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Proteomic signatures associated with p53 mutational status in lung adenocarcinoma.

ABSTRACT: p53 is commonly mutated in lung adenocarcinoma. Mutant p53 loses wild-type function and some missense mutations further acquire oncogenic functions, while p53 wild-type may also induce pro-survival signaling. Therefore identification of signatures based on p53 mutational status has relevance to our understanding of p53 signaling pathways in cancer and identification of new therapeutic targets. To this end, we compared proteomic profiles of three cellular compartments (whole-cell extract, cell surface, and media) from 28 human lung adenocarcinoma cell lines that differ based on p53 mutational status. In total, 11,598, 11,569, and 9090 protein forms were identified in whole-cell extract, cell surface, and media, respectively. Bioinformatic analysis revealed that representative pathways associated with epithelial adhesion, immune and stromal cells, and mitochondrial function were highly significant in p53 missense mutations, p53 loss and wild-type p53 cell lines, respectively. Of note, mRNA levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-?), a transcription coactivator that promotes mitochondrial oxidative phosphorylation and mitochondrial biogenesis, was substantially higher in p53 wild-type cell lines compared to either cell lines with p53 loss or with missense mutation. Small interfering RNA targeting PGC1-? inhibited cell proliferation in p53 wild-type cell lines, indicative of PGC1-? and its downstream molecules as potential therapeutic targets in p53 wild-type lung adenocarcinoma.

SUBMITTER: Taguchi A

PROVIDER: S-EPMC4403731 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Proteomic signatures associated with p53 mutational status in lung adenocarcinoma.

Taguchi Ayumu A Delgado Oliver O Celiktaş Müge M Katayama Hiroyuki H Wang Hong H Gazdar Adi F AF Hanash Samir M SM

Proteomics 20141120 23-24

p53 is commonly mutated in lung adenocarcinoma. Mutant p53 loses wild-type function and some missense mutations further acquire oncogenic functions, while p53 wild-type may also induce pro-survival signaling. Therefore identification of signatures based on p53 mutational status has relevance to our understanding of p53 signaling pathways in cancer and identification of new therapeutic targets. To this end, we compared proteomic profiles of three cellular compartments (whole-cell extract, cell su ...[more]

PMID: 25331784

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Project description:BackgroundTumor mutational burden (TMB) has been identified as one of the predictors for the response to anti-programmed cell death-1 (anti-PD-1) antibody therapy and reported to correlate with smoking history in lung adenocarcinoma. However, in squamous cell carcinoma of the lung, the association between TMB and clinicopathological background factors, such as smoking history, has not been reported, including in our previous study. The mutational signature is a tool to identify the mutagens that are contributing to the mutational spectrum of a tumor by investigating the pattern of DNA changes. Here, we analyzed the mutational signature in lung squamous cell carcinoma to identify mutagens affecting the TMB.MethodsSeven representative mutational signatures including signature 7 (SI7) [ultraviolet (UV)-related], SI4 (smoking), SI6/15 [mismatch repair (MMR)], SI2/13 [apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)], and SI5 (clock-like) were analyzed in Japanese patients with lung squamous cell carcinoma (n=67) using data generated by next-generation sequencing consisting of a 415-gene panel. The relationships between signatures and clinico-pathological data including TMB and programmed death-ligand 1 (PD-L1) expression were analyzed.ResultsAlthough the reconstructed mutational counts were small with targeted sequencing (median: 30.1, range: 13.3-98.7), the distributions of signatures were comparable among samples, with 56 cases containing more than four signatures. The smoking-related SI4 was found in 45 cases and was significantly related with pack-year index (PYI) (P=0.026). The reconstructed mutation counts were highly correlated with SI4 (r=0.51, P<0.0001), whereas the correlation was weak with SI6/15 (MMR-related) and SI2/13 (APOBEC-related). There was no mutational signature related with PD-L1 expression. Some patients exhibited unique signatures; the patient with the highest mutational counts had a MMR signature, and another patient with a prominent UV signature had occupational exposure to UV, as he was employed as a neon sign engineer.ConclusionsMutational signatures can predict the cause of lung squamous cell carcinoma. Tobacco smoking is the mutagen most related with TMB.

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Proteomic signatures associated with p53 mutational status in lung adenocarcinoma.

Publications

Proteomic signatures associated with p53 mutational status in lung adenocarcinoma.

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