Genomic instability analysis in DNA from Papanicolaou test provides proof-of-principle early diagnosis of high-grade serous ovarian cancer.
Lara ParacchiniLaura MannarinoChiara RomualdiRiccardo ZadroLuca BeltrameIlaria Fuso NeriniPaolo ZolaMaria E LaudaniEva PaganoLivia GiordanoRobert FruscioFabio LandoniSilvia FranceschiMaria L DalessandroVincenzo CanzonieriLuca BoccioloneDomenica LorussoCristina BosettiFrancesco RaspagliesiIsabella M G Garassinonull nullMaurizio D'IncalciSergio MarchiniPublished in: Science translational medicine (2023)
Late diagnosis and the lack of screening methods for early detection define high-grade serous ovarian cancer (HGSOC) as the gynecological 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 gynecological 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 tumor 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.
Keyphrases
- high grade
- copy number
- polycystic ovary syndrome
- circulating tumor
- low grade
- cell free
- single molecule
- mitochondrial dna
- pregnancy outcomes
- genome wide
- breast cancer risk
- dna methylation
- high throughput
- insulin resistance
- cardiovascular disease
- pregnant women
- cross sectional
- coronary artery disease
- type diabetes
- structural basis