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Mesothelioma: t(14;22)(q32;q12) EWSR1/YY1

Written2014-05Ioannis Panagopoulos
Section for Cancer Cytogenetics, Institute for Cancer Genetics, Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, Oslo 031, Norway

(Note : for Links provided by Atlas : click)

Abstract

Abstract Mesothelioma is an aggressive tumor derived from mesothelial cells. Losses of chromosome bands 14q32 and 22q12 have been found in more than 35% of the cases. Using RNA sequencing EWSR1-YY1 and its reciprocal YY1-EWSR1 fusion transcripts were detected in a mesothelioma carrying a t(14;22)(q32;q12) as the sole chromosomal aberration. Screening 15 additional cases of mesothelioma one more tumor was identified to carry an EWSR1-YY1 fusion gene but not the reciprocal YY1-EWSR1 transcript. In both cases exon 8 of EWSR1 (nucleotide 1139 accession number NM_013986 version 3, former exon 7 in sequence with accession number X66899) was fused to exon 2 of YY1 (nucleotide 1160 accession number NM_003403 version 3). 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 and also the direct involvement of YY1 in oncogenesis.

Identity

Atlas_Id 6460
Phylum Lung, Heart,Skin, Other: Peritoneum: Mesothelioma::Mesothelioma : t(14;22)(q32;q12) EWSR1/YY1
Note Mesothelioma is an aggressive tumor derived from mesothelial cells. It is primarily found in the pleura (75%), peritoneum (10-20%), pericardium (1%) and tunica vaginalis (< 1%) (Moore et al., 2008). Mesothelioma is strongly associated with exposure to asbestos which can be documented in about 50-80% of pleural cases and 30% of peritoneal mesothelioma in men (Bianchi and Bianchi, 2007). Genetic predisposition, smoking, radiation, and viral infection can also contribute to mesothelioma. The onset of mesothelioma is insidious with a latency of 30 years (range: 20 to 50 years). The mean age of the patients is 60 years, but the disease can occur at any age (Moore et al., 2008). Survival rates vary but they generally remain low (Asbestos.com).

Clinics and Pathology

Disease Mesothelioma
Phenotype / cell stem origin Mesothelioma is derived from mesothelial cells.
Embryonic origin Unknown.
Etiology Mesothelioma is strongly associated with exposure to asbestos which can be documented in about 50-80% of pleural cases and 30% of peritoneal mesothelioma in men (Bianchi and Bianchi, 2007). Genetic predisposition, smoking, radiation, and viral infection can also contribute to mesothelioma either alone or together with exposure to asbestos.
Epidemiology For a detailed and update epidemiology of mesothelioma see: http://www.uptodate.com/contents/epidemiology-of-malignant-pleural-mesothelioma.

Genetics

Note Abnormal karyotypes detected by cytogenetic analysis have been reported in 128 mesotheliomas (Mitelman database). The changes are mostly complex, but a number of nonrandom abnormalities have been found involving chromosome arms 1p, 3p, 6q, 9p, and 22q. Studies using comparative genomic hybridization, loss of heterozygosity, and fluorescence in situ hybridization (FISH) have also shown repeated regional chromosomal gains and losses. Among them, losses of chromosome bands 14q32 and 22q12 were found in 43-50% and 36% of the cases, respectively (Taniguchi et al., 2007; Takeda et al., 2012). On band 22q12, the NF2 gene was found to be mutated in 40% of mesotheliomas leading to complete functional inactivation of NF2 (see Thurneysen et al., 2009; and references therein). In two other studies, NF2 was found to be deleted (Taniguchi et al., 2007; Takeda et al., 2012). On chromosome band 14q32, the CHGA and ITPK1 genes were found to be deleted (Taniguchi et al., 2007; Takeda et al., 2012).

Cytogenetics

Note In a mesothelioma, which was diagnosed as epithelioid type, the G-banding analysis yielded a karyotype with only a single chromosomal abnormality: 46,XY,t(14;22)(q32;q12)[10]/46,XY[5] (Panagopoulos et al., 2013).
Partial karyotype showing the two derivative chromosomes, der(14)t(14;22)(q22;q12) and der(22)t(14;22)(q22;q12), from the 14;22 translocation together with their corresponding normal homologues; breakpoints are indicated by arrows.
A. Fluorescence in situ hybridization using BAC RP11-638I2 (FITC, green) for the YY1 gene (14q32) and RP11-612D3 (Texas Red, red) for the EWSR1 gene (22q12). The fusion signals are seen on both derivative chromosomes. B. Mapping position of the RP11-638I2. C. Mapping position of the RP11-612D3.

