The expression patterns and prognostic significance of pleckstrin homology-like domain family A (PHLDA) in lung cancer and malignant mesothelioma

Our plain-English summary of The expression patterns and prognostic significance of pleckstrin homology-like domain family A (PHLDA) in lung cancer and malignant mesothelioma, by C.M. Baldavira, J. Machado-Rugolo, T.G. Prieto, et al (Journal of Thoracic Disease, 2021).

The study

• Authors: C.M. Baldavira, J. Machado-Rugolo, T.G. Prieto, D.R. Bastos, M. Balancin, A.M. Ab'Saber, L.B. Yaegashi, P.C. Souza, C. Farhat, T.Y. Takagaki, M.A. Nagai, V.L. Capelozzi
• Journal: Journal of Thoracic Disease
• Published: 2021;13(2):689-707
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Pleckstrin homology domain family A (PHLDA) genes play important roles in cancer cellular processes, including inhibiting Akt activation, repressing growth factor signaling, inhibiting the negative feedback of EGFR/ErbB2 signaling cells, and inducing apoptosis. However, the prognostic significance of PHLDA in non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MM) remains unclear. The present study investigates the associations between PHLDA expression patterns and their prognostic value in lung adenocarcinoma (LUAD) and MM.

Methods: We analyzed PHLDA family members at the genomic level in silico to explore their mRNA expression pattern and predictive significance in LUAD and MM. We then created a PHLDA-drug interaction network and a protein-protein interaction (PPI) network using different databases. Finally, we immunohistochemically assessed the protein expression of each PHLDA family member on tissue microarrays (TMAs) in both LUAD and MM cohorts with long-term follow-up.

Results: While PHLDA1 mRNA expression in both LUAD and MM was lower than that of normal tissue, PHLDA2 mRNA was significantly overexpressed in LUAD, and PHLDA3 mRNA was overexpressed in MM. In NSCLC, both low PHLDA1 mRNA expression and high PHLDA3 mRNA expression correlated with worse overall survival (OS) (P<0.01), whereas high PHLDA2 mRNA expression was associated with better OS (P<0.01). In MM, patients presenting high PHLDA1 and PHLDA2 mRNA expression had poor OS (P=0.01 and P<0.01, respectively). In addition, the PHLDA-drug interaction network indicated that several common drugs could potentially modulate PHLDA expression, and the PPI network suggested that PHLDA1 interacts with Notch family members, whereas PHLDA3 interacts with TP53. Our results also showed that the expression of PHLDA2 and PHLDA3 was significantly higher in LUAD and MM than that of PHLDA1 (P<0.05) and was associated with the risk of death. While patients with PHLDA2 >85.09 cells/mm2 had a low risk of death (P=0.01) and a median survival time of 48 months, those with PHLDA3 <70.38 cells/mm2 had a high risk of death (P=0.03) and a median survival time of 34 months.

Conclusions: We shed light on the role of the PHLDA family as promising predictive biomarkers and potential therapeutic targets in LUAD and MM.

