Disruptive and Truncating TP53 Mutations Are Associated with African-Ancestry and Worse Prognosis in Brazilian Patients with Lung Adenocarcinoma

Abstract

INTRODUCTION: TP53 is the most frequently mutated gene in lung tumors, but its prognostic role in admixed populations, such as Brazilians, remains unclear. In this study, we aimed to evaluate the frequency and clinicopathological impact of TP53 mutations in non-small cell lung cancer (NSCLC) patients in Brazil. METHODS: We analyzed 446 NSCLC patients from Barretos Cancer Hospital. TP53 mutational status was evaluated through targeted next-generation sequencing (NGS) and the variants were biologically classified as disruptive/nondisruptive, and as truncating/non-truncating. We also assessed genetic ancestry using 46-ancestry informative markers. Analysis of lung adenocarcinomas from the cBioportal dataset was performed. We further examined associations of TP53 mutations with patients’ clinicopathological features. RESULTS: TP53 mutations were detected in 64.3% (287/446) of NSCLC cases, with a prevalence of 60,4% (n=221/366) in lung adenocarcinomas. TP53 mutations were associated with brain metastasis at diagnosis, tobacco consumption, and higher African ancestry. Disruptive and truncating mutations were associated with a younger age at diagnosis. Additionally, cBioportal dataset revealed that TP53 mutations were associated with younger age and Black skin color. Patients harboring disruptive/truncating TP53 mutations had worse overall survival than nondisruptive/non-truncating and wild-type patients. CONCLUSION: TP53 mutations are common in Brazilian lung adenocarcinomas, and their biological characterization as disruptive and truncating mutations is associated with African ancestry and shorter overall survival.

Single-Cell Analysis Differentiates the Effects of p53 Mutation and p53 Loss on Cell Compositions of Oncogenic Kras-Driven Pancreatic Cancer

“…In comparison, The KP loss mouse model can recapitulate the human PDAC cases with KRAS G12D mutation and p53 lossof-function mutations/truncations, with 25 cases within the TCGA PDAC cohort. The p53 loss-of-function mutations and truncations have been widely observed in various cancer types [47][48][49]. The previous findings are consistent with our results showing that patients with p53 gain-of-function mutations exhibit worse prognosis than patients with p53 loss-of-function mutations, based on the analysis of TCGA pancreatic cancer cohort data.…”

Association ofESR1germline variants withTP53somatic variants in breast tumors in a genome-wide study

“…Genetic ancestry is associated with specific somatic driver mutations in EGFR, KRAS and STK11 in lung cancer in individuals of Indigenous American ancestry relative to those of EUR or EAS ancestry [122,123]. TP53 mutations are found at a higher frequency in individuals of AFA relative to individuals of EUR tumors in multiple tumor types (lung, colon, gastric, human papilloma virus negative head and neck), suggesting that genetic background and/or differences in exposures/socio-determinants of health may influence selection of TP53 somatic mutations [124][125][126][127].…”