2023 World Conference on Lung Cancer (Posters)-EP06.03. Genetic Characterization of Driving Metastasis in TP53-Mutant Non-small Cell Lung Cancer Patients

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Researchers from Shanghai Chest Hospital in China have conducted a study to investigate the genetic mechanisms driving metastasis in non-small cell lung cancer (NSCLC) patients with TP53 mutations. TP53 mutations are associated with highly metastatic potential, but the underlying genetic mechanisms remain unclear. The aim of the study was to characterize the molecular features contributing to driving distant metastasis in TP53-mutant NSCLC patients.<br /><br />The researchers assembled three cohorts of NSCLC patients who had previously received surgical resection or various lines of standard therapy. The correlation between genetic profiling and metastatic potential was analyzed in these cohorts, specifically focusing on the TP53-mutant subgroup.<br /><br />In stage I and II NSCLC patients, the frequency of TP53 mutations differed significantly among different pathological subtypes. TP53 mutation burden increased with an increase in TP53 mutation frequency and TP53-mutant patients harbored more driver genes. The study also found that low malignant subtypes of NSCLC had more EGFR gene mutations, while high malignant subtypes had more TP53 gene mutations.<br /><br />In stage IV NSCLC patients who had received 2nd line or more standard therapy, TP53-mutant patients had a higher tumor mutation burden (TMB). However, the study found that a high TMB did not necessarily correspond to increased metastatic potential in TP53-mutant patients. Specific co-mutations in genes like EGFR, KEAP1, ARID1A, ERBB2, and BRCA2 were identified as potentially contributing to increased metastatic potential in TP53-mutant patients.<br /><br />In stage IV NSCLC patients who had received 1st line standard therapy, there was no correlation between TMB and metastases in TP53-mutant patients. However, the frequency of TP53 mutations was positively correlated with metastasis sites, and specific co-mutations in genes such as EGFR, KEAP1, ARID1A, ERBB2, and BRCA2 were associated with increased metastatic potential.<br /><br />Lastly, the study showed that co-inhibition of TP53 and specific co-mutations, such as EGFR, demonstrated significant synergistic anti-tumor efficacy in vitro.<br /><br />The findings of this study provide insight into the genetic mechanisms of metastasis in TP53-mutant NSCLC patients and may contribute to the development of novel therapeutic strategies for this patient population.

Asset Subtitle

Jun Lu

Meta Tag

Speaker Jun Lu

Topic Pathology & Biomarkers: Genetic Biomarkers

Keywords

Shanghai Chest Hospital

genetic mechanisms

metastasis

non-small cell lung cancer

NSCLC

TP53 mutations

molecular features

driver genes

tumor mutation burden

co-mutations