Download Solid Tumour Section Ovary: inv(10)(q11q11) in ovarian germ cell tumors

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Ovary: inv(10)(q11q11) in ovarian germ cell tumors
Douglas S Richardson, Lois M Mulligan
Department of Pathology and Molecular Medicine, Division of Cancer Biology and Genetics, Cancer
Research Institute, Queen's University, Kingston, ON, Canada (DSR, LMM)
Published in Atlas Database: October 2009
Online updated version : http://AtlasGeneticsOncology.org/Tumors/inv10q11q11OvaryGermID5465.html
DOI: 10.4267/2042/44835
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Cytogenetics
Note
Ovarian germ cell (OGC) tumours arise in the primitive
germ cells of the ovary and primarily affect younger
women. Struma ovarii are the most common
monodermal teratomas arising from OGCs. Struma
Ovarii are characterized by a composition of at least
50% mature thyroid tissue. Two reports have shown
that oncogenic mutations characteristic of thyroid
carcinoma in situ, most notably mutations found in
thyroid follicular cells that give rise to papillary thyroid
carcinoma (PTC), can be found within the thyroid
tissue of Struma Ovarii. These mutations can promote
oncogenesis, resulting in initiation of PTC within the
teratoma.
Cytogenetics Molecular
inv(10)(q11q11)
Genes involved and proteins
Note
The inv(10)(q11q11) fuses the promoter and 5' coding
regions of NCOA4 to the 3' kinase domain coding
region of RET.
RET
Location
10q11.21
Protein
RET encodes a 175 kDa transmembrane receptor
tyrosine kinase that is required for development of the
kidney and enteric nervous system. Three isoforms of
RET have been identified that arise through 3'
alternative splicing involving exons 19, 20 and 21, and
encode proteins of 1072, 1106, and 1114 amino acids.
Clinics and pathology
Disease
Papillary thyroid carcinoma arising in struma ovarii.
Phenotype / cell stem origin
NCOA4
Struma ovarii originate from ovarian germ cells.
Malignant transformation of these monodermal
teratomas primarily occurs in follicular-like cells of the
thyroid tissue contained within struma ovarii,
producing a tumour that resembles papillary thyroid
carcinoma.
Location
10q11.23
Protein
NCOA4 is a 70 kDa co-activator protein that serves to
enhance transcriptional activity downstream of the
androgen receptor, other steroid receptors, and
peroxisome proliferator-activated receptor gamma.
Treatment
Surgical resection of tumour, 131I radioablation therapy.
Diagrammatic representation of RET and NCOA4 exon locations on Chromosome 10. Introns and exons are to scale within respective
genes. Breakpoints within each gene are indicated (BP).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8)
804
Ovary: inv(10)(q11q11) in ovarian germ cell tumors
Richardson DS, Mulligan LM
Diagrammatic representation of RET/NCOA4 (PTC3) fusion protein. Amino acids surrounding each breakpoint (arrows) are indicated,
and numbered according to their position within RET or NCOA4, respectively. Peptide sequences from RET are in red, from NCOA4 in
green. The transmembrane domain (TM) of RET is shown in yellow. IC - intracellular domain.
Result of the chromosomal
anomaly
To be noted
Although RET/NCOA4 fusion proteins are known to
play a role in initiating papillary thyroid carcinoma,
they can also occur as a late mutational event. As with
all tumours, care must be taken in attributing
oncogenesis to a single genetic event.
Hybrid Gene
The RET/NCOA4 fusion gene is also referred to as
PTC3.
Description
The inv(10)(q11q11) results in fusion of exons 1-6 of
NCOA4 with exon 12-through to the C-terminus of
RET.
Detection
RT-PCR, Southern blot, and FISH (see Zu et al., 2006
for detailed methods).
References
Santoro M, et al. Molecular characterization of RET/PTC3; a
novel rearranged version of the RETproto-oncogene in a
human thyroid papillary carcinoma. Oncogene. 1994
Feb;9(2):509-16
Makani S, Kim W, Gaba AR. Struma Ovarii with a focus of
papillary thyroid cancer: a case report and review of the
literature. Gynecol Oncol. 2004 Sep;94(3):835-9
Fusion Protein
Elisei R, Romei C, Castagna MG, Lisi S, Vivaldi A, Faviana P,
Marinò M, Ceccarelli C, Pacini F, Pinchera A. RET/PTC3
rearrangement and thyroid differentiation gene analysis in a
struma ovarii fortuitously revealed by elevated serum
thyroglobulin concentration. Thyroid. 2005 Dec;15(12):1355-61
The RET/NCOA4 fusion protein is also referred to as
PTC3. Chimeric protein consisting of the tyrosine
kinase domain of RET fused downstream of the
homodimerization domain of NCOA4. Constitutive
dimerization of fusion proteins results in continuous
downstream signalling through canonical cell growth
and proliferation pathways, promoting oncogenesis.
Description
Fusion protein consists of amino acids 1-238 of
NCOA4 and 712-C-terminus of RET. The N-terminal
region
donated
by
NCOA4
contains
a
homodimerization domain that results in constitutive
dimerization and activation of the RET kinase domain
in the C-terminal region of the molecule. Constitutive
activation increases signalling through a number of
downstream signalling pathways involved in cell
proliferation and survival, promoting oncogenesis.
Expression / Localisation
Cytoplasm.
Oncogenesis
RET/NCOA4 fusion proteins have been implicated
in the oncogenesis of papillary thyroid carcinoma.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8)
Zhu Z, Ciampi R, Nikiforova MN, Gandhi M, Nikiforov YE.
Prevalence of RET/PTC rearrangements in thyroid papillary
carcinomas: effects of the detection methods and genetic
heterogeneity. J Clin Endocrinol Metab. 2006 Sep;91(9):360310
Boutross-Tadross O, Saleh R, Asa SL. Follicular variant
papillary thyroid carcinoma arising in struma ovarii. Endocr
Pathol. 2007 Fall;18(3):182-6
Yassa L, Sadow P, Marqusee E. Malignant struma ovarii. Nat
Clin Pract Endocrinol Metab. 2008 Aug;4(8):469-72
Richardson DS, Gujral TS, Peng S, Asa SL, Mulligan LM.
Transcript level modulates the inherent oncogenicity of
RET/PTC oncoproteins. Cancer Res. 2009 Jun 1;69(11):48619
This article should be referenced as such:
Richardson DS, Mulligan LM. Ovary: inv(10)(q11q11) in
ovarian germ cell tumors. Atlas Genet Cytogenet Oncol
Haematol. 2010; 14(8):804-805.
805