Concomitant TP53 Mutation Confers Worse Prognosis in EGFR-Mutated Non-Small Cell Lung Cancer Patients Treated with TKIs

Canale, Matteo; Petracci, Elisabetta; Delmonte, Angelo; Bronte, Giuseppe; Chiadini, Elisa; Ludovini, Vienna; Dubini, Alessandra; Papi, Maximilian; Baglivo, Sara; Luigi, Nicoletta De; Verlicchi, Alberto; Chiari, Rita; Landi, Lorenza; Metro, Giulio; Burgio, Marco Angelo; Crinò, Lucio; Ulivi, Paola

doi:10.3390/jcm9041047

Cited by 52 publications

(61 citation statements)

References 30 publications

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“…We found that the TP53 gene had a higher mutation rate in people younger than or equal to 65 years old, reaching 53.8%, and it was only 40% in people over 65 years old, which was consistent with the results of previous studies [32,33]. We also con rmed that TP53 mutations did not affect the prognosis of patients with LUAD, it was consistent with the result of the study by Szymanowska, A., et al [34][35][36][37][38][39]. However, other studied suggested that patients with mutations of the TP53 gene had a poor prognosis [15,32,33,40,41].…”

Section: Discussionsupporting

confidence: 92%

Differences in Genetics and Microenvironment of Lung Adenocarcinoma Patients with or without TP53 Mutation

Zeng

et al. 2021

Preprint

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Background: Differences in genetics and microenvironment of lung adenocarcinoma (LUAD) patients with or without TP53 mutation were analyzed to illustrate the role of TP53 mutation within the carcinogenesis of LUAD, which will provide new concepts for the treatment of LUAD.Methods: In this study, we used genetics and clinical info from the TCGA database, including somatic mutations data, RNA-seq, miRNA-seq, and clinical data. More than one bioinformatics tools were used to analyze the unique genomic pattern of TP53-related LUAD.Results: According to TP53 gene mutation status, we divided the LUAD patients into two groups, including 265 in the mutant group (MU) and 295 in the wild-type group (WT). 787 significant somatic mutations were detected between the groups, includingmutations in titin (TTN), type 2 ryanodine receptor (RYR2) and CUB and Sushi multiple domains 3(CSMD3), which were up-regulated in the MU. However, no significant survival difference was observed. At the RNA level, we obtained 923 significantly differentially expressed genes; in the MU, α-defensin 5(DEFA5),pregnancy-specific glycoprotein 5(PSG5) and neuropeptide Y(NPY) were the most up-regulated genes, glucose-6-phosphatase (G6PC), alpha-fetoprotein (AFP) and carry gametocidal (GC) were the most down-regulated genes. GSVA analysis revealed 30 significant pathways. Compared with the WT, the expression of 12 pathways in the mutant group was up-regulated, most of which pointed to cell division. There were significant differences in tumor immune infiltrating cells, such as Macrophages M1, T cells CD4 memory activated, Mast cells resting, and Dendritic cells resting. In terms of immune genes, a total of 35 immune-related genes were screened, of which VGF (VGF nerve growth factor inducible) and PGC (peroxisome proliferator-activated receptor gamma coactivator) were the most significant up-regulated and down-regulated genes, respectively. Research on the expression pattern of immunomodulators found that 9 immune checkpoint molecules and 6 immune costimulatory molecules were considerably wholly different between the two groups.Conclusion: Taking the mutant group as a reference, LUAD patients in the mutant group had significant differences in somatic mutations, mRNA-seq, miRNA-seq, immune infiltration, and immunomodulators, indicating that TP53 mutation plays a crucial role in the occurrence and development of LUAD.

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Section: Discussionsupporting

confidence: 92%

Differences in Genetics and Microenvironment of Lung Adenocarcinoma Patients with or without TP53 Mutation

Zeng

et al. 2021

Preprint

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“…Lung cancer is linked with somatic mutations in the EGFR , TP53 , KRAS , and ALK genes [ 4 , 5 ]. Concomitant TP53 mutation in EGFR -mutated NSCLC patients is associated with poor prognosis [ 6 ]. Another lung cancer feature is a high ability to invade neighboring tissues and metastasize to distant organs.…”

Section: Introductionmentioning

confidence: 99%

BNIP3 in Lung Cancer: To Kill or Rescue?

