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TP53 somatic evolution in cervical liquid-based cytology and blood from individuals with and without ovarian cancer and BRCA1 or BRCA2 germline mutations

Oncogene (2024)Cite this article

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Abstract

Somatic TP53 mutations are prevalent in normal tissue but little is known about their association with cancer risk. Cervical liquid-based cytology (LBC), commonly known as Pap test, provides an accessible gynecological sample to test the value of TP53 somatic mutations as a biomarker for high-grade serous ovarian cancer (HGSC), a cancer type mostly driven by TP53 mutations. We used ultra-deep duplex sequencing to analyze TP53 mutations in LBC and blood samples from 70 individuals (30 with and 40 without HGSC) undergoing gynecologic surgery, 30 carrying BRCA1 or BRCA2 germline pathogenic variants (BRCApv). Only 30% of the tumor mutations were found in LBC samples. However, TP53 pathogenic mutations were identified in nearly all LBC and blood samples, with only 5.4% of mutations in LBC (20/368) also found in the corresponding blood sample. TP53 mutations were more abundant in LBC than in blood and increased with age in both sample types. BRCApv carriers with HGSC had more TP53 clonal expansions in LBC than BRCApv carriers without cancer. Our results show that, while not useful for direct cancer detection, LBC samples capture TP53 mutation burden in the gynecological tract, presenting potential value for cancer risk assessment in individuals at higher hereditary risk for ovarian cancer.

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Fig. 1: Summary of clinical data and coding TP53 mutations found in liquid-based cytology (LBC) and blood leukocyte samples.
Fig. 2: Comparison of TP53 mutations in blood and liquid-based cytology (LBC) samples with TP53 mutations found in cancers.
Fig. 3: TP53 mutation frequency comparison between blood (BLO) and liquid-based cytology (LBC) samples by group.
Fig. 4: Comparison of TP53 mutation frequencies in blood and liquid-based cytology (LBC) samples of patients with and without cancer.

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Data availability

Sequencing data from this study have been submitted to the NCBI BioProject database (https://www.ncbi.nlm.nih.gov/bioproject) under BioProject number PRJNA1123301.

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Acknowledgements

We deeply thank all the patients who donated samples, without whom this research would not have been possible. This work was supported in part by T32 CA009515 (TSG), R21 CA240885 (RAR), Rivkin Center for Ovarian Cancer grant 567612 (RAR), Mary Kay Foundation grant 045-15 (RAR), and R01 CA259384 (RAR).

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  1. Talayeh S. Ghezelayagh

    Present address: Department of Obstetrics & Gynecology, Stanford University, Palo Alto, CA, USA

Authors and Affiliations

  1. Department of Obstetrics & Gynecology, University of Washington, Seattle, WA, USA

    Talayeh S. Ghezelayagh, Marc R. Radke, Enna Manhardt, Barbara M. Norquist, Ronit Katz & Elizabeth M. Swisher

  2. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA

    Brendan F. Kohrn, Jeanne Fredrickson, Jeffrey D. Krimmel-Morrison, Elena Latorre-Esteves, Xin-Ray Tee & Rosa Ana Risques

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Contributions

TSG designed the study, processed samples, analyzed data, and wrote the manuscript; BFK wrote scripts and analyzed data; JF processed samples and coordinated sequencing; JDK processed samples; EL processed samples; XRT processed samples; MRR retrieved samples; EM retrieved samples; BMN provided feedback on the manuscript; RK performed statistical analyses; EMS provided samples and feedback on the manuscript; RAR acquired funding, designed the study, analyzed data, and wrote the manuscript.

Corresponding author

Correspondence to Rosa Ana Risques.

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Competing interests

RAR is a consultant and equity holder at TwinStrand Biosciences Inc. and an equity holder at NanoString Technologies Inc. RAR is named inventor on patents owned by the University of Washington and licensed to TwinStrand Biosciences Inc. RAR received research funding from a joined research grant with TwinStrand Biosciences Inc. and Ovartec GmbH.

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This research was approved by the Human Subjects Division at the University of Washington (Institutional Review Board numbers 2872 and 7385) and was carried out in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants.

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Ghezelayagh, T.S., Kohrn, B.F., Fredrickson, J. et al. TP53 somatic evolution in cervical liquid-based cytology and blood from individuals with and without ovarian cancer and BRCA1 or BRCA2 germline mutations. Oncogene (2024). https://doi.org/10.1038/s41388-024-03089-y

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