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

• Published in: British journal of cancer Vol. 122; no. 3; pp. 405 - 412
• Main Authors: Tuna, Musaffe, Ju, Zhenlin, Yoshihara, Kosuke, Amos, Christopher I., Tanyi, Janos L., Mills, Gordon B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.02.2020; Nature Publishing Group
• Subjects: 631/67/1517/1709; 692/53/2422; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Ovarian Epithelial - genetics; Carcinoma, Ovarian Epithelial - metabolism; Carcinoma, Ovarian Epithelial - pathology; Clinical outcomes; Disease-Free Survival; Drug Resistance; Epidemiology; Female; Gain of Function Mutation; Humans; Loss of Function Mutation; Middle Aged; Missense mutation; Molecular Medicine; Mutation; Mutation hot spots; Neoplasm Grading; Neoplasm Staging; Oncology; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; p53 Protein; Population studies; Prognosis; Proportional Hazards Models; Survival; Survival Rate; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-019-0654-8

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.