Prognostic Value of Diverse TP53 Mutations in Metastatic Cancers: An Analysis of the Cbioportal Database

Background: Functional heterogeneity among TP53 mutations necessitates a need to dissect the prognostic potential of TP53 mutations at different sites or against different molecular background. Methods: The information of TP53 mutations and overall survival time among 7572 patients with metastatic cancers in the MSK-IMPACT clinical sequencing cohort were collected. The effects of TP53 mutations on survival were conducted using the Kaplan-Meier approach, log-rank test and Cox regression model in pan-cancer, and in major subtypes of lung, breast, and colon cancers. Findings: Mutations in exons 4, 5, 6, 7, 8, and 10, p.R342*, p.Y220C, and p.G245S were identified as potential pan-cancer poor prognosticators (p < 0.05 for all). R213* was identified as a significant poor prognosticator only in metastatic lung adenocarcinoma (p = 0.01). The negative prognostic effect of mutated TP53 was statistically significant in lung adenocarcinoma patients harboring EGFR p.L858R (p = 0.002), but not in those with exon 19 deletion (p = 0.173). Compared with wild-type TP53, higher risk of death correlated with TP53 mutational status located in exon 4, 5, 6, 7, or 8 among patients with metastatic breast invasive ductal carcinoma. In addition, p.R282W substitution was significantly associated with poor prognosis in metastatic colon adenocarcinoma (mCOAD), while TP53 mutation was also significantly negative associated with poor survival in COAD patients carrying driving mutations (KRAS or RAS/RAF). Interpretation: The prognostic values of TP53 mutation depended on cancer type and concurrent genomic abnormality. Our results may facilitate prognosis, patient identification for further investigation, and development of TP53 -targeted anti-cancer therapy. Funding: This work was supported by the Logistics Support Department of PLA [grant number 19BJZ03, 2019], Military Medicine Fund of Changzheng Hospital [grant number 2019CZJS208-1, 2019], Science and Technology Commission of Shanghai Municipality [grant number17511103403, 2017], Medical Innovation Research Project of Shanghai Science and Technology Commission (grant number 20Y11914400, 2020), Chinese National Natural Science Funding [grant number 82002522, 2020]and State Key Program for Chronic non- communicable Disease Prevention and Control of the Ministry of Science and Technology, China (grant number 2017YFC1309202, 2017). Declaration of Interest: All authors declare no conflicts of interest.