Solid Tumour Section Carcinoma with t(15;19) translocation Atlas of Genetics and Cytogenetics

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Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Solid Tumour Section
Mini Review
Carcinoma with t(15;19) translocation
Anna Collin
Department of Clinical Genetics, Lund University Hospital, 221 85 Lund, Sweden
Published in Atlas Database: February 2007
Online updated version: http://AtlasGeneticsOncology.org/Tumors/Carcinot1519q14p13ID5474.html
DOI: 10.4267/2042/38455
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2007 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Cytology
Identity
Focal reactivity with pan-cytokeratin markers. Negative
for CD30, CD45, PLAP, HMB45, S100 and
neuroendocrine markers.
Other
names:
Mediastinal
carcinoma
with
chromosome translocation t(15;19); Midline carcinoma
of children and young adults with NUT rearrangement;
Midline carcinoma with t(15;19); Poorly differentiated
carcinoma with t(15;19); Poorly differentiated thymic
carcinoma; t(15;19) positive tumor.
Pathology
The tumor cells are typically undifferentiated, of
intermediate size and the mitotic index is high.
Treatment
Clinics and pathology
Disease
Intensive combined chemotherapy and occasionally
radiotherapy.
Carcinoma with t(15;19) translocation.
Prognosis
Phenotype stem cell origin
Extremely poor. Among the cases reported so far, the
median survival time was 18 weeks (range 6-67).
It has been suggested that a critical prognostic
difference exists between BRD4-NUT/t(15;19) positive
tumors and tumors where NUT is rearranged but fused
to an as yet unknown partner.
It has been suggested that tumor cells derive from early
epithelial progenitor cells.
Embryonic origin
The majority of the cases presumably derive from
various (midline) epithelial surfaces. One tumor,
localized to the iliac bone and staining negative for
epithelial, endothelial, germ cell and neuroendocrine
markers has been reported, suggesting that the tumor
might also derive from non-epithelial structures.
Cytogenetics
Cytogenetics morphological
The characteristic t(15;19) has been observed in all
reported cases. The reported breakpoints on
chromosome 15 have varied (15q11-q15). The
breakpoints on chromosome 19 clustered to 19p13 in
the majority of the cases. In one case the breakpoint
was interpreted as 19q13.
Etiology
Unknown.
Epidemiology
A total of 13 cases have been reported to date. All
tumors occurred in children or young adults with a
median age of 15 years of age (range 3-35). There seem
to be no sex predilection (8 males, 5 females).
Cytogenetics molecular
Various FISH protocols for the detection of 15q and
19p rearrangements, strongly indicating the presence of
a t(15;19), have been reported. The material used has
been paraffin-embedded sections of tumor biopsy or
metaphase spreads of cultured tumor tissue.
Clinics
The growth pattern is typically aggressive and locally
invasive. Metastatic growth is common in particular in
bone, but also in lymph nodes and lungs.
Atlas Genet Cytogenet Oncol Haematol. 2007;11(3)
249
Carcinoma with t(15;19) translocation
Collin A
Probes
Result of the chromosomal
anomaly
Probes for NUT: RP11-194H7 covering the gene or
BAC 87M17 and YAC 766E7 flanking the gene.
Probes for BRD4: RP11-637P24 covering the gene or
BACs 1H8+64O3 and BACs 412E10+3D4 flanking the
gene.
Hybride Gene
Description
The t(15;19)(q14;p13) results in a BRD4-NUT
chimeric gene where exon 10 of BRD4 is fused to exon
2 of NUT.
Detection protocole
The hybrid gene can be visualized by FISH using gene
specific probes or by RT-PCR.
Additional anomalies
The t(15;19) is typically seen as the sole change. In one
case a variant t(11;15;19) was reported.
Variants
t(15;?)(q14;?) leading to rearrangement and fusion of
NUT to an unknown partner gene.
Fusion protein
Genes involved and Proteins
Description
The BRD4-NUT fusion protein is composed of the Nterminal of BRD4 (amino acids 1-720 out of 1372) and
almost the entire protein sequence of NUT (amino
acids 6-1127). The N-terminal of BRD4 includes
bromodomains 1 and 2 and other, less well
characterized functional domains.
Oncogenesis
It has been suggested that the oncogenic effect of the
NUT-BRD4 fusion is caused not only by the abnormal
regulation of NUT by BRD4 promotor elements but
also by the consequent ectopic expression of NUT in
non-germinal tissues.
NUT (nuclear protein in testis)
Location: 15q14 (position 32425358-32437221 on the
chromosome 15 genomic sequence according to the
UCSC database; assembly of May 2004)
DNA/RNA
The gene consists of 7 exons that span approximately
12 kb of genomic DNA in the centromere-to-telomere
orientation. The translation initiation codon and the
stop codon are predicted to exon 1 and exon 7,
respectively. The corresponding wildtype mRNA
transcript is 3.6 kb.
