Detection of <i>TP53</i> Clonal Variants in Papanicolaou Test Samples Collected up to 6 Years Prior to High-Grade Serous Epithelial Ovarian Cancer Diagnosis

Paracchini, Lara; Pesenti, Chiara; Marchette, Martina Delle; Beltrame, Luca; Bianchi, Tommaso; Grassi, Tommaso; Buda, Alessandro; Landoni, Fabio; Ceppi, Lorenzo; Bosetti, Cristina; Paderno, Mariachiara; Adorni, Marco; Vicini, Debora; Perego, Patrizia; Leone, Biagio Eugenio; D’Incalci, Maurizio; Marchini, Sergio; Fruscio, Robert

doi:10.1001/jamanetworkopen.2020.7566

Cited by 11 publications

(11 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been hypothesized that progression from p53 signature to STIC requires 20 years and another 6 years are needed from STIC to high-grade serous ovarian cancer 7 15 16. In support of this hypothesis, we recently demonstrated that the same p53 mutations found in high-grade serous ovarian cancer biopsies are present in vaginal swabs taken up to 6 years before the diagnosis of high-grade serous ovarian cancer 17. These observations, taken together, suggest that the occurrence of a p53 signature is a common event in the life of every woman, regardless of BRCA mutational status and not all p53 signatures necessarily lead to the development of high-grade serous ovarian cancer.…”

Section: Discussionsupporting

confidence: 67%

Tubal histopathological abnormalities inBRCA1/2mutation carriers undergoing prophylactic salpingo-oophorectomy: a case–control study

Sina

Cassani

Comerio

et al. 2021

Int J Gynecol Cancer

Self Cite

View full text Add to dashboard Cite

ObjectiveTo describe tubal histopathological abnormalities in women with germline BRCA1/2 mutations and in controls.MethodsConsecutive women with BRCA1/2 mutations undergoing bilateral salpingo-oophorectomy between 2010 and 2020 in two centers (San Gerardo Hospital, Monza and San Matteo Hospital, Pavia) were considered in this analysis and compared with controls who had the same surgical procedure for benign conditions. Frequency of p53 signature, serous tubal intraepithelial carcinoma, and high-grade serous ovarian cancer were compared between the two groups.ResultsA total of 194 women with pathogenic BRCA1/2 mutations underwent prophylactic salpingo-oophorectomy. Of these, 138 women (71%) had a completely negative histological examination, while in 56 (29%) patients an ovarian or tubal alteration was reported. Among controls, 84% of patients had a p53wt signature, while 16% had a p53 signature. There was no difference in the frequency of a p53 signature between cases and controls; however, women with BRCA1/2 mutations were more likely to have pre-malignant or invasive alterations of tubal or ovarian epithelium (p=0.015). Among mutation carriers, older age both at genetic testing and at surgery was associated with an increased risk of having malignancies (OR=1.07, p=0.006 and OR=1.08, p=0.004, respectively). The risk of malignancy seems to be increased in patients with a familial history of high-grade serous ovarian cancer. Previous therapy with tamoxifen was significantly more frequent in patients with malignant lesions (40.0% vs 21.3%, p=0.006).ConclusionWe found that a p53 signature is a frequent finding both in BRCA1/2 mutation carriers and in controls, while pre-invasive and invasive lesions are more frequent in BRCA1/2 mutation carriers. Genetic and clinical characteristics are likely to affect the progression to malignancy.

show abstract

Section: Discussionsupporting

confidence: 67%

Tubal histopathological abnormalities inBRCA1/2mutation carriers undergoing prophylactic salpingo-oophorectomy: a case–control study

Sina

Cassani

Comerio

et al. 2021

Int J Gynecol Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…A recent study by Paracchini at el. (36) provides further evidence that mutated TP53 variants can be detected in Pap smears up to six years prior HGSC diagnosis. Their work focused exclusively on detection of mutated variants of TP53, in a rather small cohort of 17 patients.…”

Section: Dna Mutations In Cervical Cell Swabs In Early Detection Of Ocmentioning

confidence: 61%

“…This proportion was higher (ca. 60%) in some studies focused only on detection of TP53 alterations in HGSC (35,36). This can be partly explained by cancer cells either not being present in the location where the sample is being collected or not present in sufficient amounts.…”

Section: Early Oc Diagnosis -New Strategies and Ideas For Improvementmentioning

confidence: 99%

Prospects of Improving Early Ovarian Cancer Diagnosis Using Cervical Cell Swabs

et al. 2021

View full text Add to dashboard Cite

Ovarian cancer (OC) has the poorest prognosisand the highest mortality rate among gynecological malignancies, which is largely due to delayed diagnosis. Therefore, an effective detection strategy is a compelling need. Here, we review the potential use of cervical cell swabs (Pap specimens, liquid) for early detection of OC. It has been shown, that malignant cells exfoliate from the ovaries and may be detected in Pap specimens, routinely collected through cervical cancer screening. Using Medical Subject Headings (MeSH) for searching the PubMed database we identified eight studies reporting the use of Pap specimen in early detection of OC. Six focused on detection of gene mutations, using gene panels or analysis of TP53 variants. Two studies reported analysis of methylation profiles. Seven studies were published in 2018 or later. Additionally, we found one study without MeSH terms assigned yet, which postulated using peptide biomarkers present in Pap-test fluid. In this review we present their main findings, discuss challenges this approach presents and include ideas for improved detection.

show abstract

“…1). Cases enrolled in group B were used to validate, through analysis of clonal pathogenic TP53 somatic variants, the previous findings that shedding of tumor cells from fimbriae to the uterine cavity is a continual and common event in cases who progress toward HGSOC ( 18 ). The median age at diagnosis was 60 and 61 years for groups A and B, respectively (range, 40 to 81 years for group A, and 42 to 80 for group B).…”

Section: Resultsmentioning

confidence: 99%

“…Other studies reproduced similar findings on panels of 18 ( 13 ) or 8 genes ( 14 ), further corroborating the evidence that DNA from ovarian cancer cells can be detected in cervical smears. Further studies focused on TP53 mutations common in HGSOC ( 15 – 18 ). By using ultrasensitive methods, the same tumor TP53 mutations were found in endocervical swabs in more than 60% of cases and up to 80% in the lavage of the uterine cavity ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

Genomic instability analysis in DNA from Papanicolaou test provides proof-of-principle early diagnosis of high-grade serous ovarian cancer

Paracchini,

Mannarino,

Romualdi

et al. 2023

Sci. Transl. Med.

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Detection of TP53 Clonal Variants in Papanicolaou Test Samples Collected up to 6 Years Prior to High-Grade Serous Epithelial Ovarian Cancer Diagnosis

Cited by 11 publications

References 11 publications

Tubal histopathological abnormalities inBRCA1/2mutation carriers undergoing prophylactic salpingo-oophorectomy: a case–control study

Tubal histopathological abnormalities inBRCA1/2mutation carriers undergoing prophylactic salpingo-oophorectomy: a case–control study

Prospects of Improving Early Ovarian Cancer Diagnosis Using Cervical Cell Swabs

Genomic instability analysis in DNA from Papanicolaou test provides proof-of-principle early diagnosis of high-grade serous ovarian cancer

Contact Info

Product

Resources

About