In a study led by the researchers of the Department of Oncology and Hematology, Kaiser Permanente in Santa Clara, CA, US non–gain-of-function p53 mutations were associated with worse prognosis of right-sided versus left-sided metastatic colorectal cancer (mCRC), while gain-of-function versus non–gain-of-function p53 mutations were associated with worse prognosis in the left-sided, but not right-sided mCRC. The findings published on 29 November 2021 in the Journal of Clinical Oncology by Dr Min-Gui Pan and colleagues suggest that different p53 mutations may differentially affect survival of patients with mCRC on the basis of anatomic location and shed new light on the potential oncogenic mechanisms of p53 mutations in CRC.
TP53 mutation is present in more than 50% of CRC, and is implicated in the majority of Li-Fraumeni syndrome cases. The spectrum of p53 mutation is broad and varies in various malignancies, including missense mutation, nonsense mutation, deletion, frameshift, insertion, etc. Approximately 80% of these mutations occur in the DNA binding domain, most of which are missense mutations. Approximately 30% of the mutations cluster within six mutation hotspots in the DNA binding domain. Several of these p53 mutations have been shown to exhibit gain-of-function properties, possessing novel functions that are not part of the wild-type p53 protein.
Numerous experimental studies have found that gain-of-function mutants increase cell invasion and proliferation, chemoresistance, colony formation, genomic instability, angiogenesis, etc. Gain-of-function mutants can bind to novel proteins, form new interactions, enhance the signalling of receptor tyrosine kinases, and drive the expression of NF-kB, etc.
In addition to the established molecular features (RAS, BRAF, and PIK3CA mutations, and microsatellite instability-high [MSI-high]) that are closely related to the survival of patients with mCRC, anatomic location of the primary tumour has emerged in recent years as an important prognostic factor. Many studies have shown that right-sided mCRC is associated with worse survival than left-sided tumours, including findings from several randomised clinical studies and a large meta-analysis. The poorer survival of patients with right-sided mCRC appears to be independent of the molecular features; however, its underlying mechanism remains unclear.
Despite many lines of experimental evidence for p53 gain-of-function in cell lines and animals, the data in human malignancies are limited. The goal of this study was to investigate the p53 gain-of-function concept in human malignancy using the next-generation sequencing (NGS) data within Kaiser Permanente Northern California and to explore the relations between the sidedness of mCRC, p53 mutation, and overall survival (OS).
This cohort study included patients with mCRC who had NGS performed from November 2017 to January 2021. The study team defined R175H, R248W, R248Q, R249S, R273H, R273L, and R282W as gain-of-function and all other p53 mutations as non–gain-of-function. They used Cox regression modelling to examine the association between gain-of-function and non–gain-of-function p53 mutations and OS, adjusting for age, sex, ethnicity, performance status, Charlson comorbidity index and receipt of chemotherapy.
Among 1,043 patients, 735 had tumours with p53 mutation and 308 had wild-type p53. Gain-of-function was associated with worse OS than non–gain-of-function p53 mutation only in left-sided tumours (hazard ratio [HR] 1.66; 95% confidence interval [CI] 1.20 to 2.29), but not in right-sided (HR 0.79; 95% CI 0.49 to 1.26). Importantly, right-sided mCRC was associated with worse OS than left-sided only in the subset of patients whose CRC carried non–gain-of-function (HR 1.76; 95% CI 1.30 to 2.39), but not gain-of-function p53 mutation (HR 0.92; 95% CI 0.55 to 1.53) or wild-type p53 (HR 0.88; 95% CI 0.60 to 1.28). These associations were largely unchanged after also adjusting for RAS, BRAF, and PIK3CA mutations, and MSI-high.
The researchers wrote that in this study they have uncovered unexpected associations between p53 mutations and sidedness-dependent prognosis of patients with mCRC: gain-of-function versus non–gain-of-function p53 mutation was associated with inferior survival in patients with left-sided but not right-sided tumours, whereas non–gain-of-function but not gain-of-function p53 mutation was associated with poorer survival of right-sided versus left-sided. The magnitude of OS difference between patients with RAS or BRAF mutation versus RAS and BRAF wild-type, and between patients with right-sided versus left-sided tumours was consistent with what has been reported in the literature, which supports the validity of their data set.
In conclusion, the study suggests that the functional classification of p53 mutations into gain-of-function and non–gain-of-function could help define the prognosis of mCRC by sidedness. If confirmed, the findings could have important implications in clinical practice, future clinical trial design, and understanding the mechanism of CRC oncogenesis.
The study was supported by The Permanente Medical Group.
Pan M, Jiang C, Tse P, et al. TP53 Gain-of-Function and Non–Gain-of-Function Mutations Are Differentially Associated With Sidedness-Dependent Prognosis in Metastatic Colorectal Cancer. JCO; Published on 29 November 2021. DOI: 10.1200/JCO.21.02014