Integrated high-resolution array CGH and SKY analysis of homozygous deletions and other genomic alterations present in malignant mesothelioma cell lines

Our plain-English summary of Integrated high-resolution array CGH and SKY analysis of homozygous deletions and other genomic alterations present in malignant mesothelioma cell lines, by G. Klorin, E. Rozenblum, O. Glebov, et al (Cancer Genetics, 2013).

The study

• Authors: G. Klorin, E. Rozenblum, O. Glebov, R.L. Walker, Y. Park, P.S. Meltzer, I.R. Kirsch, F.J. Kaye, A.V. Roschke
• Journal: Cancer Genetics
• Published: 2013;206(5):191-205
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

High-resolution oligonucleotide array comparative genomic hybridization (aCGH) and spectral karyotyping (SKY) were applied to a panel of malignant mesothelioma (MMt) cell lines. SKY has not been applied to MMt before, and complete karyotypes are reported based on the integration of SKY and aCGH results. A whole genome search for homozygous deletions (HDs) produced the largest set of recurrent and non-recurrent HDs for MMt (52 recurrent HDs in 10 genomic regions; 36 non-recurrent HDs). For the first time, LINGO2, RBFOX1/A2BP1, RPL29, DUSP7, and CCSER1/FAM190A were found to be homozygously deleted in MMt, and some of these genes could be new tumor suppressor genes for MMt. Integration of SKY and aCGH data allowed reconstruction of chromosomal rearrangements that led to the formation of HDs. Our data imply that only with acquisition of structural and/or numerical karyotypic instability can MMt cells attain a complete loss of tumor suppressor genes located in 9p21.3, which is the most frequently homozygously deleted region. Tetraploidization is a late event in the karyotypic progression of MMt cells, after HDs in the 9p21.3 region have already been acquired.

Published by Elsevier Inc.

In plain English

This laboratory study analyzed DNA from malignant mesothelioma cell lines (cancer cells grown in the lab). It did not study patients or any exposure, including asbestos. The authors tested 18 cell lines with array comparative genomic hybridization (aCGH), which detects DNA gains and losses; one was excluded for poor quality. Spectral karyotyping (SKY), which maps chromosomes, gave complete karyotypes for 10 lines. All 10 had abnormal chromosome numbers and partial or complete loss of chromosome 22, present in under half the cells in four lines. Across the 17 lines the authors found 88 homozygous deletions (DNA missing from all copies of a region): 52 recurring in 10 regions, 36 in single lines. A chromosome 9 region (9p21.3) containing CDKN2A was homozygously deleted in all 17. The authors reported, for the first time, recurrent homozygous deletion of LINGO2, RBFOX1/A2BP1, RPL29, DUSP7 and CCSER1/FAM190A in this cell-line panel, suggesting some could be new candidate tumor suppressor genes. They suggested that complete 9p21.3 loss may require chromosomal instability, and that doubling of chromosome sets (tetraploidization) comes late, after the 9p21.3 deletions.

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 genetic study of cancer cell lines using array comparative genomic hybridization (aCGH) and spectral karyotyping (SKY)
• Who was studied: 18 malignant mesothelioma cell lines: 7 epithelioid, 4 sarcomatoid, 1 biphasic, and 6 of unknown type. aCGH was run on all 18, but one line (H2804) was excluded for hybridization quality, leaving 17. Complete SKY karyotypes were obtained for 10 lines, and chromosome 9 was examined by SKY in 3 more. The article does not say where the patients who supplied the cell lines came from or what their exposures were.
• Exposure: No exposure was studied. Asbestos is mentioned only as background in the introduction; the study looked at genetic changes in the cell lines.
• Main results:
  • All 10 cell lines karyotyped by SKY had abnormal (aneuploid) karyotypes.
  • Partial or complete loss of chromosome 22 was found in all 10 cell lines studied by SKY (100%). In four lines (H2795, H2810, H2731 and H28) the loss was present in fewer than 50% of cells.
  • No recurrent translocations were found, apart from i(5)(p10) in two cell lines, H513 and H2461.
  • 88 homozygous deletions were found in the 17 cell lines: 52 recurrent deletions in 10 genomic regions and 36 non-recurrent deletions.
  • In the 9p21.3 region, the DNA for p14ARF (part of the CDKN2A gene) was missing in all 17 cell lines. The DNA for p16INK4A was missing in 16 lines by aCGH.
  • In the remaining line, H2869, a PCR test showed that CDKN2A exon 2a was also homozygously deleted.
  • Regions targeting LINGO2 (9p21.2) and RBFOX1/A2BP1 (16p13.3) were each homozygously deleted in 41% of the 17 cell lines.
  • The authors reported for the first time that LINGO2, RBFOX1/A2BP1, RPL29, DUSP7 and CCSER1/FAM190A were recurrently homozygously deleted in this mesothelioma cell-line panel. They suggested some could be new candidate tumor suppressor genes.
  • Combining SKY and aCGH showed that the 9p21.3 deletions arose in at least two different ways.
  • The authors' data suggested that tetraploidization is a late event, occurring after the 9p21.3 homozygous deletions had been acquired.
• The authors' conclusion: The authors suggested that mesothelioma cells could reach complete loss of the 9p21.3 region only after acquiring structural or numerical chromosomal instability. They also suggested that tetraploidization is a late event, occurring after the 9p21.3 deletions.
• Limitations the authors state:
  • In cell line H2869, the spacing of the array probes meant the limits of the minimal deleted region could not be defined more precisely by aCGH.
  • Some recurrent deletions (GSTT1, ADAM5P and ADAM3A, and the 3q26 region) lay entirely within known normal copy number variation regions. The authors said these may not be related to mesothelioma development.

Topics

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

Medical terms in this study, explained in our Lexicon: Homozygous Deletion, Malignant Mesothelioma, Tumor Suppressor Gene.

Related studies

• Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma — Q. Hu, S. Akatsuka, et al. (2010)
• Low homozygous/high heterozygous deletion status by p16 FISH correlates with a better prognostic group than high homozygous deletion status in malignant pleural mesothelioma — M. Hamasaki, S. Matsumoto, et al. (2016)
• Morphological difference between pleural mesothelioma cells in effusion smears with either BAP1 loss or 9p21 homozygous deletion and reactive mesothelial cells without the gene alterations — S. Matsumoto, M. Hamasaki, et al. (2019)
• Homozygous deletion of p16INK4a and tobacco carcinogen exposure in nonsmall cell lung cancer — K.S. Kraunz, H.H. Nelson, et al. (2006)
• Genomic copy number alterations in 33 malignant peritoneal mesothelioma analyzed by comparative genomic hybridization array — P. Chirac, D. Maillet, et al. (2016)
• Fluorescence in situ hybridization (FISH) provides estimates of minute and interstitial BAP1, CDKN2A, and NF2 gene deletions in peritoneal mesothelioma — S. Brich, F. Bozzi, et al. (2020)

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