The early detection of ovarian cancer is becoming more feasible than ever, with the results of a recent Italian study suggesting it may be possible to identify – years before the first clinical manifestations of the disease – molecular alterations specific to ovarian cancer DNA in swabs already in use for the common Pap test.
Symptoms of the disease usually manifest only in the last stages of the disease, so early detection is critical for survival. In fact, the survival rate at five years is just 30% for cancers diagnosed at stage three (or more), the most abundant, but 90% when the tumour is diagnosed at stage one.
“Ovarian cancer survival is highly dependent on the timing of diagnosis: changing our ability to make early diagnosis means changing the chances of cure. And that is exactly what we believe is possible through an innovative, yet fairly simple approach: applying specific genomic analysis on the samples collected during Pap tests in search of the molecular signature of ovarian cancer: its genomic instability,” said Maurizio D’Incalci, professor of pharmacology at Milan’s Humanitas University/head of the Laboratory of Antitumor Pharmacology at Humanitas Research Hospital, and Sergio Marchini, head of the Translational Genomics Unit in the same institute, who designed and co-ordinated the study.
Their findings were published in Science Translational Medicine.
The role of genomic instability
Globally, reports Politico, more than 250 000 women each year are diagnosed with ovarian cancer. Its most frequent form is called high-grade serous ovarian carcinoma (HGSOC), which accounts for 70% of all diagnoses and which is the most aggressive and lethal form of the disease, often resistant to chemotherapy, especially because it is diagnosed at an advanced stage.
In fact, ovarian cancer does not give easily identifiable symptoms.
In recent decades, several research groups worldwide have tried – unsuccessfully – to develop early detection techniques for the disease.
One such technique, like that proposed by the Humanitas researchers, was based on the analysis of samples collected through Pap tests, but in that case, scientists were looking for a genetic mutation that turned out to be not specific enough.
"What makes the difference now is the idea of looking at a macro molecular feature of cancer cells: their genomic instability,” said Marchini.
“Today we know that in the early stages of the tumour transformation process, the DNA of future neoplastic cells is characterised by profound abnormalities in its structure and organisation. Thus, genomic instability is a primitive feature that is not shared with healthy cells: an excellent starting point for developing an early detection test.”
Retrospective study
For the study, researchers collected Pap tests samples taken years before diagnosis from 113 women with ovarian cancer. The swabs were analysed using a DNA sequencing technique that allows them to detect even small traces of tumour DNA and measure their genomic instability.
The results obtained were compared with a control group: the Pap tests of 77 healthy women who had not received any cancer diagnosis in subsequent years.
“For the first time, the data are really promising: they show that the technique used is able to recognise the presence of tumour DNA years before the manifestation of the disease, in one case even nine years before.
“The number of false positives in the control group is very low, as is the number of false negatives among the swabs of cancer patients,” said Lara Paracchini and Laura Mannarino, first authors of the study.
This is only the first, although fundamental, step in demonstrating the feasibility and effectiveness of an early diagnostic technique for ovarian cancer.
“Diagnostic approaches are particularly complex to test because they have to be evaluated in the real world, in large numbers of patients and in prospective studies. Only by doing so will it be possible to show that by detecting these traces of highly unstable DNA can we really predict the disease and implement monitoring pathways able to save lives,” said D’Incalci.
“Our data trace a possible a way forward: now we need the support of all necessary stakeholders to start a large and robust prospective study aimed at confirming the data and turning the dream of early detection of ovarian cancer into a concrete reality.”
Study details
Genomic instability analysis in DNA from Papanicolaou test provides proof-of-principle early diagnosis of high-grade serous ovarian cancer
Lara Paracchini , Laura Mannarino Chiara Romualdi , Riccardo Zadro, Sergio Marchini, et al.
Published in Science Translational Medicine on 6 December 2023
Abstract
Late diagnosis and the lack of screening methods for early detection define high-grade serous ovarian cancer (HGSOC) as the gynaecological malignancy with the highest mortality rate. In the work presented here, we investigated a retrospective and multicentric cohort of 250 archival Papanicolaou (Pap) test smears collected during routine gynaecological screening. Samples were taken at different time points (from 1 month to 13.5 years before diagnosis) from 113 presymptomatic women who were subsequently diagnosed with HGSOC (pre-HGSOC) and from 77 healthy women. Genome instability was detected through low-pass whole-genome sequencing of DNA derived from Pap test samples in terms of copy number profile abnormality (CPA). CPA values of DNA extracted from Pap test samples from pre-HGSOC women were substantially higher than those in samples from healthy women. Consistently with the longitudinal analysis of clonal pathogenic TP53 mutations, this assay could detect HGSOC presence up to 9 years before diagnosis. This finding confirms the continual shedding of tumour cells from fimbriae toward the endocervical canal, suggesting a new path for the early diagnosis of HGSOC. We integrated the CPA score into the EVA (early ovarian cancer) test, the sensitivity of which was 75% (95% CI, 64.97 to 85.79), the specificity 96% (95% CI, 88.35 to 100.00), and the accuracy 81%. This proof-of-principle study indicates that the early diagnosis of HGSOC is feasible through the analysis of genomic alterations in DNA from endocervical smears.
Politico article – Ovarian cancer: New steps toward early diagnosis (Open access)
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