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Gynecol Oncol. 2020 Feb;156(2):407-414. doi: 10.1016/j.ygyno.2019.11.124. Epub 2019 Dec 12.

Characterization of TP53 mutations in Pap test DNA of women with and without serous ovarian carcinoma.

Author information

1
Department of Medicine, University of Washington, Seattle, WA 98195, USA; Department of Pathology, University of Washington, Seattle, WA 98195, USA.
2
Department of Pathology, University of Washington, Seattle, WA 98195, USA; Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195, USA.
3
Department of Pathology, University of Washington, Seattle, WA 98195, USA.
4
Department of Obstetrics and Gynecology, University of Washington, Seattle, WA 98195, USA.
5
Department of Statistics, University of Washington, Seattle, WA 98195, USA.
6
Department of Pathology, University of Washington, Seattle, WA 98195, USA. Electronic address: rrisques@uw.edu.

Abstract

OBJECTIVE:

Pap tests hold promise as a molecular diagnostic for serous ovarian cancer, but previous studies reported limited sensitivity. Furthermore, the presence of somatic mutations in normal tissue is increasingly recognized as a challenge to the specificity of mutation-based cancer diagnostics. We applied an ultra-deep sequencing method with the goal of improving sensitivity and characterizing the landscape of low-frequency somatic TP53 mutations in Pap tests.

METHODS:

We used CRISPR-DS to deeply sequence (mean Duplex depth ~3000×) the TP53 gene in 30 Pap tests from 21 women without cancer and 9 women with serous ovarian carcinoma with known TP53 driver mutations. Mutations were annotated and compared to those in the TP53 cancer database.

RESULTS:

The tumor-derived mutation was identified in 3 of 8 Pap tests from women with ovarian cancer and intact tubes. In addition, 221 low-frequency (≲0.001) exonic TP53 mutations were identified in Pap tests from women with ovarian cancer (94 mutations) and without ovarian cancer (127 mutations). Many of these mutations resembled TP53 mutations found in cancer: they impaired protein activity, were predicted to be pathogenic, and clustered in exons 5 to 8 and hotspot codons. Cancer-like mutations were identified in all women but at higher frequency in women with ovarian cancer.

CONCLUSIONS:

Pap tests have low sensitivity for ovarian cancer detection and carry abundant low-frequency TP53 mutations. These mutations are more frequently pathogenic in women with ovarian cancer. Determining whether low-frequency TP53 mutations in normal gynecologic tissues are associated with an increased cancer risk warrants further study.

KEYWORDS:

Biomarker; Deep sequencing; Epithelial ovarian cancer; Papanicolaou test; TP53 gene

PMID:
31839337
PMCID:
PMC7018621
[Available on 2021-02-01]
DOI:
10.1016/j.ygyno.2019.11.124

Conflict of interest statement

Declaration of competing interest RAR shares equity in NanoString Technologies Inc. and is the principal investigator on a NIH SBIR R44CA221426 subcontract research agreement with TwinStrand Biosciences Inc.

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