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

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.

Prognostic significance of TP53 and PIK3CA mutations analyzed by next-generation sequencing in breast cancer

“…TP53 has also been associated with worse outcomes in hormone receptor-positive or HER2-negative and TNBC metastatic breast cancer, such as shorter survival and resistance to endocrine treatment. [ 17 ] Tamoxifen is the most widely used endocrine therapy for hormone-positive breast cancer, and TP53 mutations have been suggested to be associated with resistance to tamoxifen. [ 18 ] TP53 mutations are highly expressed in many types of cancer, including breast cancer, and are highly correlated with cancer development.…”

Exploring the Advantages and Limitations of CRISPR-Cas in Breast Cancer

“…43 An increase in TP53 mutation burden (predominantly missense mutations) in BC, has been correlated with advanced disease, higher genetic instability and metastatic risk, 44 worse overall survival and poor clinical outcome. 45,46 Given the high implications of TP53 gene mutations in cancer prognosis, this gene constitutes an attractive therapeutic target for cancer therapy. In fact, several studies have been directed at reversing mutations in TP53 (Fig.…”

The Bioinformatics Application in Detecting Germline and Somatic Variants towards Breast Cancer using Next Generation Sequencing

“…The TP53 gene plays a role in the initiation of gene transcription involved in cell cycle processes, cellular senescence, metabolism, apoptosis, DNA repair, and cell stress response. Mutations in the TP53 gene in breast cancer were found in more than 30% of cases, especially in HER2-positive type breast cancer and Triple Negative Breast Cancer (TNBC) (Bai et al, 2021). Moreover, the PIK3CA gene is a gene that encodes the p110 alpha protein, a subunit of the phosphatidylinositol 3-kinase (PI3K) protein that plays an important role in various biological functions, such as cell survival, cell differentiation, and cell proliferation through the PI3K/AKT/mTOR signaling pathway.…”

“…Breast cancer is a form of uncontrolled growth accumulation of breast cell, causing the formation of masses or tissues characterized by lumps on the breast. The uncontrolled growth of cells can spread to other body tissues and form new tumors or called metastases (Bai et al, 2021;Sun et al, 2017). The majority of breast cancers are experienced by women and are known to be the type of cancer that has the highest prevalence rate in the world rather than other types of cancer.…”