Genomic analysis of early-stage lung cancer reveals a role for TP53 mutations in distant metastasis

Abstract

Patients with non-small cell lung cancer (NSCLC) who have distant metastases have a poor prognosis. To determine which genomic factors of the primary tumor are associated with metastasis, we analyzed data from 759 patients originally diagnosed with stage I–III NSCLC as part of the AACR Project GENIE Biopharma Collaborative consortium. We found that TP53 mutations were significantly associated with the development of new distant metastases. TP53 mutations were also more prevalent in patients with a history of smoking, suggesting that these patients may be at increased risk for distant metastasis. Our results suggest that additional investigation of the optimal management of patients with early-stage NSCLC harboring TP53 mutations at diagnosis is warranted in light of their higher likelihood of developing new distant metastases.

A cellular and spatial atlas ofTP53-associated tissue remodeling in lung adenocarcinoma

“…Increased TGF-β signaling likely also helps shape an EMT-supporting niche in TP53 mut tumor samples, where TGFB2 - TGFBR2 interactions involving malignant cells were significantly enriched in spatial data. Previous studies linking mutant p53 to metastatic potential have focused on malignant cell-intrinsic processes 11,12,95 , as the effects of mutant p53 on tumor-stromal and tumor-immune crosstalk have been described only recently in model systems 96 . Our study is the first to profile the cellular and spatial context of TP53 mutated LUAD tumors to provide insight into how TP53 mutations could remodel the TME to promote tumor survival and metastasis in patients, leading to poorer outcomes.…”

“…Tumor protein p53 (TP53) is the most commonly mutated gene in NSCLC (~50%) as well as across many other cancers 8 . TP53 mutations are more common in smokers 9 , and are associated with tumor progression and metastasis, leading to shorter survival in patients with NSCLC 10,11,12 .…”

“…Tumor protein p53 ( TP53 ) is the most commonly mutated gene in NSCLC (∼50%) as well as across many other cancers 8 . TP53 mutations are more common in smokers 9 , and are associated with tumor progression and metastasis, leading to shorter survival in patients with NSCLC 10,11,12 . Despite being the most extensively studied tumor suppressor, TP53 has been challenging to target therapeutically due to the diversity of mutations reported and its involvement in a wide range of regulatory pathways 13–15 .…”

Clinical significance of TP53 alterations in advanced NSCLC patients treated with EGFR, ALK and ROS1 tyrosine kinase inhibitors: An update

“…The tumor protein 53 gene (TP53) is frequently mutated in NSCLC (in approximately 40% of LUAD and 51% of LUSC) [13], resulting in the loss of its tumor suppressor function (impaired protein expression) or the gain of oncogenic activity (aberrant protein expression). Importantly, TP53-mutated NSCLC in patients with a history of smoking present an increased risk of distant metastases [14]. Recent studies emphasize the influence of TP53 gene alterations on the prognosis and the overall responsiveness to targeted therapies in NSCLC [15] (Table 1).…”