Influence of mutation type on prognostic and predictive values of TP53 status in primary breast cancer patients

Abstract

Abstract. High rates of mutation in the TP53 tumor suppressor gene have been found in many human cancers, including breast tumors, making p53 one of the most studied proteins in oncology. However, the prognostic and predictive value of alterations in this gene remains ambiguous. To analyze the clinical value of somatic TP53 mutations, we collected clinical and molecular data on 210 women with primary breast cancer. We found significant associations of p53 mutations with tumor grade, metastasis, molecular subtype, Her2 status and inverse correlations with estrogen and progesterone receptor status. Cox proportional hazard analysis confirmed a strong prognostic value of p53 mutation for overall survival rate and highlighted significant interactions with lymph node involvement and tumor size. In relation to treatment options, TP53 mutations were associated with poor response to anthracyclines and radiotherapy. Categorization of TP53 mutations according to their type and location revealed that patients with nonsense mutation have the poorest prognosis in comparison with wild-type cases and other types of mutations in this gene. Classification of TP53 mutations with respect to the degree of disturbance of protein structure showed association of disruptive mutations with poorer patients' outcome in contrast to wild-type and non-disruptive mutations. In conclusion, the present study confirms p53 as a potential predictive and prognostic factor in oncology practice and highlights the growing evidence that distinct types of mutations have different clinical impacts.

Predictive Biomarker Profiling of > 6000 Breast Cancer Patients Shows Heterogeneity in TNBC, With Treatment Implications

“…TP53 mutations, although not considered clinically actionable, were also commonly seen and have been associated with poor response to anthracyclines and radiotherapy. 20 TP53, PIK3CA, and PTEN were found at greater frequencies in metastatic TNBC compared with primary disease. All other mutations occurred at very low levels ( 1% of cases), similar to what has been reported in previous studies on somatic mutations in breast cancer.…”

Novel role of PELP1 in regulating chemotherapy response in mutant p53-expressing triple negative breast cancer cells

“…TNBC tumors commonly exhibit gain-of-function mutations in p53 (MTp53), and patients with MTp53 have a poor response to chemo/radiation therapy, poor prognosis, and reduced survival (38,39). PELP1 is a recently discovered substrate of the ATM kinase, and plays a critical role in WTp53-mediated apoptosis in ER+ breast cancer (24) but its role in MTp53 expressing TNBC subtype of breast cancer remains unknown.…”

The role of protein disulphide isomerase AGR2 in the tumour niche

“…These findings indicate that oestrogen receptor‐dependent induction of AGR2 may also contribute to attenuation of p53 activity. p53 plays an important role in sensitivity to chemotherapy, as illustrated by many studies linking TP53 mutations to drug resistance [Chrisanthar et al., ; Dobes et al., ]. One explanation could be that oestrogen receptor‐dependent signalling, including AGR2 up‐regulation, actively participates in attenuation of p53 activity and thereby contributes to the malignant phenotype in the early stages of breast cancer development.…”