RNA sequencing identifies fusion of the EWSR1 and YY1 genes in mesothelioma with t(14;22)(q32;q12)

Our plain-English summary of RNA sequencing identifies fusion of the EWSR1 and YY1 genes in mesothelioma with t(14;22)(q32;q12), by I. Panagopoulos, J. Thorsen, L. Gorunova, et al (Genes, Chromosomes & Cancer, 2013).

The study

• Authors: I. Panagopoulos, J. Thorsen, L. Gorunova, F. Micci, L. Haugom, B. Davidson, S. Heim
• Journal: Genes, Chromosomes & Cancer
• Published: 2013;52(8):733-40
• Cited by: 64 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Mesothelioma is a rare but very aggressive tumor derived from mesothelial cells. A number of often complex but nonrandom cytogenetic abnormalities have been found in these tumors, resulting in loss of chromosome bands 14q32 and 22q12 in more than 35% of the cases. In this study, we used RNA sequencing to search for fusion transcripts in a mesothelioma carrying a t(14;22)(q32;q12) as the sole chromosomal aberration and found an EWSR1-YY1 and its reciprocal YY1-EWSR1 fusion transcript. Screening 15 additional cases of mesothelioma from which we had RNA but no cytogenetic information, we identified one more tumor carrying an EWSR1-YY1 fusion gene but not the reciprocal YY1-EWSR1 transcript. RT-polymerase chain reaction and sequencing showed that in both cases exon 8 of EWSR1 (nucleotide 1,139, accession number NM_013986 version 3, former exon 7 in sequence with accession number X66899) was fused to exon 2 of YY1 (nucleotide 1,160, accession number NM_003403 version 3). The EWSR1 breakpoint in exon 8 in the EWSR1-YY1 chimeric transcript is similar to what is found in other fusions involving EWSR1 such as EWSR1-FLI1, EWSR1-DDIT3, and EWSR1-ATF1. The EWSR1-YY1-encoded protein is an abnormal transcription factor with the transactivation domain of EWSR1 and the DNA-binding domain of YY1. This is the first study to detect a specific fusion gene in mesothelioma (the reason how frequent the EWSR1-YY1 fusion is remains uncertain) and also the first time that direct involvement of YY1 in oncogenesis has been demonstrated.

Copyright © 2013 Wiley Periodicals, Inc.

In plain English

This Norwegian laboratory study looked for abnormally joined ("fusion") genes in mesothelioma. It did not test for a link with asbestos; a table recorded no asbestos exposure for 8 of 14 fusion-negative patients and unknown exposure for 6. The first tumor came from a 61-year-old man with epithelioid mesothelioma of the omentum, an abdominal tissue. His tumor cells had one chromosome change, an exchange between chromosomes 14 and 22. RNA sequencing and other tests showed this had joined the EWSR1 and YY1 genes in both directions. Of 15 more mesotheliomas tested, one carried the same EWSR1–YY1 fusion but not the reverse version. It came from a 68-year-old man with epithelioid mesothelioma found in abdominal fluid and a hernia sac. In total, 2 of 16 tumors carried the fusion. Asbestos exposure was not reported for the two positive cases. The authors concluded that a subgroup of mesotheliomas carries the EWSR1–YY1 fusion gene. They proposed that its protein product may act as an abnormal transcription factor (a protein that switches genes on or off). They cautioned that these numbers might not accurately reflect how common the fusion is.

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 tumor samples. The index case had chromosome analysis, RNA sequencing, RT-PCR with sequencing, and FISH. PCR was then used to screen 15 further mesotheliomas.
• Who was studied: 16 mesotheliomas studied at the Norwegian Radium Hospital, Oslo University Hospital, Norway. Case 1 (the index case) was a 61-year-old man with epithelioid mesothelioma of the omentum, biopsied January to February 2012 and operated on in May 2012. Case 2 was a 68-year-old man with epithelioid mesothelioma found with massive ascites and in a hernial sac, operated on in January 2011. The other 14 were effusion samples, all epithelioid; per Table 1, 4 were from ascites and 10 from pleura. None of these 14 had cytogenetic data.
• Exposure: Not an exposure study: the study examined gene fusions, not fibers or jobs. Asbestos exposure is not reported for the two fusion-positive cases. Table 1 lists asbestos as "No" for 8 of the 14 fusion-negative cases (M1 to M8) and "Unknown" for 6 (M9 to M14). No fiber types are named.
• Main results:
  • In Case 1, 10 tumor cells showed a single chromosomal abnormality, a 14;22 translocation, and 5 cells were normal.
  • In Case 1, RNA sequencing found 385 potential fusion genes. YY1–EWSR1 ranked first (76 seed counts) and EWSR1–YY1 ranked 15th (11 seed counts). No other fusions were examined.
  • In Case 1, RT-PCR and sequencing confirmed an EWSR1–YY1 fusion, with exon 8 of EWSR1 joined to exon 2 of YY1.
  • In Case 1, RT-PCR and sequencing also confirmed the reciprocal YY1–EWSR1 fusion, with exon 1 of YY1 joined to exon 12 of EWSR1.
  • In Case 1, FISH showed fusion signals on both rearranged chromosomes, in agreement with the chromosome analysis, PCR and sequencing.
  • Of the 15 additional mesotheliomas, only Case 2 carried the EWSR1–YY1 fusion, and it was identical to Case 1's. None of the 15 carried the reciprocal YY1–EWSR1 fusion. All 15 expressed the normal EWSR1 and YY1 genes.
  • Overall, the EWSR1–YY1 fusion was found in 2 of the 16 mesotheliomas.
• The authors' conclusion: The authors concluded that they had identified a subgroup of mesotheliomas carrying an EWSR1–YY1 fusion gene, and that the putative protein it encodes may act as an abnormal transcription factor. Because the chromosome regions involved are often rearranged in mesothelioma, they suggested that EWSR1 and/or YY1 rearrangements might be substantial in frequency. They also stated that the study showed YY1 is directly involved in tumor formation.
• Limitations the authors state:
  • The authors stated that the figure of 2 in 16 might not accurately reflect how often this fusion, or other EWSR1 and/or YY1 rearrangements, occur in mesothelioma.
  • Chromosome (cytogenetic) information was available only for the index case, not for Case 2 or the other 14 tumors.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Mesothelial Cells, Carcinogenesis.

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• EWSR1::YY1 fusion positive peritoneal epithelioid mesothelioma harbors mesothelioma epigenetic signature: Report of 3 cases in support of an emerging entity — J.K. Dermawan, D. Torrence, et al. (2022)
• Malignant Mesothelioma With EWSR1-ATF1 Fusion in Two Adolescent Male Patients — H. Ren, S.R. Rassekh, et al. (2021)
• Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations — R. Bueno, E.W. Stawiski, et al. (2016)
• A Subset of Malignant Mesotheliomas in Young Adults Are Associated With Recurrent EWSR1/FUS-ATF1 Fusions — P. Desmeules, P. Joubert, et al. (2017)
• Generation of human embryonic stem cell models to exploit the EWSR1-CREB fusion promiscuity as a common pathway of transformation in human tumors — F. Vanoli, B. Meskauskaite, et al. (2021)

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