A Subset of Malignant Mesotheliomas in Young Adults Are Associated With Recurrent EWSR1/FUS-ATF1 Fusions

Our plain-English summary of A Subset of Malignant Mesotheliomas in Young Adults Are Associated With Recurrent EWSR1/FUS-ATF1 Fusions, by P. Desmeules, P. Joubert, L. Zhang, et al (The American Journal of Surgical Pathology, 2017).

The study

• Authors: P. Desmeules, P. Joubert, L. Zhang, H.A. Al-Ahmadie, C.D. Fletcher, E. Vakiani, D.F. Delair, N. Rekhtman, M. Ladanyi, W.D. Travis, C.R. Antonescu
• Journal: The American Journal of Surgical Pathology
• Published: 2017;41(7):980-988
• Cited by: 93 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is a rare, aggressive tumor often associated with asbestos exposure and characterized by complex genetic abnormalities, including deletions of chromosome 22. A gene fusion involving EWSR1 and YY1 gene on 14q32 has been reported in 2 patients over the age of 60 with peritoneal MM. However, the incidence of EWSR1 rearrangements in MM and the spectrum of its fusion partners remain unknown. We recently encountered 2 MM cases with EWSR1-ATF1 fusions and sought to investigate the prevalence and clinicopathologic features associated with this abnormality. As both index cases occurred as intra-abdominal tumors in young adults, we searched our files for pleural and peritoneal MM occurring in adults younger than age of 40. All cases were tested by fluorescence in situ hybridization using custom bacterial artificial chromosomes probes for EWSR1, FUS, and ATF1 genes. When available, immunohistochemistry for BAP1 was performed. A total of 25 MM from patients aged 40 or less were screened, either from peritoneum (n=13) or pleura (n=12), with a median age of 31 (range: 7 to 40 y). Two additional ATF1-rearranged tumors were identified at pleural and peritoneal sites with EWSR1 and FUS as fusion partners, respectively, for a total of 4 cases (16%, 4/25). The fusion-positive cases displayed classic epithelioid morphology, immunoreactivity for cytokeratins and WT1, and negativity for S100. BAP1 expression was retained in the 3 fusion-positive cases with available material, and in 80% (12/15) of the fusion-negative cases. Our results expand the spectrum of tumor types harboring EWSR1/FUS-ATF1 gene fusions to include a subgroup of conventional epithelioid MM. Other features of this unique MM subset include young age at presentation, lack of asbestos exposure and retained BAP1 expression.

In plain English

This was a laboratory study of stored tumor samples from Memorial Sloan Kettering Cancer Center and the consultation files of two senior authors. After finding two abdominal (peritoneal) mesotheliomas in young adults with a gene fusion joining EWSR1 to ATF1, the authors searched their files from 1995 to 2016 for mesotheliomas in younger patients. They tested 25 tumors: 13 peritoneal and 12 pleural, median age 31, range 7 to 40. Four of the 25 (16%) carried an ATF1 fusion: three EWSR1-ATF1 and one FUS-ATF1. Three of these were peritoneal and one was pleural, and all four were epithelioid. BAP1 protein was retained in 15 of 18 tumors tested, including the three fusion-positive tumors that could be tested. Of 16 patients with exposure information, none had direct asbestos exposure, and three with fusion-negative tumors had possible indirect exposure. Exposure information was not available for one fusion-positive patient. The authors concluded that these fusions are rare in mesothelioma and appear restricted to younger patients without significant asbestos exposure or BAP1 loss. They noted that the small number of cases prevented firm conclusions about how these tumors behave, and that inherited BAP1 status was unknown.

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: Retrospective molecular pathology case series of archival tumor tissue (FISH gene-rearrangement testing, BAP1 immunohistochemistry, targeted sequencing in one case), prompted by 2 index cases
• Who was studied: 25 malignant mesotheliomas from patients aged 40 or less: the 2 index cases plus 23 additional cases (11 peritoneal, 12 pleural) identified from 1995 to 2016; 13 peritoneal and 12 pleural in total
• Exposure: The study examined gene fusions (EWSR1/FUS-ATF1), not asbestos dose. Asbestos history was recorded where available, and no fiber types were named. Among 16 patients with information, none had direct asbestos exposure, and 3 with fusion-negative tumors had possible secondary (indirect) exposure.
• Main results:
  • Among the 25 patients, the median age at diagnosis was 31 years (range 7 to 40), and the sex ratio differed by tumor site (P=0.047).
  • 77% of peritoneal tumors occurred in males, compared with 33% of thoracic (pleural) tumors.
  • 4 of 25 tumors (16%) carried an EWSR1 or FUS-ATF1 fusion.
  • Of the 4 fusion-positive tumors, 3 had EWSR1-ATF1 and 1 had FUS-ATF1.
  • All 4 fusion-positive tumors were conventional epithelioid mesotheliomas.
  • The one pleural fusion-positive tumor (EWSR1-ATF1) occurred in a 34-year-old woman.
  • The FUS-ATF1 tumor was peritoneal, in a 25-year-old woman.
  • Table 1 lists asbestos exposure as not available (NA) for the first fusion-positive case (a 21-year-old man with a peritoneal tumor). It lists 'None' for the other three fusion-positive cases.
  • BAP1 expression was retained in 15 of 18 tumors tested (83%). Loss was seen only in 3 pleural tumors, all of them fusion-negative (3 of 15 fusion-negative tumors tested, 20%). The 3 fusion-positive tumors that could be tested retained BAP1.
  • Among the 21 fusion-negative tumors, 5 (24%) showed large deletions of EWSR1 and SMARCB1 on chromosome 22.
  • In the one fusion-positive case tested by targeted sequencing, no other mutations, copy number changes or structural variants were found.
  • Among the fusion-positive cases, the 3 peritoneal cases were at advanced stage and the 1 pleural case was not (0/1). Disease recurred in all 3 cases with follow-up.
• The authors' conclusion: The authors concluded that EWSR1 or FUS-ATF1 fusions are rare in mesothelioma, appear restricted to younger patients without significant asbestos exposure or BAP1 loss, and occur in tumors that look like conventional mesothelioma.
• Limitations the authors state:
  • The low number of fusion-positive cases prevented a more definitive conclusion about how these tumors behave clinically.
  • The inherited (germline) BAP1 status of the patients was not known.
  • The findings on BAP1 loss were limited by the small size of the cohort.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Asbestos Exposure, Fluorescence In Situ Hybridization (FISH), Immunohistochemistry, BAP1, Peritoneum, Pleura, Epithelioid.

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• RNA sequencing identifies fusion of the EWSR1 and YY1 genes in mesothelioma with t(14;22)(q32;q12) — I. Panagopoulos, J. Thorsen, et al. (2013)
• 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)
• Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations — R. Bueno, E.W. Stawiski, et al. (2016)
• Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion in Adolescent and Young Adults with Peritoneal Metastases — M. Dhir, L. Ramalingam, et al. (2017)

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