Cyclin-Dependent Kinase and Antioxidant Gene Expression in Cancers with Poor Therapeutic Response

Our plain-English summary of Cyclin-Dependent Kinase and Antioxidant Gene Expression in Cancers with Poor Therapeutic Response, by G.S. Scaria, B.T. Kren, M.A. Klein (Pharmaceuticals, 2020).

The study

• Authors: G.S. Scaria, B.T. Kren, M.A. Klein
• Journal: Pharmaceuticals
• Published: 2020;13(2)
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Pancreatic cancer, hepatocellular carcinoma (HCC), and mesothelioma are treatment-refractory cancers, and patients afflicted with these cancers generally have a very poor prognosis. The genomics of these tumors were analyzed as part of The Cancer Genome Atlas (TCGA) project. However, these analyses are an overview and may miss pathway interactions that could be exploited for therapeutic targeting. In this study, the TCGA Pan-Cancer datasets were queried via cBioPortal for correlations among mRNA expression of key genes in the cell cycle and mitochondrial (mt) antioxidant defense pathways. Here we describe these correlations. The results support further evaluation to develop combination treatment strategies that target these two critical pathways in pancreatic cancer, hepatocellular carcinoma, and mesothelioma.

In plain English

This was a computer analysis of existing genetic data, not a study of asbestos exposure. The authors used the online tool cBioPortal to search The Cancer Genome Atlas (TCGA) Pan-Cancer datasets for mesothelioma, pancreatic cancer and hepatocellular carcinoma (a liver cancer). They examined a set of 40 genes involved in the cell cycle and in antioxidant defense inside mitochondria. The article does not say how many patients' tumors were included. In mesothelioma, the mRNA expression levels of several gene pairs had correlation coefficients above 0.3 in absolute value; for example, CDK2 and TXN2 mRNA expression levels were negatively correlated. Overall survival was significantly higher for mesothelioma and liver cancer patients whose tumors had gene-set z-scores below 2, but not for pancreatic cancer patients. Progression-free survival showed no association for any of the three cancers. In mesothelioma, the top copy number changes included CDKN2A, CDKN2B and MTAP, and the most often mutated genes were BAP1, NF2 and SETD2. The authors concluded that further laboratory studies of drugs that target both pathways may lead to new treatment strategies.

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: Bioinformatic analysis of publicly available tumor genomic data (The Cancer Genome Atlas, accessed through the cBioPortal web tool), with no new patients or laboratory experiments
• Who was studied: TCGA Pan-Cancer tumor datasets for mesothelioma, pancreatic cancer and hepatocellular carcinoma. The article text does not state the number of tumors or patients, the locations or the time periods.
• Exposure: No asbestos or other environmental exposure was studied. The analysis used a 40-gene set of cell cycle-related and mitochondrial antioxidant defense genes (for example CDK2, CDK4, CDK5, FOXM1, TXN2, TXNRD2, SOD2, HIF1A, NFKB1), which the authors compiled from the literature.
• Main results:
  • In heatmaps of the gene set (z-score threshold 2.0, unsupervised hierarchical clustering), the cell cycle-related genes formed a distinct cluster in all three cancers.
  • In mesothelioma, gene pairs whose mRNA expression levels had Spearman and/or Pearson coefficients of absolute value greater than 0.3 included CDK2-TXN2 (negative), CDK2-FOXM1 (positive), CDK4-FOXM1 (positive) and CDK5-TXN2 (positive), among others.
  • Overall survival was significantly higher for patients whose tumors had gene-set z-scores below 2 in hepatocellular carcinoma and mesothelioma, but not in pancreatic cancer. The text gives no figures or p-values.
  • Altered mRNA expression of the gene set was not associated with progression-free survival in any of the three cancers.
  • The top copy number variants were the same in mesothelioma and pancreatic cancer (the article lists CDKN2A, CDKN2B, MTAP, DMRTA1 and LINC01239), with no overlap with hepatocellular carcinoma.
  • In mesothelioma, the most commonly mutated genes were BAP1, NF2 and SETD2, and TP53 was the 4th most common mutation.
• The authors' conclusion: The authors concluded that the possible relationships between the two pathways suggest that further laboratory studies combining inhibitors of each pathway may lead to new treatment strategies for at least some of these tumors. They noted that palbociclib and auranofin are already FDA-approved for other diseases.

Topics

Medical terms in this study, explained in our Lexicon: Carcinoma, Mesothelioma, Prognosis.

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