Горбунова¹,

Yapryntseva²,

Denisenko³

et al. 2020

Cancers

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Bcl-2/adenovirus E1B 19kDa interacting protein 3 (BNIP3) is a pro-apoptotic BH3-only protein of the Bcl-2 family. Initially, BNIP3 was described as one of the mediators of hypoxia-induced apoptotic cell death in cardiac myocytes and neurons. Besides apoptosis, BNIP3 plays a crucial role in autophagy, metabolic pathways, and metastasis-related processes in different tumor types. Lung cancer is one of the most aggressive types of cancer, which is often diagnosed at an advanced stage. Therefore, there is still urgent demand for reliable biochemical markers for lung cancer and its efficient treatment. Mitochondria functioning and mitochondrial proteins, including BNIP3, have a strong impact on lung cancer development and progression. Here, we summarized current knowledge about the BNIP3 gene and protein features and their role in cancer progression, especially in lung cancer in order to develop new therapeutic approaches associated with BNIP3.

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“…It is not uncommon for patients to have concurrent mutations alongside exon 20 insertions ( 21 ); therefore, we speculate that the difference in afatinib response could be owing to the presence of an additional mutation. For example, TP53 mutations are one of the most common concurrent mutations alongside exon 20 insertion ( 21 ) and is possibly associated with a lower likelihood of response to EGFR TKIs ( 22 ). Overall, these findings are particularly interesting and suggest that afatinib may provide a new therapeutic option for the particular type of mutation discussed here.…”

Section: Discussion and Concluding Remarksmentioning

confidence: 99%

Case Report: Afatinib Treatment in a Patient With NSCLC Harboring a Rare EGFR Exon 20 Mutation

et al. 2021

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Unlike most other primary epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC), exon 20 insertions, comprising approximately 4% to 10% of all EGFR mutations, are generally considered to be resistant to EGFR tyrosine kinase inhibitors (TKIs). However, EGFR exon 20 insertions are structurally and pharmacologically heterogeneous, with variability in their position and size having implications for response to different EGFR TKIs. The second-generation ErbB family blocker, afatinib, is approved for the first-line treatment of EGFR mutation-positive NSCLC and has been shown to have a broad inhibitory profile against common and uncommon EGFR mutations. Here, we describe a patient with bilateral multifocal lung adenocarcinoma harboring a very rare EGFR exon 20 insertion (c.2317_2319dup3; p.H773dup), who has been receiving treatment with afatinib for 4.5 years. To our knowledge, this is the first report describing long-term benefit for a patient treated with afatinib with this rare exon 20 insertion. We are aware of two further cases with this rare EGFR mutation. One patient, also reported here, has early-stage lung adenocarcinoma and has not yet received systemic therapy for NSCLC. The other patient received afatinib in the context of a global compassionate use program and had progressive disease. Our findings may be of clinical relevance for patients carrying tumors with this rare mutation as epidemiological evidence suggests that p.H773dup may function as a driver mutation in NSCLC. Together with previous preclinical and clinical evidence for the activity of afatinib against certain EGFR exon 20 insertions, these findings warrant further investigation.

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Concomitant TP53 Mutation Confers Worse Prognosis in EGFR-Mutated Non-Small Cell Lung Cancer Patients Treated with TKIs

Cited by 52 publications

References 30 publications

Differences in Genetics and Microenvironment of Lung Adenocarcinoma Patients with or without TP53 Mutation

Differences in Genetics and Microenvironment of Lung Adenocarcinoma Patients with or without TP53 Mutation

BNIP3 in Lung Cancer: To Kill or Rescue?

Case Report: Afatinib Treatment in a Patient With NSCLC Harboring a Rare EGFR Exon 20 Mutation

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