2021 Journal of Thoracic Disease. All rights reserved.

In plain English

This study examined three genes called PHLDA1, PHLDA2 and PHLDA3 in lung adenocarcinoma and malignant pleural mesothelioma. It did not assess asbestos exposure. First, the authors searched public gene databases. In those data, high PHLDA1 or PHLDA2 mRNA expression in 87 mesothelioma samples went with worse overall survival (hazard ratios 1.80, 95% CI 1.1 to 2.9, and 1.87, 95% CI 1.2 to 3.0). PHLDA3 showed no clear link (P=0.27). In non-small cell lung cancer, low PHLDA1 and high PHLDA3 mRNA expression went with worse survival, and high PHLDA2 with better survival. Second, they stained archived tumors from 41 lung adenocarcinoma and 61 mesothelioma patients treated in São Paulo, Brazil, between 1995 and 2018. PHLDA2 and PHLDA3 protein levels were higher in the lung adenocarcinomas than in the mesotheliomas. Across both tumor types together, PHLDA2 above 85.09 positive cells per square millimetre went with a lower risk of death (median survival 48 months). PHLDA3 below 70.38 positive cells per square millimetre went with a higher risk of death (median survival 34 months). The authors concluded these genes might be promising biomarkers and treatment targets. They noted their tissue sample was not large enough.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Biomarker study combining analysis of public gene-expression databases (in silico data mining) with immunohistochemistry on tissue microarrays from a retrospective clinical cohort
• Who was studied: Database samples: lung adenocarcinoma and normal tissue (TCGA), malignant mesothelioma and normal tissue (GEO dataset GSE51024), non-small cell lung cancer survival data (Kaplan-Meier plotter), and 87 mesothelioma samples (TCGA Firehose Legacy). Clinical cohort: archived tumors from 41 lung adenocarcinoma and 61 malignant mesothelioma patients (epithelioid and sarcomatoid types), treated at three São Paulo institutions between 1995 and 2018, none of whom had received neoadjuvant therapy
• Exposure: The article does not report asbestos or any occupational exposure. Smoking history was collected as a patient characteristic. The study measured expression of the PHLDA1, PHLDA2 and PHLDA3 genes and proteins (and P53 protein) in tumor tissue. It also searched a database for drugs and chemicals reported to change PHLDA expression.
• Main results:
  • In the mesothelioma GEO data, PHLDA1 mRNA was lower in tumor than in normal tissue (P=0.01). PHLDA2 showed no statistically significant difference (P=0.13). PHLDA3 was significantly increased compared with normal samples (P less than 0.01).
  • In non-small cell lung cancer patients (Kaplan-Meier plotter), low PHLDA1 mRNA expression was correlated with worse overall survival (HR=0.77; 95% CI 0.63 to 0.94; P less than 0.01).
  • In non-small cell lung cancer patients, high PHLDA2 mRNA expression was associated with better overall survival (HR 0.84; 95% CI 0.74 to 0.96; P less than 0.01).
  • In non-small cell lung cancer patients, high PHLDA3 mRNA expression went with poor overall survival (HR 1.25; 95% CI 1.1 to 1.42; P less than 0.01).
  • In mesothelioma patients from TCGA (n=87 samples), high PHLDA1 mRNA expression went with poor overall survival (HR 1.80; 95% CI 1.1 to 2.9; P=0.01). High PHLDA2 mRNA expression did as well (HR 1.87; 95% CI 1.2 to 3.0; P less than 0.01).
  • In the same mesothelioma patients, PHLDA3 mRNA expression showed no correlation with survival (HR 1.29; 95% CI 0.8 to 2.1; P=0.27).
  • In mesothelioma patients, after adjustment for age, sex, lymph node metastases, stage and TP53, PHLDA1 mRNA expression remained an independent predictor of worse overall survival (HR 1.64; 95% CI 1.0 to 2.6; P=0.04). PHLDA2 mRNA expression also remained one (HR 1.71; 95% CI 1.1 to 2.7; P=0.03).
  • In the clinical tissue cohort, PHLDA2 and PHLDA3 protein levels were higher in lung adenocarcinoma than in mesothelioma. For PHLDA2 the medians were 88.16 vs 79.51 cells per square millimetre (P=0.01). For PHLDA3 they were 84.90 vs 67.80 (P less than 0.01). PHLDA1 did not differ significantly (P=0.37).
  • In multivariate Cox analysis of the combined lung adenocarcinoma and mesothelioma cohort, patients with PHLDA2 above 85.09 cells per square millimetre had a low risk of death (HR 0.98; 95% CI 0.96 to 0.99; P=0.01) and a median survival time of 48 months.
  • In the same analysis, patients with PHLDA3 below 70.38 cells per square millimetre had a high risk of death (HR 1.02; 95% CI 1.00 to 1.05; P=0.03) and a median survival time of 34 months.
  • A database search of drug and chemical interactions indicated that chemotherapy agents including cisplatin could potentially decrease PHLDA1 levels. Carcinogenic substances such as tetrachlorodibenzodioxin were able to increase expression of all PHLDA family members.
• The authors' conclusion: The authors concluded that PHLDA family members might be adopted as promising predictive biomarkers and potential therapeutic targets in lung adenocarcinoma and malignant mesothelioma.
• Limitations the authors state:
  • The research was an analysis based on previous data, so additional experimental studies are needed to confirm the results.
  • The clinical tissue microarray sample was not large enough and may have produced false negatives.
  • Because this was a retrospective cohort, no patient received a targeted therapy that could test PHLDA's role in treatment outcome.

Topics

Medical terms in this study, explained in our Lexicon: Lung Cancer, Mesothelioma, EGFR, Apoptosis, Non-Small Cell Lung Cancer, Pleural Mesothelioma, Lung Adenocarcinoma, Overall Survival.

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