Large-scale copy number analysis reveals variations in genes not previously associated with malignant pleural mesothelioma

Our plain-English summary of Large-scale copy number analysis reveals variations in genes not previously associated with malignant pleural mesothelioma, by M. Hylebos, G. Van Camp, G. Vandeweyer, et al (Oncotarget, 2017).

The study

• Authors: M. Hylebos, G. Van Camp, G. Vandeweyer, E. Fransen, M. Beyens, R. Cornelissen, A. Suls, P. Pauwels, J.P. van Meerbeeck, K. Op de Beeck
• Journal: Oncotarget
• Published: 2017;8(69):113673-113686
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive tumor that is often causally associated with asbestos exposure. Comparative genomic hybridization techniques and arrays demonstrated a complex set of copy number variations (CNVs) in the MPM-genome. These techniques however have a limited resolution, throughput and flexibility compared to next-generation sequencing platforms. In this study, the presence of CNVs in the MPM-genome was investigated using an MPM-cohort (N = 85) for which genomic microarray data are available through 'The Cancer Genome Atlas' (TCGA). To validate these results, the genomes of MPMs and matched normal samples (N = 21) were analyzed using low-pass whole genome sequencing on an 'Illumina HiSeq' platform. CNVs were detected using in-house developed analysis pipelines and frequencies of copy number loss and gain were calculated. In both datasets, losses on chromosomes 1, 3, 4, 6, 9, 13 and 22 and gains on chromosomes 1, 5, 7 and 17 were found in at least 25% and 15% of MPMs, respectively. Besides the well-known MPM-associated genes, CDKN2A, NF2 and BAP1, other interesting cancer-associated genes were listed as frequently involved in a copy number loss (e.g. EP300, SETD2 and PBRM1). Moreover, four cancer-associated genes showed a high frequency of copy number gain in both datasets (i.e. TERT, FCGR2B, CD79B and PRKAR1A). A statistically significant association between overall survival and the presence of copy number loss in the CDKN2A-containing region was observed in the TCGA-set. In conclusion, recurrent CNVs were detected in both datasets, occurring in regions harboring known MPM-associated genes and genes not previously linked to MPM.

In plain English

This study looked for copy number variations (stretches of chromosomes lost or gained) in tumor DNA from malignant pleural mesothelioma. The authors analyzed array data on 85 tumors from The Cancer Genome Atlas (TCGA). They then checked the results by low-pass whole genome sequencing of 21 tumors with matched normal samples from tissue banks in Antwerp and Rotterdam. In both sets, losses on chromosomes 1, 3, 4, 6, 9, 13 and 22 occurred in at least 25% of tumors, and gains on chromosomes 1, 5, 7 and 17 in more than 15%. Besides the known mesothelioma genes CDKN2A, NF2 and BAP1, other cancer-related genes were often lost. EP300 was lost in 69% of TCGA tumors and 71% of sequenced tumors. In the TCGA group, median survival was 982 days for patients whose tumors lacked CDKN2A loss, versus 456 days with loss. Also in the TCGA group, no statistically significant association was found between the gene changes examined and asbestos exposure history. The authors concluded that these changes lie in regions holding genes potentially useful for diagnosis, treatment and prognosis.

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: Genomic study of tumor tissue: analysis of existing array data from The Cancer Genome Atlas, checked against low-pass whole genome sequencing of an independent set of tumor and matched normal samples
• Who was studied: 85 malignant pleural mesothelioma patients in the TCGA dataset (87 available, 2 excluded because they had received neo-adjuvant treatment), plus 21 malignant pleural mesothelioma tumors with matched normal samples from the tumor bank of Antwerp University Hospital (Belgium) and the tissue bank of Erasmus University Medical Center Rotterdam (the Netherlands). Collection dates are not given.
• Exposure: Not an exposure study. History of asbestos exposure was recorded only as yes, no or unknown: in the TCGA set, 54 (64%) yes, 14 (16%) no and 17 (20%) unknown; in the sequencing set, 12 (57%) yes, 0 no and 9 (43%) unknown. No fiber types or doses are given.
• Main results:
  • In both datasets, losses on chromosomes 1, 3, 4, 6, 9, 13 and 22 were found in at least 25% of tumors.
  • In both datasets, gains on chromosomes 1, 5, 7 and 17 were found in more than 15% of tumors.
  • Loss frequencies for the known mesothelioma genes (TCGA tumors versus in-house sequenced tumors): CDKN2A 51% and 52%; NF2 62% and 48%; BAP1 44% and 43%.
  • EP300 had the highest frequency of copy number loss among the cancer census genes: 69% of TCGA tumors and 71% of sequenced tumors.
  • Six cancer census genes were among the most frequently lost in both datasets: EP300, SETD2, PBRM1, CHEK2, MKL1 and MAPK1.
  • Four cancer census genes were among the most frequently gained in both datasets: TERT, FCGR2B, CD79B and PRKAR1A. TERT was gained in up to 27% of TCGA tumors. PMS2 was gained in up to 33% of sequenced tumors.
  • In the TCGA set, copy number loss in the region containing CDKN2A was statistically significantly associated with survival of less than 36 months (p = 0.01).
  • In the TCGA set, median survival was 982 days for patients whose tumors lacked CDKN2A loss, versus 456 days for patients whose tumors had the loss (p = 4.54e-6).
  • In the TCGA set, no statistically significant associations were found between the copy number changes examined and gender, age at diagnosis, asbestos exposure or histological diagnosis.
  • In the sequencing set, no statistically significant associations were found between any of the clinical or pathological factors examined and the copy number changes.
• The authors' conclusion: The authors concluded that recurrent copy number losses and gains were found in the TCGA set and confirmed in their own samples. In their view, these changes lie in regions holding cancer-associated genes that are potentially useful for diagnosis, treatment and prognosis.
• Limitations the authors state:
  • Differences between the two datasets might be explained by the much smaller size of the sequencing set (21 versus 85 tumors).
  • The two datasets were analyzed with different techniques of different resolution (SNP array versus low-pass sequencing).
  • Not all listed genes will matter equally; some may appear only because they lie near more important genes.
  • Further functional studies are needed to clarify the role of each listed gene.
  • The mean-ratio approach cannot identify regions that are lost in some tumors and gained in others.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Asbestos Exposure, Flexibility, Next-Generation Sequencing (NGS), CDKN2A, BAP1, Overall Survival.

Related studies

• Comparison of DNA copy number changes in malignant mesothelioma, adenocarcinoma and large-cell anaplastic carcinoma of the lung — A.M. Björkqvist, L. Tammilehto, et al. (1998)
• Genome-wide analysis of abdominal and pleural malignant mesothelioma with DNA arrays reveals both common and distinct regions of copy number alteration — A.C. Borczuk, J. Pei, et al. (2016)
• Identification of specific gene copy number changes in asbestos-related lung cancer — P. Nymark, H. Wikman, et al. (2006)
• Gene expression and copy number profiling suggests the importance of allelic imbalance in 19p in asbestos-associated lung cancer — H. Wikman, S. Ruosaari, et al. (2007)
• Gene expression profiling and gene copy-number changes in malignant mesothelioma cell lines — C. Zanazzi, R. Hersmus, et al. (2007)
• Elevated PDGFRB gene copy number gain is prognostic for improved survival outcomes in resected malignant pleural mesothelioma — A.S. Tsao, N. Harun, et al. (2014)

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