Protein
The open reading frame is predicted to encode a 1127
amino acid protein with an estimated molecular weight
of 120 kDa. The protein is nuclear and Northern blot
analysis has indicated that the normal expression of the
NUT gene is highly restricted to the testis.
References
Kees UR, Mulcahy MT, Willoughby MLN. Intrathoracic
carcinoma in an 11-year-old girl showing a translocation
t(15;19). Am J Pediatr Hematol Oncol 1991;13:459-464.
Kubonishi I, Takehara N, Iwata J, Sonobe H, Ohtsuki Y, Abe T,
Miyoshi I. Novel t(15;19) chromosome abnormality in a thymic
carcinoma. Cancer Res 1991;51:3327-3328.
BRD4 (bromodomain containing 4)
Lee ACW, Kwong Y-I, Fu KH, Chan GCF, Ma L, Lau Y-I.
Disseminated mediastinal carcinoma with chromosomal
translocation (15;19). A distinctive clinicopathologic syndrome.
Cancer 1993;72:2273-2276.
Location: 19p13 (position 15252262-15209302 on the
chromosome 19 genomic sequence according to the
UCSC database; assembly of May 2004).
DNA/RNA
The gene consists of 20 exons that span approximately
43 kb of genomic DNA in the centromere-to-telomere
orientation. The translation initiation codon and stop
codon are located to exon 2 and exon 20, respectively.
Two isoforms of BRD4 have been reported. The BRD4
long isoform encodes a 6.0 kb mRNA that corresponds
to the full length transcript. The BRD4 short isoform
encodes a 4.4 kb mRNA that corresponds to an
alternative splicing variant lacking exons 12-20.
Protein
The open reading frame encodes a 1362 amino acid
protein with a molecular weight of 200 kDa. The
protein is nuclear and Northern blot analysis has shown
an ubiquitous normal expression of both BRD4
isoforms.
Atlas Genet Cytogenet Oncol Haematol. 2007;11(3)
Dang TP, Gazdar AF, Virmani AK, Sepetavec T, Hande KR,
Minna JD, Roberts JR, Carbone DP. Chromosome 19
translocation, overexpression of Notch3, and human lung
cancer. J Natl Cancer Inst 2000;92:1355-1357.
French CA, Miyoshi I, Aster JC, Kubonishi I, Kroll TG, Dal Cin
P, Vargas SO, Perez-Atayde AR, Fletcher JA. BRD4
bromodomain gene rearrangement in aggressive carcinoma
with translocation t(15;19). Am J Pathol 2001;159:1987-1992.
Vargas SO, French CA, Faul PN, Fletcher JA, Davis IJ, Dal Cin
P, Perez-Atayde AR. Upper respiratory tract carcinoma with
chromosomal translocation 15;19. Evidence for a distinct
disease entity of young patients with a rapidly fatal course.
Cancer 2001;92:1195-1203.
French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR,
Fletcher JA. BRD4-NUT fusion oncogene: a novel mechanism
in aggressive carcinoma. Cancer Res 2003;63:304-307.
Toretsky JA, Jenson J, Sun C-C, Eskenazi AE, Campbell A,
Hunger SP, Caires A, Frantz C, Hill JL, Stamberg J.
Translocation t(11;15;19): a highly specific chromosome
250
Carcinoma with t(15;19) translocation
Collin A
rearrangement associated with poorly differentiated thymic
carcinoma in young patients. Am J Clin Oncol 2003;26:300306.
You J, Croyle JL, Nishimura A, Ozato K, Howley P. Interaction
of the bovine papillomavirus E2 protein with Brd4 tethers the
viral DNA to host mitotic chromosomes. Cell 2004;117:349360.
French CA, Kutok JL, Faquin WC, Toretsky JA, Antonescu CR,
Griffin CA, Nose V, Vargas SO, Moschovi M, TzortzatouStathopoulo F, Miyoshi I, Perez-Atayde AR, Aster JC, Fletcher
JA. Midline carcinoma of children and young adults with NUT
rearrangement. J Clin Oncol 2004;22:4135-4139.
Engleson J, Soller M, Panagopoulos I, Dahlén A, Dictor M,
Jerkeman M. Midline carcinoma with t(15;19) and BRD4-NUT
fusion oncogene in a 30-year-old female with response to
docetaxel and radiotherapy. BMC Cancer 2006;6:69.
Marx A, French CA, Fletcher JA. Carcinoma with t(15;19)
translocation. In:World Health Organization classification of
tumours. Pathology and genetics of tumours of the lung,
thymus, pleura and heart. Travis WD, Brambilla E, MullerHermelink K, Harris CC, editors. Oxford University Press 2004.
pp185-186.
Atlas Genet Cytogenet Oncol Haematol. 2007;11(3)
Mertens F, Wiebe T, Adlercreutz C, Mandahl N, French CA.
Successful treatment of a child with t(15;19)-positive tumor.
Pediatr Blood Cancer 2006.
This article should be referenced as such:
Collin A. Carcinoma with t(15;19) translocation. Atlas Genet
Cytogenet Oncol Haematol.2007;11(3):249-251.
251
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