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Ovary: Germ cell tumours with inv(10)(q11q11) RET::NCOA

Written2009-10Douglas S Richardson, Lois M Mulligan
Department of Pathology, Molecular Medicine, Division of Cancer Biology, Genetics, Cancer Research Institute, Queen's University, Kingston, ON, Canada

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ICD-Morpho 9090/3 Struma ovarii, malignant
Atlas_Id 5465
Phylum Female organs: Ovary::Germ cell tumor
WHO/OMS Classification Female organs
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.

Clinics and Pathology

Disease Papillary thyroid carcinoma arising in struma ovarii
Phenotype / cell stem origin 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.
Treatment Surgical resection of tumour, 131I radioablation therapy.


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.
Gene NameRET (REarranged during Transfection)
Location 10q11.21
Protein RET encodes a 175kDa 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.

Gene NameNCOA4 (Nuclear Receptor Coactivator 4)
Location 10q11.23
Protein NCOA4 is a 70kDa co-activator protein that serves to enhance transcriptional activity downstream of the androgen receptor, other steroid receptors, and peroxisome proliferator-activated receptor gamma.

Result of the chromosomal anomaly

Hybrid Gene
Note The RET/NCOA4 fusion gene is also referred to as PTC3.
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).
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).
Fusion Protein
Note 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 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.
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.

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.


Follicular variant papillary thyroid carcinoma arising in struma ovarii.
Boutross-Tadross O, Saleh R, Asa SL.
Endocr Pathol. 2007 Fall;18(3):182-6.
PMID 18058267
RET/PTC3 rearrangement and thyroid differentiation gene analysis in a struma ovarii fortuitously revealed by elevated serum thyroglobulin concentration.
Elisei R, Romei C, Castagna MG, Lisi S, Vivaldi A, Faviana P, Marinò M, Ceccarelli C, Pacini F, Pinchera A.
Thyroid. 2005 Dec;15(12):1355-61.
PMID 16405408
Struma Ovarii with a focus of papillary thyroid cancer: a case report and review of the literature.
Makani S, Kim W, Gaba AR.
Gynecol Oncol. 2004 Sep;94(3):835-9.
PMID 15350384
Transcript level modulates the inherent oncogenicity of RET/PTC oncoproteins.
Richardson DS, Gujral TS, Peng S, Asa SL, Mulligan LM.
Cancer Res. 2009 Jun 1;69(11):4861-9.
PMID 19487296
Molecular characterization of RET/PTC3; a novel rearranged version of the RET proto-oncogene in a human thyroid papillary carcinoma.
Santoro M, Dathan NA, Berlingieri MT, Bongarzone I, Paulin C, Grieco M, Pierotti MA, Vecchio G, Fusco A.
Oncogene. 1994 Feb;9(2):509-16.
PMID 8290261
Malignant struma ovarii.
Yassa L, Sadow P, Marqusee E.
Nat Clin Pract Endocrinol Metab. 2008 Aug;4(8):469-72. Epub 2008 Jun 17.
PMID 18560398
Prevalence of RET/PTC rearrangements in thyroid papillary carcinomas: effects of the detection methods and genetic heterogeneity.
Zhu Z, Ciampi R, Nikiforova MN, Gandhi M, Nikiforov YE.
J Clin Endocrinol Metab. 2006 Sep;91(9):3603-10. Epub 2006 Jun 13.
PMID 16772343


This paper 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.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

Genes RET

Translocations implicated (Data extracted from papers in the Atlas)

 inv(10)(q11q11) RET/NCOA4

External links

Mitelman database inv(10)(q11q11) [CaseList]     inv(10)(q11q11) [Transloc - MCList]   RET/NCOA4 Fusion - MCList]
arrayMap Topo ( C56) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
COSMIC_fusionRET (10q11.21) NCOA4 (10q11.23)    [fusion1494] [fusion1495] [fusion1496] [fusion1497] [fusion1502]
Mitelman databaseRET/NCOA4[MCList]    RET (10q11.21) NCOA4 (10q11.23)   t(10;10)(q11;q11)
TCGA_FusionRET/NCOA4    RET (10q11.21) NCOA4 (10q11.23)
Disease databaseOvary: Germ cell tumours with inv(10)(q11q11) RET::NCOA
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed

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