomenon called aneuploidy. Instead of having two copies of each gene, HGSOC cancer cells can have one copy (genomic material loss) or more than two copies (genomic material gain).
Researchers led by Maurizio D’Incalci, at Humanitas Research Hospital in Milan, have developed a test based on the analysis of the genomic instabilities in the DNA of Pap tests that collect cells from the cervix1. The new test, named EVA, was used to analyse Pap results dating back several years, belonging to 77 healthy women and to 62 women who later developed HGSOC, and for which tumour samples were available. Data were collected from eight hospitals in Italy.
For the woman who then developed cancer, the scientists sequenced the DNA extracted from the Pap tests and that of the tumour tissue. They confirmed that loss or gain of genomic materials was present in several location of the genome from the Pap tests, even in those taken years before the diagnosis. They then computed for each sequence the overall amount of copy number alterations.
“These instabilities affect different regions of the genome during tumour evolution, thus we decided to look for the overall instability, rather than trying to find overlaps between the Pap tests and tumour sequences”, explains Laura Mannarino, bioinformatician at Humanitas and author of the study. Co-author Lara Paracchini, molecular biologist at Humanitas, adds that they did not focus on specific DNA regions also because there is no alteration that is common to all patients.
The researchers were able to identify two ranges in the genomic instability values: a higher one which included most of the women who developed cancer, and a lower one which included most of the healthy women.
“Since we aimed at developing a test for screening, we set the ranges in order to minimize the false positive ratio of the test, which is the fraction of healthy women which would be diagnosed with early-stage ovarian cancer”, says Mannarino. The test had a false positive ratio of 4% and a true positive ratio, that is the fraction of women with cancer that were correctly identified by the test, of 75%. The test was able to identify women who ended up having HGSOC, up to nine years before the diagnosis.
Now the authors want to test their idea on a larger sample, and plan to start from women with mutations on the BRCA genes, who have an augmented risk. Currently, women who carry these mutations are offered breast removal surgery, and a large number opt the removal of ovaries and tubes. “The result of the EVA test conducted on their Pap smears could be compared with the pathology analysis on the removed tissues,” Paracchini concludes.
