# Molecular Characteristics and Treatment Implications of TP53 Gain‐of‐Function Mutations in Non‐Small Cell Lung Cancer

## TL;DR

This study explores how TP53 gain-of-function mutations affect treatment outcomes and immune responses in non-small cell lung cancer.

## Contribution

The study identifies distinct molecular and clinical features of TP53 gain-of-function mutations in NSCLC.

## Key findings

- TP53 GOF mutations are linked to higher tumor mutation burdens and immune checkpoint expression.
- Patients with TP53 GOF mutations show better immunotherapy response but worse ROS1-TKI outcomes.
- GOF mutations are associated with elevated immune cell infiltration and distinct genetic profiles.

## Abstract

TP53 gain‐of‐function (GOF) effects lead to cellular responses beyond the capabilities of wild‐type TP53 and are known to promote cancer progression, resulting in poorer outcomes in cancer.

A total of 486 patients diagnosed with non‐small cell lung cancer (NSCLC) with baseline DNA sequencing data were enrolled in our study cohort. In addition, clinical and sequencing data from external NSCLC cohorts, including a cohort with histologic data (N = 219), a combined cohort from two studies treated with immunotherapy (N = 315), and a cohort treated with ROS1 tyrosine kinase inhibitor (TKI) (N = 50), were analyzed to assess the relationships between TP53 GOF mutations and histologic subtypes, immunotherapy outcomes, and ROS1‐TKI treatment efficacy.

Compared to TP53 non‐GOF mutations, patients with TP53 GOF mutations showed higher mutation rates in PIK3CA, STK11, and CTNNB1 but lower in NTRK1; increased VEGFA but decreased DLL3 and HRAS amplification rates. Patients with TP53 GOF mutations exhibited significantly higher tumor mutation burdens compared to those with non‐GOF TP53 statuses. Patients with TP53 mutations, both GOF and non‐GOF, showed significantly higher expression of immune checkpoints compared to TP53 wild‐type patients. GOF‐mutated patients also had higher M1 macrophage and CD8+ T cell infiltration, along with elevated B cell receptor signaling. Consistent with our findings, analysis of external cohorts revealed that TP53 GOF mutations were associated with improved prognosis in the context of immunotherapy. Among ROS1 fusion‐positive patients treated with ROS1‐TKIs, those harboring TP53 GOF mutations had a longer median PFS compared to patients with non‐GOF TP53, although both were shorter than those with wild‐type TP53. Additionally, TP53 GOF mutations were associated with a relatively lower histologic grade than non‐GOF mutations.

TP53 GOF mutations were associated with poorer ROS1‐TKI treatment outcomes but improved immunotherapy response in NSCLC, with elevated immune activities and distinct molecular profiles.