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. 2021 Apr 15:13:3303-3316.
doi: 10.2147/CMAR.S298729. eCollection 2021.

Prognostic Value of the TP53 Mutation Location in Metastatic Breast Cancer as Detected by Next-Generation Sequencing

Han Bai  1 , Jianjun Yu  2 , Shidong Jia  2 , Xiaoran Liu  1 , Xu Liang  1 , Huiping Li  1
Affiliations

Prognostic Value of the TP53 Mutation Location in Metastatic Breast Cancer as Detected by Next-Generation Sequencing

Han Bai et al. Cancer Manag Res. .

Abstract

Purpose: The status of TP53 mutations was measured in cell-free DNA from patients with metastatic breast cancer (MBC) to investigate disease characteristics and the prognostic role of different locations of the TP53 mutation site.

Patients and methods: Blood samples were taken from a total of 187 patients diagnosed with MBC who were treated at the Department of Breast Oncology, Peking University Cancer Hospital between January 2013 and March 2020. Next-generation sequencing was used to investigate the TP53 mutation spectra of circulating free DNA in these blood samples.

Results: Among the 187 MBC patients, TP53-mutated patients had a significantly shorter median disease-free survival (DFS) and overall survival (OS) compared with TP53 wild-type patients (P=0.001 and P=0.006, respectively). Additionally, in hormone receptor positive/HER2 negative (HR+/HER2-) and triple negative (TNBC) cohorts, TP53-mutated patients had a significantly shorter median DFS than TP53 wild-type patients (P=0.038 and P=0.023, respectively). The 79 patients with TP53 mutations carried 87 somatic TP53 mutations, of which most (77.0%) mapped to the DNA-binding domain (DBD) of the protein encoded by TP53 exons 5-8. In patients with TP53 mutations, those occurring in the non-DBD had a significantly shorter median DFS and OS than TP53 wild type (P<0.001 and P=0.001, respectively). Additionally, patients with non-missense mutations in the DBD had a significantly shorter median DFS and OS than TP53 wild-type patients (P=0.001 and P<0.001, respectively). TP53-mutated patients had a significantly shorter DFS than TP53 wild-type patients in the adjuvant endocrine therapy sensitive group (P=0.008), but differences in the endocrine therapy resistant group were not significant.

Conclusion: TP53-mutated MBC patients had a significantly worse outcome than TP53 wild-type patients especially those in HR+/HER2- and TNBC cohorts. Of TP53-mutated patients, those with non-missense mutations in the DBD had worse breast cancer-related survival. TP53 mutations were also associated with endocrine resistance.

Keywords: DNA-binding domain; NGS; TP53 mutation; adjuvant endocrine therapy; advanced breast cancer.

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Conflict of interest statement

Jianjun Yu and Shidong Jia are employees and stockholders of Huidu Shanghai Medical Sciences, Ltd. The authors declare that they have no other competing interests.

Figures

Figure 1
Figure 1
Flowchart of patient inclusion.
Figure 2
Figure 2
The mutational spectra of TP53 in TP53-mutated patients. (formula image) Missense (formula image) Truncating (formula image) Inframe.
Figure 3
Figure 3
Survival analyses by Kaplan–Meier according to TP53 status in MBC patients. (A and B) TP53 wild-type patients had a significantly better clinical outcome than TP53-mutated patients. (C and D) there were no significant differences between TP53 wild-type and -mutated patients in the HER2-positive cohort. (E and F) TP53 wild-type patients had a significantly longer median DFS and OS than TP53-mutated patients in the HR+/HER2– cohort. (G and H) TP53 wild-type patients had a significantly longer median DFS than TP53-mutated patients in the TNBC cohort.
Figure 4
Figure 4
Survival analyses by Kaplan–Meier according to TP53 mutation sites in MBC patients. (A) Patients with a mutation in the non-DNA binding domain had a significantly shorter median DFS than TP53 wild-type patients and those with mutations in the DNA-binding domain. (B) Patients with a mutation in the non-DNA binding domain had shorter median OS than TP53 wild-type patients and those with mutations in the DNA-binding domain. (C) Patients with protein non-stable mutation had shortest median DFS than patients with protein stable mutation and TP53 wild-type patients. (D) Patients with protein non-stable mutation had shortest median OS than patients with protein stable mutation and TP53 wild-type patients.
Figure 5
Figure 5
Survival analyses by Kaplan–Meier according to TP53 mutation type in the DNA binding domain. (A and B) Patients with non-missense mutations in the DNA binding domain had a significantly shorter median DFS and OS than TP53 wild-type patients and those with missense mutations in the DNA binding domain.
Figure 6
Figure 6
Survival analyses by Kaplan–Meier according to TP53 status in MBC receiving adjuvant endocrine therapy. (A) There was no significant difference in TP53 status in the endocrine therapy-resistant cohort. (B) TP53 wild-type patients had a significantly better clinical outcome than TP53-mutated patients in the endocrine therapy sensitive cohort.
See this image and copyright information in PMC

References

    1. Kastenhuber ER, Lowe SW. Putting p53 in context. Cell. 2017;170(6):1062–1078. doi:10.1016/j.cell.2017.08.028 - DOI - PMC - PubMed
    1. Hainaut P, Pfeifer GP. Somatic TP53 mutations in the era of genome sequencing. Cold Spring Harb Perspect Med. 2016;6(11):a026179. doi:10.1101/cshperspect.a026179 - DOI - PMC - PubMed
    1. Stephens PJ, Tarpey PS, Davies H, et al. The landscape of cancer genes and mutational processes in breast cancer. Nature. 2012;486(7403):400–404. doi:10.1038/nature11017 - DOI - PMC - PubMed
    1. Basho RK, de Melo Gagliato D, Ueno NT, et al. Clinical outcomes based on multigene profiling in metastatic breast cancer patients. Oncotarget. 2016;7(47):76362–76373. doi:10.18632/oncotarget.12987 - DOI - PMC - PubMed
    1. Ellis MJ, Ding L, Shen D, et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature. 2012;486(7403):353–360. doi:10.1038/nature11143 - DOI - PMC - PubMed