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Molecular characteristics of malignant ovarian germ cell tumors and comparison with testicular counterparts: implications for pathogenesis - PubMed

Review

Molecular characteristics of malignant ovarian germ cell tumors and comparison with testicular counterparts: implications for pathogenesis

Sigrid Marie Kraggerud et al. Endocr Rev. 2013 Jun.

Abstract

This review focuses on the molecular characteristics and development of rare malignant ovarian germ cell tumors (mOGCTs). We provide an overview of the genomic aberrations assessed by ploidy, cytogenetic banding, and comparative genomic hybridization. We summarize and discuss the transcriptome profiles of mRNA and microRNA (miRNA), and biomarkers (DNA methylation, gene mutation, individual protein expression) for each mOGCT histological subtype. Parallels between the origin of mOGCT and their male counterpart testicular GCT (TGCT) are discussed from the perspective of germ cell development, endocrinological influences, and pathogenesis, as is the GCT origin in patients with disorders of sex development. Integrated molecular profiles of the 3 main histological subtypes, dysgerminoma (DG), yolk sac tumor (YST), and immature teratoma (IT), are presented. DGs show genomic aberrations comparable to TGCT. In contrast, the genome profiles of YST and IT are different both from each other and from DG/TGCT. Differences between DG and YST are underlined by their miRNA/mRNA expression patterns, suggesting preferential involvement of the WNT/β-catenin and TGF-β/bone morphogenetic protein signaling pathways among YSTs. Characteristic protein expression patterns are observed in DG, YST and IT. We propose that mOGCT develop through different developmental pathways, including one that is likely shared with TGCT and involves insufficient sexual differentiation of the germ cell niche. The molecular features of the mOGCTs underline their similarity to pluripotent precursor cells (primordial germ cells, PGCs) and other stem cells. This similarity combined with the process of ovary development, explain why mOGCTs present so early in life, and with greater histological complexity, than most somatic solid tumors.

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Figures

Figure 1.
Figure 1.

A simplified diagram illustrating the development of GCT. The main aberrant signaling pathways and ploidy levels identified in this paper are indicated. Development from zygote via PGC to normal oocyte or to mOGCT and TGCT is also shown. For the description of DSD patient groups with gonadal dysgenesis and increased risk for GCT, see Section I.E. Ter, teratoma.

Figure 2.
Figure 2.

Low-resolution genome instability of mOGCT histological subtypes. A, Results from ploidy analyses from the following 15 articles: Refs. and . The percentage of nondiploid samples is indicated above each bar. B, DNA copy number gain at chromosome arm 12p, as reported in 8 FISH articles (137, 146, 153, 155–158, 291) and 7 CGH articles (both chromosomal and array-based) (131, 132, 149–152, 340). The percentages of samples with gain at chromosome arm 12p are indicated above each bar. In both plots, the number of cases analyzed is shown on the y-axis. *, EC is represented by only 2 specimens, both nondiploid.

Figure 3.
Figure 3.

DNA copy number alterations for histological subtypes of mOGCT as reported by 6 CGH articles (131, 132, 149–152). The percentages of samples with gains and losses are shown in green and red, respectively, on the y-axis. Genomic positions given by the chromosome numbers are indicated along the x-axis. Centromere positions are indicated by vertical, dashed lines, and alterations on the p- and q-arms are mapped to the left and right of the dashed lines, respectively. The different panels summarize the findings per histology for DG (n = 35), YST (n = 14), and IT (n = 16).

Figure 4.
Figure 4.

Overlapping results among genome-wide mRNA and among miRNA expression studies of mOGCTs are shown in Venn diagrams where each number indicates the number of common mRNAs or miRNAs identified as overexpressed. A, To the left, mRNAs overexpressed in DG/seminoma vs other GCT types as described, and to the right, mRNAs overexpressed in YST vs other GCT types as described. B, To the left, miRNA overexpressed in DG/seminoma vs YST, and to the right, miRNAs overexpressed in YST vs DG/seminoma. Abbreviations: ova., ovarian; Sem, seminoma (TGCT histological subtype); test., testicular.

Figure 5.
Figure 5.

Overview of single-marker results in mOGCT ordered by number of cases for protein expression (A) and gene mutations (B). The number of cases with positive protein staining or gene mutation of the total number analyzed is shown within each circle. The circles are color-coded according to the percentage of positive staining. The total number of tumors studied (n) for each protein is followed by the relevant references (Ref).

Figure 6.
Figure 6.

An overview of histology-specific differences in DNA copy number alterations (solid bars), mRNA/miRNA expression (gene names, italics), and protein level (protein names) in mOGCT. Significant differences in DNA copy number gains and losses detected by CGH are presented as colored bars. For DG vs YST, light green bars reflect gains in DG as compared with YST and light red bars reflect losses in YST as compared with DG. For DG vs IT, dark red and dark green bars reflect regions of loss and gain, respectively. The significant gains and losses in YST vs IT are represented by blue and purple bars. Histology-specific gene expression identified from our overlap analysis of microarray results (Figure 4) is indicated to the left of chromosomes. The histology-specific protein expression from IHC studies (Figure 5A) is indicated to the right of chromosomes. The proteins included in the figure are those that were positive in ≥50% of the samples tested and with significantly different expression (P ≤ .02) among histology subtypes. Gene/protein symbols are color-coded according to the histological subtype associated with overexpression.

Figure 7.
Figure 7.

Molecular characteristics of the main histological subtypes of mOGCT. Hematoxylin- and eosin-stained sections of the subtypes DG, YST, and IT are illustrated to the left. The typical diploid or nondiploid stem line is shown, followed by copy number alterations reported in ≥30% of the subtypes (Figure 3). Also listed are recurrent differentially expressed mRNAs and miRNAs, reported in at least 2 papers (Figure 4), and proteins with positive staining in ≥50% of at least 6 samples per subtype (Figure 5A).

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