Identification of novel candidate oncogenes and tumor suppressors in malignant pleural mesothelioma using large-scale transcriptional profiling

Our plain-English summary of Identification of novel candidate oncogenes and tumor suppressors in malignant pleural mesothelioma using large-scale transcriptional profiling, by G.J. Gordon, G.N. Rockwell, R.V. Jensen, et al (The American Journal of Pathology, 2005).

The study

• Authors: G.J. Gordon, G.N. Rockwell, R.V. Jensen, J.G. Rheinwald, J.N. Glickman, J.P. Aronson, B.J. Pottorf, M.D. Nitz, W.G. Richards, D.J. Sugarbaker, R. Bueno
• Journal: The American Journal of Pathology
• Published: 2005;166(6):1827-40
• Cited by: 160 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a highly lethal, poorly understood neoplasm that is typically associated with asbestos exposure. We performed transcriptional profiling using high-density oligonucleotide microarrays containing approximately 22,000 genes to elucidate potential molecular and pathobiological pathways in MPM using discarded human MPM tumor specimens (n = 40), normal lung specimens (n = 4), normal pleura specimens (n = 5), and MPM and SV40-immortalized mesothelial cell lines (n = 5). In global expression analysis using unsupervised clustering techniques, we found two potential subclasses of mesothelioma that correlated loosely with tumor histology. We also identified sets of genes with expression levels that distinguish between multiple tumor subclasses, normal and tumor tissues, and tumors with different morphologies. Microarray gene expression data were confirmed using quantitative reverse transcriptase-polymerase chain reaction and protein analysis for three novel candidate oncogenes (NME2, CRI1, and PDGFC) and one candidate tumor suppressor (GSN). Finally, we used bioinformatics tools (ie, software) to create and explore complex physiological pathways. Combined, all of these data may advance our understanding of mesothelioma tumorigenesis, pathobiology, or both.

In plain English

This laboratory study measured activity of about 22,000 genes in 40 malignant pleural mesothelioma tumors removed at surgery in Boston from 1998 to 2000, plus 9 normal lung and pleura samples and 5 cell lines. Asbestos exposure was not reported. Gene-activity sorting produced two tumor subgroups: C1 (17 tumors, 88% epithelial) and C2 (14 tumors, 78% mixed). Survival did not differ significantly between them, possibly, the authors said, because few specimens were examined. The authors found 328 genes more active in tumors and 311 more active in normal tissue, naming NME2, CRI1 and PDGFC as candidate oncogenes and gelsolin (GSN) as a candidate tumor suppressor. On a tissue array, NME2 protein appeared in 35 of 45 epithelial and 14 of 19 mixed tumors and none of 4 normal pleura samples, though a Western blot found similar levels in pooled normal pleura and cell lines. A previously described test for telling mesothelioma from lung adenocarcinoma, checked only on these 40 tumors, correctly classified 39 (97.5%). The authors concluded that mesothelioma may have at least two gene-expression subclasses loosely matching histology.

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 of surgical tumor specimens, normal tissues and cell lines, with follow-up checks by RT-PCR, Western blot and immunohistochemistry
• Who was studied: 40 malignant pleural mesothelioma surgical specimens, 5 normal pleura specimens and 4 normal lung specimens from patients operated on at Brigham and Women's Hospital, Boston, October 1998 to August 2000, plus 5 cell lines (4 mesothelioma-derived, 1 nontumorigenic mesothelial line). A tissue array of 66 mesothelioma tumors, 2 lung adenocarcinomas and 4 normal pleura tissues was used for protein staining.
• Exposure: Not studied: the article reports no information on the patients' asbestos or other exposures. It compared gene activity in tumors with gene activity in normal tissues.
• Main results:
  • Cluster analysis found two tumor subclasses, C1 (17 tumors) and C2 (14 tumors)
  • C1 tumors were almost entirely epithelial (88%) and C2 tumors almost entirely mixed (78%) histological subtype
  • No statistically significant survival differences were found between C1 and C2
  • Nine tumors fell outside C1 and C2; the authors concluded these did not form a distinct third subclass
  • 328 genes were significantly more active in mesothelioma tumors and 311 significantly more active in normal samples, with an estimated false-discovery rate of 10%
  • Gelsolin (GSN) was significantly less active in mesothelioma tumor tissue
  • NME2, CRI1 and PDGFC were identified as candidate oncogenes and GSN as a candidate tumor suppressor
  • Among the 10 tumors with the highest and the 10 with the lowest NME2 levels on microarray, 8 and 7 respectively were similarly ranked by quantitative RT-PCR
  • A previously described six-gene test for distinguishing mesothelioma from lung adenocarcinoma, applied to the 40 mesothelioma tumors of this study, correctly classified 39 of 40 (97.5%), misdiagnosing one tumor
  • CRI1 protein was detected by Western blot in four of the five mesothelioma cell lines examined but not in normal pleural tissue
  • By Western blot, NME2 protein levels were roughly similar in the Met-5A line, mesothelioma cell lines and pooled normal pleura
  • GSN protein was detected by Western blot only in normal pleural tissue and in none of the cell lines examined
  • On the tissue array, NME2 protein was detected in 78% (35 of 45) of epithelial and 74% (14 of 19) of mixed mesothelioma tumors
  • On the tissue array (immunohistochemistry), no NME2 protein was detected in any of the 4 normal pleura tissues
  • There was no statistically significant correlation between histological subtype and NME2 protein expression on the tissue array
• The authors' conclusion: The authors concluded that they had identified at least two possible subclasses of malignant pleural mesothelioma with different gene expression patterns that correlate loosely with tumor histology, and had identified and validated tumor-related genes that may contribute to mesothelioma development.
• Limitations the authors state:
  • The absence of a survival difference between subclasses may reflect the relatively small number of specimens examined
  • Because the tumors were anonymized, gene-activity (mRNA) data could not be compared with protein data patient by patient

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, Neoplasm, Asbestos Exposure, Pleura, SV40, Mesothelial Cells, Mesothelioma, Histology.

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