Association of TP53 Gain-of-Function and Non–Gain-of-Function Mutations With Outcomes in Left-Sided vs Right-Sided Metastatic Colorectal Cancer

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In a study reported in the Journal of Clinical Oncology, Pan et al found that overall survival was poorer among patients with metastatic right-sided vs left-sided colorectal cancer with TP53 mutations, driven by poorer outcomes in those with non–gain-of-function mutations, and that gain-of-function vs non–gain-of-function TP53 mutations were associated with poorer survival only in left-sided tumors.

Study Details

The study involved data from the Kaiser Permanente Northern California dataset on 1,043 patients with next-generation sequencing performed between November 2017 and January 2021. TP53 gain-of-function mutations were defined as R175H, R248W, R248Q, R249S, R273H, R273L, and R282W; all other mutations were defined as non­–gain-of-function. The association between gain-of-function and non­–gain-of-function mutations and overall survival was assessed using Cox regression modeling adjusted for age, sex, ethnicity, performance status, Charlson comorbidity index, and receipt of chemotherapy.

Key Findings

Among the 1,043 patients, 735 had tumors with TP53 mutations and 308 had wild-type TP53. Among the 735 patients with mutations, 204 had gain-of-function and 531 had non–gain-of-function mutations.

In the entire cohort, adjusted overall survival was similar for patients with TP53 mutations vs wild-type TP53. In adjusted analysis, overall survival was worse for gain-of-function vs non–gain-of-function mutations (hazard ratio [HR] = 1.30, 95% confidence interval [CI] = 1.00–1.68). No meaningful difference in survival was observed for right-sided vs left-sided colorectal cancer with wild-type TP53. Overall survival was worse in right-sided vs left-sided colorectal cancer with TP53 mutations (HR = 1.48, 95% CI = 1.14–1.91, P = .004).

Overall survival was worse with gain-of-function vs non–gain-of-function mutations in left-sided colorectal cancer (HR = 1.66, 95% CI = 1.20–2.29), but not in right-sided disease (HR = 0.79, 95% CI = 0.49–1.26). Right-sided colorectal cancer was associated with worse overall survival vs left-sided colorectal cancer in patients with non–gain-of-function mutations (HR = 1.76, 95% CI = 1.30–2.39) but not in those with gain-of-function mutations (HR = 0.92, 95% CI = 0.55–1.53) or those with wild-type TP53 (HR = 0.88, 95% CI = 0.60–1.28).

The associations were largely unchanged after additional adjustment for RAS, BRAF, and PIK3CA mutations, as well as microsatellite instability–high status.

The investigators concluded, “Poorer survival of patients with metastatic right-sided colorectal cancer vs left-sided colorectal cancer appeared to be restricted to the subset with non–gain-of-function TP53 mutations, whereas gain-of-function vs non–gain-of-function mutations were associated with poorer survival only among patients with left-sided colorectal cancer. This approach of collectively classifying TP53 mutations into gain-of-function and non–gain-of-function provides new insight for prognostic stratification and for understanding the mechanism of sidedness-dependent prognosis. If confirmed, future colorectal cancer clinical trials may benefit from incorporating this approach.”

Minggui Pan, MD, PhD, of the Division of Research and Department of Oncology and Hematology, Kaiser Permanente, is the corresponding author for the Journal of Clinical Oncology article. 

Disclosure: The study was supported by The Permanente Medical Group, Jiayan Foundation, and National Cancer Institute. For full disclosures of the study authors, visit

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