Detection of somatic TP53 mutation in surgically resected small-cell lung cancer by targeted exome sequencing: association with longer relapse-free survival

Abstract

Objectives Few reports have explored clinical biomarkers, including those identified by targeted exome sequencing (TES) of surgically resected small-cell lung cancer (SCLC) and correlation with patient survival. Patients and methods We collected formalin-fixed paraffin-embedded tumor samples from 127 patients with SCLC who had undergone surgery and analysed nonsynonymous somatic gene mutation profiles by TES of 26 cancer-related genes using next-generation sequencing (NGS) and web databases (UMIN Registration No. 000010117). Results We detected 38 nonsynonymous somatic tumor protein p53 ( TP53 ) mutations in 43 (54.4%) patients. Among these TP53 lesions, we identified clinically relevant mutations including those encoding Y220C, R248W, R249M, M237I, and R273L substitutions in the p53 protein. These mutations have been reported to be associated with certain clinical outcomes or biology in other types of malignancies but not in SCLC. Moreover, nonsynonymous somatic mutations of TP53 were positively associated with relapse-free survival (RFS) (median, 17.33 months [95% confidence interval (CI), 3.86–30.79] in a mutation-positive group vs 10.39 months (6.96–13.82) in a mutation-negative group, p = 0.042). Multivariate analysis revealed that nonsynonymous somatic TP53 mutation was an independent factor of prolongation of RFS (hazard ratio: 0.51, 95% CI: 0.29–0.89, p = 0.019) but not overall survival (OS). Conclusion These data suggested that TES may play a critical role for promoting reverse-translational studies, including investigations of the biology of TP53 mutations in different stages of SCLC. Accumulation of the data using cancer panels with a broader range of genes, including TP53 , is expected to be useful for future clinical applications for patients with SCLC.

Immune pathways and TP53 missense mutations are associated with longer survival in canine osteosarcoma

“…13). A study in human small-cell lung cancer associated TP53 mutations identified in 54% of patients with longer relapse free intervals compared to patients with wild-type TP53 55 . Similarly, TP53 mutant human cancers including breast, are significantly more likely to achieve pathological complete responses to chemotherapy [56][57][58][59][60] .…”

Circulating Tumor DNA Profiling of a Diffuse Large B Cell Lymphoma Patient with Secondary Acute Myeloid Leukemia

“…TP53 p.R273L is an oncogenic missense mutation according to Variant Interpretation for Cancer Consortium (VICC) criteria [16]. It has been described as gain of function or driver mutation in numerous malignancies [17][18][19]. TP53 p.R273 mutations are known tumor hotspot mutations and have been detected in DLBCL recurrences, interpreted as evolutionary alterations of therapy resistance [15,20].…”

Small Cell Lung Cancer: State of the Art of the Molecular and Genetic Landscape and Novel Perspective

“…RB1 acts as a transcriptional corepressor, is located in 13q14.2, has 28 exons, negatively regulates the cell cycle, and stabilizes the chromatin structure. When activated, it binds to the transcription factor E2F1 (Gene ID: 5925, updated on 7 February 2021) [ 16 , 17 ]. Inactivation of RB1 can occur through different mechanisms: Point mutations, deletion, exon inversions, splice site mutations, and loss of mRNA expression [ 18 ].…”