Malignant pleural mesothelioma: genome-wide expression patterns reflecting general resistance mechanisms and a proposal of novel targets

Our plain-English summary of Malignant pleural mesothelioma: genome-wide expression patterns reflecting general resistance mechanisms and a proposal of novel targets, by O.D. Røe, E. Anderssen, H. Sandeck, et al (Lung Cancer, 2010).

The study

• Authors: O.D. Røe, E. Anderssen, H. Sandeck, T. Christensen, E. Larsson, S. Lundgren
• Journal: Lung Cancer
• Published: 2010;67(1):57-68
• Cited by: 53 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma is an asbestos-related multi-resistant tumour with increasing incidence worldwide. Well-characterized snap-frozen normal parietal, visceral pleura and mesothelioma samples were analysed with Affymetrix Human Genome U133 Plus 2.0 GeneChip oligoarray of 38500 genes. We discovered a close relation between gene profile and resistance towards topoisomerase poisons, alkylating agents, antitubulines, antifolates, platinum compounds and radiation therapy. Target genes of chemo- (e.g. TOP2A, BIRC5/Survivin and proteasome) and radiotherapy (e.g. BRCA2, FANCA, FANCD2, CCNB1 and RAD50) were significantly overexpressed. The Fanconi anemia/BRCA2 pathway, responsible for homologous recombination DNA repair appears as a key pathway in both chemo- and radio-resistance of mesothelioma. Leukocyte trans-endothelial migration gene down-regulation could partly explain resistance against immunological therapies. Gene expression features found in other resistant cancer types related to DNA repair and replication are shared by mesothelioma and could represent general features of tumour resistance. Targeted suppression of some of those key genes and pathways combined with chemotherapy or radiation could improve the outcome of mesothelioma therapy. We propose CHEK1, RAD21, FANCD2 and RAN as new co-targets for mesothelioma treatment. The pro-angiogenic AGGF1 mRNA and protein was highly overexpressed in all tumours and may serve as a target for anti-angiogenic treatment. Overexpression of NQO1 may render mesothelioma sensitive to the novel compound beta-Lapachone.

In plain English

This laboratory study, by authors based in Trondheim, Norway, compared gene activity in tumour samples from patients diagnosed with malignant pleural mesothelioma between 2003 and 2005 with normal pleura from people undergoing video-assisted thoracoscopy for recurrent pneumothorax (collapsed lung). The article does not state how many patients or samples were included. It did not study asbestos exposure. Using a chip covering 38,500 genes, the authors found that mesothelioma had a gene profile distinct from normal pleura. Compared with normal parietal pleura, many genes involved in DNA repair, DNA copying, cell division and the proteasome were more active in tumour. These included genes other research has linked to chemotherapy and radiation resistance, such as TOP2A, TYMS, BRCA2, FANCA, FANCD2, CHEK1 and RAD21. In the white-blood-cell migration pathway, 8 of the 11 genes that differed significantly were less active. Protein staining supported some findings: Chk1 appeared in over 15% of epithelial tumour nuclei in all but one sample, and not in control samples. The authors proposed CHEK1, RAD21, BRCA2, AGGF1, NQO1 and RAN as possible additional drug targets. They said their material was too small to link gene activity to survival.

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: Laboratory gene-expression (microarray) study comparing mesothelioma tissue with normal pleura, with protein checks by immunohistochemistry
• Who was studied: Patients with malignant pleural mesothelioma diagnosed 2003 to 2005, and control persons who had video-assisted thoracoscopy for recurrent pneumothorax. Authors are based in Trondheim, Norway. The number of patients and samples is not stated in the text.
• Exposure: Not studied. The article compared gene activity in mesothelioma tissue with normal parietal and visceral pleura. Asbestos is mentioned only as background.
• Main results:
  • Mesothelioma, parietal pleura and visceral pleura samples had distinct gene expression profiles.
  • In mesothelioma versus parietal pleura, 31 of 237 DNA repair genes on the chip were overexpressed (corrected P-value 3.38E-08).
  • Genes linked to radiation resistance, including RAD21 and RAD50, and several proteasome genes were overexpressed in tumour.
  • In the leukocyte trans-endothelial migration pathway, 8 of the 11 differentially expressed genes were down-regulated, mainly those that help leukocytes migrate.
  • Chk1 protein stained more than 15% of epithelial mesothelioma nuclei, except in the only long-term survivor (under 1%). No nuclear staining was seen in control samples.
  • Thymidylate synthase protein was found in most tumour cells. Parietal pleura samples were completely negative.
  • VG5Q (AGGF1) protein stained more than 75% of tumour cells. Strong staining was also seen in normal mesothelial and endothelial cells.
  • Patient 8, a long-term survivor, had the gene profile most similar to normal parietal pleura.
• The authors' conclusion: The authors concluded that mesothelioma's resistance to therapy is reflected in its gene profile. They proposed CHEK1, RAD21, BRCA2, AGGF1, NQO1 and RAN as novel putative drug co-targets.
• Limitations the authors state:
  • The authors stated that their material was too small to draw conclusions about survival and gene expression.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Visceral Pleura, Mesothelioma, Antifolate, Chemotherapy.

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