[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 34.238.248.103. Please contact the publisher to request reinstatement.
[Skip to Content Landing]
1.
Cancer Genome Atlas Research Network.  Integrated genomic analyses of ovarian carcinoma.   Nature. 2011;474(7353):609-615. doi:10.1038/nature10166PubMedGoogle ScholarCrossref
2.
Vang  R, Levine  DA, Soslow  RA, Zaloudek  C, Shih  IeM, Kurman  RJ.  Molecular alterations of TP53 are a defining feature of ovarian high-grade serous carcinoma: a rereview of cases lacking TP53 mutations in The Cancer Genome Atlas Ovarian Study.   Int J Gynecol Pathol. 2016;35(1):48-55. doi:10.1097/PGP.0000000000000207PubMedGoogle ScholarCrossref
3.
Labidi-Galy  SI, Papp  E, Hallberg  D,  et al.  High grade serous ovarian carcinomas originate in the fallopian tube.   Nat Commun. 2017;8(1):1093. doi:10.1038/s41467-017-00962-1PubMedGoogle ScholarCrossref
4.
Soong  TR, Howitt  BE, Miron  A,  et al.  Evidence for lineage continuity between early serous proliferations (ESPs) in the fallopian tube and disseminated high-grade serous carcinomas.   J Pathol. 2018;246(3):344-351. doi:10.1002/path.5145PubMedGoogle ScholarCrossref
5.
Kinde  I, Bettegowda  C, Wang  Y,  et al.  Evaluation of DNA from the Papanicolaou test to detect ovarian and endometrial cancers.   Sci Transl Med. 2013;5(167):167ra4. doi:10.1126/scitranslmed.3004952PubMedGoogle Scholar
6.
Erickson  BK, Kinde  I, Dobbin  ZC,  et al.  Detection of somatic TP53 mutations in tampons of patients with high-grade serous ovarian cancer.   Obstet Gynecol. 2014;124(5):881-885. doi:10.1097/AOG.0000000000000484PubMedGoogle ScholarCrossref
7.
Wang  Y, Li  L, Douville  C,  et al.  Evaluation of liquid from the Papanicolaou test and other liquid biopsies for the detection of endometrial and ovarian cancers.   Sci Transl Med. 2018;10(433):eaap8793. doi:10.1126/scitranslmed.aap8793PubMedGoogle Scholar
8.
National Center for Biotechnology Information. dbSNP. Accessed May 29, 2020. https://www.ncbi.nlm.nih.gov/snp/
9.
Catalog of Somatic Mutations in Cancer. Accessed May 29, 2020. https://cancer.sanger.ac.uk/cosmic
10.
National Center for Biotechnology Information. ClinVar. Accessed May 29, 2020. https://www.ncbi.nlm.nih.gov/clinvar/
11.
World Health Organization. IARC TP53 Database. Accessed May 29, 2020. https://p53.iarc.fr/
12.
Chang  MT, Bhattarai  TS, Schram  AM,  et al.  Accelerating discovery of functional mutant alleles in cancer.   Cancer Discov. 2018;8(2):174-183. doi:10.1158/2159-8290.CD-17-0321PubMedGoogle ScholarCrossref
13.
Arildsen  NS, Martin de la Fuente  L, Måsbäck  A,  et al.  Detecting TP53 mutations in diagnostic and archival liquid-based Pap samples from ovarian cancer patients using an ultra-sensitive ddPCR method.   Sci Rep. 2019;9(1):15506. doi:10.1038/s41598-019-51697-6PubMedGoogle ScholarCrossref
14.
Yizhak  K, Aguet  F, Kim  J,  et al.  RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues.   Science. 2019;364(6444):eaaw0726. doi:10.1126/science.aaw0726PubMedGoogle Scholar
15.
Krimmel-Morrison  JD, Ghezelayagh  TS, Lian  S,  et al.  Characterization of TP53 mutations in PAP test DNA of women with and without serous ovarian carcinoma.   Gynecol Oncol. 2020;156(2):407-414. doi:10.1016/j.ygyno.2019.11.124PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    Views 2,661
    Citations 0
    Original Investigation
    Oncology
    July 1, 2020

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

    Author Affiliations
    • 1Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
    • 2Department of Obstetrics and Gynecology, Università degli Studi Milano-Bicocca, San Gerardo Hospital, Monza, Italy
    • 3Department of Obstetrics and Gynecology, Azienda Socio Sanitaria Territoriale -Monza, Desio Hospital, Desio, Italy
    • 4Department of Pathology, Università degli Studi Milano-Bicocca, San Gerardo Hospital, Monza, Italy
    JAMA Netw Open. 2020;3(7):e207566. doi:10.1001/jamanetworkopen.2020.7566
    Key Points español 中文 (chinese)

    Question  Can clonal TP53 variants be detected in Papanicolaou tests performed several years before high-grade serous epithelial ovarian cancer (HGS-EOC) diagnosis?

    Findings  This cohort study including 17 patients with HGS-EOC found that in 11 patients, tumor-specific TP53 variants were detected in Papanicolaou tests performed up to 6 years before the diagnosis of HGS-EOC.

    Meaning  These findings suggest that very early diagnosis of HGS-EOC is potentially achievable and that further developments in highly sensitive molecular approaches could improve early diagnosis of HGS-EOC.

    Abstract

    Importance  The low 5-year survival rate of women with high-grade serous epithelial ovarian cancer (HGS-EOC) is related to its late diagnosis; thus, improvement in diagnosis constitutes a crucial step to increase the curability of this disease.

    Objective  To determine whether the presence of the clonal pathogenic TP53 variant detected in matched primary tumor biopsies can be identified in DNA purified from Papanicolaou test samples collected from women with HGS-EOC years before the diagnosis.

    Design, Setting, and Participants  This cohort study was conducted among a single-center cohort of women with histologically confirmed diagnosis of HGS-EOC recruited at San Gerardo Hospital, Monza, Italy, from October 15, 2015, to January 4, 2019. Serial dilutions of DNA derived from tumor samples and DNA extracted from healthy women’s Papanicolaou test samples were analyzed to define the sensitivity and specificity of droplet digital polymerase chain reaction assays designed to detect the TP53 variants identified in tumors. All available brush-based Papanicolaou test slides performed up to 6 years before diagnosis were investigated at the Mario Negri Institute, Milano, Italy. Data were analyzed from October 2018 to December 2019.

    Main Outcomes and Measures  The presence of tumor pathogenic TP53 variants was assessed by the droplet digital polymerase chain reaction approach in DNA purified from Papanicolaou test samples obtained from the same patients before diagnosis during cervical cancer screenings.

    Results  Among 17 included patients (median [interquartile range] age at diagnosis, 60 [53-69] years), Papanicolaou tests withdrawn before diagnosis presented tumor-matched TP53 variants in 11 patients (64%). In 2 patients for whom longitudinal Papanicolaou tests were available, including 1 patient with Papanicolaou tests from 25 and 49 months before diagnosis and 1 patient with Papanicolaou tests from 27 and 68 months before diagnosis, the TP53 clonal variant was detected at all time points.

    Conclusions and Relevance  These findings suggest that noninvasive early molecular diagnosis of HGS-EOC is potentially achievable through detection of TP53 clonal variants in the DNA purified from Papanicolaou tests performed during cervical cancer screening.

    ×