Genes involved and Proteins

Gene Name YY1
Location 14q32.2
Dna / Rna Spans 44.495 kb on plus strand.
Protein 414 amino acids, 44.7 kDa.

Gene Name EWSR1
Location 22q12.2
Dna / Rna Spans 32.5 kb on plus strand. Transcript of 2654 bp from 17 exons for the canonical form, with a coding sequence of 1971 nt.
Protein 656 amino acids, 68.5 kDa.

Result of the chromosomal anomaly

Hybrid Gene
Note The balanced 14;22-translocation generates a functional EWSR1-YY1 chimeric gene in which exon 8 of EWSR1 (nucleotide 1139 accession number NM_013986 version 3; former exon 7 in sequence with accession number X66899) is fused to exon 2 of YY1 (nucleotide 1160 accession number NM_003403 version 3). The putative EWSR1-YY1 protein would contain the transactivation domain of EWSR1 and the DNA binding domain of YY1 and thus may act as an abnormal transcription factor.
 
Partial sequence chromatogram showing the fusion of exon 8 of EWSR1 with exon 2 of YY1.
Description The EWSR1-YY1 fusion gene was detected in 2 so far mesotheliomas (Panagopoulos et al., 2013).
  

Bibliography

Malignant mesothelioma: global incidence and relationship with asbestos.
Bianchi C, Bianchi T.
Ind Health. 2007 Jun;45(3):379-87. (REVIEW)
PMID 17634686
 
Malignant mesothelioma.
Moore AJ, Parker RJ, Wiggins J.
Orphanet J Rare Dis. 2008 Dec 19;3:34. doi: 10.1186/1750-1172-3-34. (REVIEW)
PMID 19099560
 
RNA sequencing identifies fusion of the EWSR1 and YY1 genes in mesothelioma with t(14;22)(q32;q12).
Panagopoulos I, Thorsen J, Gorunova L, Micci F, Haugom L, Davidson B, Heim S.
Genes Chromosomes Cancer. 2013 Aug;52(8):733-40. doi: 10.1002/gcc.22068. Epub 2013 Apr 30.
PMID 23630070
 
Genomic gains and losses in malignant mesothelioma demonstrated by FISH analysis of paraffin-embedded tissues.
Takeda M, Kasai T, Enomoto Y, Takano M, Morita K, Kadota E, Iizuka N, Maruyama H, Nonomura A.
J Clin Pathol. 2012 Jan;65(1):77-82. doi: 10.1136/jclinpath-2011-200208. Epub 2011 Nov 12.
PMID 22081786
 
Genomic profiling of malignant pleural mesothelioma with array-based comparative genomic hybridization shows frequent non-random chromosomal alteration regions including JUN amplification on 1p32.
Taniguchi T, Karnan S, Fukui T, Yokoyama T, Tagawa H, Yokoi K, Ueda Y, Mitsudomi T, Horio Y, Hida T, Yatabe Y, Seto M, Sekido Y.
Cancer Sci. 2007 Mar;98(3):438-46.
PMID 17270034
 
Functional inactivation of NF2/merlin in human mesothelioma.
Thurneysen C, Opitz I, Kurtz S, Weder W, Stahel RA, Felley-Bosco E.
Lung Cancer. 2009 May;64(2):140-7. doi: 10.1016/j.lungcan.2008.08.014. Epub 2008 Oct 4.
PMID 18835652
 

Citation

This paper should be referenced as such :
I Panagopoulos
Mesothelioma: t(14;22)(q32;q12) in mesothelioma
Atlas Genet Cytogenet Oncol Haematol. 2015;19(1):62-64.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Tumors/t1422q32q12MesotheliomID6460.html


Translocations implicated (Data extracted from papers in the Atlas)

 t(14;22)(q32;q12) EWSR1/YY1

External links

Mitelman database t(14;22)(q32;q12) EWSR1/YY1 [Case List]    t(14;22)(q32;q12) EWSR1/YY1 [Association List] Mitelman database (CGAP - NCBI)
arrayMap arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
 
Mitelman databaseEWSR1/YY1[MCList]    EWSR1 (22q12.2) YY1 (14q32.2)   t(14;22)(q32;q12)
 
Other databaseEpidemiology of malignant pleural mesothelioma
Other databaseMesothelioma [ Genomic Data Commons - NCI TCGA-MESO]
Disease databaseMesothelioma: t(14;22)(q32;q12) EWSR1/YY1
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed


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