Clinical relevance of TP53 hotspot mutations in high-grade serous ovarian cancers

Musaffe Tuna, Zhenlin Ju, Kosuke Yoshihara, Christopher I. Amos, Janos L. Tanyi, Gordon B. Mills

    Research output: Contribution to journalArticle

    Abstract

    Background: Mutation of TP53 is the most frequent genetic alteration in high-grade serous ovarian cancer (HGSOC). The impact of hotspot mutations of TP53 and protein levels on patient outcomes in HGSOC has not been fully elucidated. Methods: The study population (n = 791) comprised of HGSOC samples with TP53 mutation from TCGA and other publicly available data. Univariate and multivariate cox proportional hazards regression analyses were used to select variables that were correlated with patient survival. Results: We assessed the effects of TP53 mutations based on type and individual hotspot mutations on patient outcomes in HGSOC. Only hotspot mutations were associated with outcomes. Three hotspot mutations: G266, Y163C, and R282, in aggregate were associated with a worsened overall and recurrence-free survival compared with other hotspot mutations (p < 0.0001 and p = 0.001), other non-hotspot missense mutations (p < 0.0001 and p = 0.008), truncated mutations (p < 0.0001 and p = 0.001), and all other mutations (p < 0.0001 and p = 0.001). Specific hotspot mutations were associated with different protein expression patterns consistent with different functions. Conclusions: This study provides evidence that individual TP53 hotspot mutations have different impact on HGSOC patient outcomes and potentially TP53 function. Thus the status of particular TP53 aberrations could influence response to therapy and selection of therapeutic agents.

    Original languageEnglish (US)
    JournalBritish Journal of Cancer
    DOIs
    StateAccepted/In press - Jan 1 2019

    Fingerprint

    Ovarian Neoplasms
    Mutation
    Tumor Suppressor Protein p53
    Survival
    Missense Mutation
    Regression Analysis
    Recurrence

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Clinical relevance of TP53 hotspot mutations in high-grade serous ovarian cancers. / Tuna, Musaffe; Ju, Zhenlin; Yoshihara, Kosuke; Amos, Christopher I.; Tanyi, Janos L.; Mills, Gordon B.

    In: British Journal of Cancer, 01.01.2019.

    Research output: Contribution to journalArticle

    Tuna, Musaffe ; Ju, Zhenlin ; Yoshihara, Kosuke ; Amos, Christopher I. ; Tanyi, Janos L. ; Mills, Gordon B. / Clinical relevance of TP53 hotspot mutations in high-grade serous ovarian cancers. In: British Journal of Cancer. 2019.
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    abstract = "Background: Mutation of TP53 is the most frequent genetic alteration in high-grade serous ovarian cancer (HGSOC). The impact of hotspot mutations of TP53 and protein levels on patient outcomes in HGSOC has not been fully elucidated. Methods: The study population (n = 791) comprised of HGSOC samples with TP53 mutation from TCGA and other publicly available data. Univariate and multivariate cox proportional hazards regression analyses were used to select variables that were correlated with patient survival. Results: We assessed the effects of TP53 mutations based on type and individual hotspot mutations on patient outcomes in HGSOC. Only hotspot mutations were associated with outcomes. Three hotspot mutations: G266, Y163C, and R282, in aggregate were associated with a worsened overall and recurrence-free survival compared with other hotspot mutations (p < 0.0001 and p = 0.001), other non-hotspot missense mutations (p < 0.0001 and p = 0.008), truncated mutations (p < 0.0001 and p = 0.001), and all other mutations (p < 0.0001 and p = 0.001). Specific hotspot mutations were associated with different protein expression patterns consistent with different functions. Conclusions: This study provides evidence that individual TP53 hotspot mutations have different impact on HGSOC patient outcomes and potentially TP53 function. Thus the status of particular TP53 aberrations could influence response to therapy and selection of therapeutic agents.",
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    AU - Ju, Zhenlin

    AU - Yoshihara, Kosuke

    AU - Amos, Christopher I.

    AU - Tanyi, Janos L.

    AU - Mills, Gordon B.

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