Molecular genetic evidence supporting the neoplastic nature of stromal cells in ‘fibrosis’ after chemotherapy for testicular germ cell tumours

Liu, Cheng; Zhang, S.; Wang, M.; Davidson, Darrell D.; Morton, Michael J.; Huang, Jiaoti; Zheng, Shu; Jones, Timothy D.; Beck, Stephen D.W.; Foster, Richard S.

doi:10.1002/path.2202

Cited by 43 publications

(27 citation statements)

References 50 publications

(69 reference statements)

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“…The concept of teratomatous stroma was confirmed by another study from our group in which the chromosome 12p anomalies were found in 9 of 27 (33%) retroperitoneal residual fibrous masses after chemotherapy. 18 Our data support the concept that the fibrous stroma of testicular teratomas is one of the malignant teratoma components and that it, like the other teratoma components, has malignant potential.…”

Section: Discussionsupporting

confidence: 77%

“…Our results indicate that the fibrous stroma in testicular teratomas frequently Most of the published studies on teratoma stromal cells have been performed on metastatic lesions and utilized loss of heterozygosity analysis and FISH to detect chromosome 12p alterations. 3,18,19 In our previous study, we found that among the 25 patients with metastatic testicular teratoma, loss of heterozygosity was seen in 22 (92%) of the teratoma specimens and in 16 (64%) of the proximate stroma. 19 Of these 16 cases, 8 had an identical pattern of allelic loss in the epithelial cells and in the proximate stroma at all 9 DNA loci studied.…”

Section: Discussionmentioning

confidence: 99%

“…It is well established that testicular teratoma patients occasionally develop secondary high-grade mesenchymal malignancies, presumably derived from the stroma. 18,[34][35][36][37] In a series by Motzer et al, 35 63% of teratomas that developed a malignant component had a sarcoma. In the study of El Mesbahi et al, 36 sarcoma was the most frequent tumor type among 14 teratoma patients with 'malignant transformation.'…”

Section: Discussionmentioning

confidence: 99%

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Molecular genetic evidence supporting the neoplastic nature of fibrous stroma in testicular teratoma

et al. 2012

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Testicular teratoma typically consists of heterogeneous mixtures of diverse epithelial and stromal components. The biological nature and genetic characteristics of the fibrous stroma of testicular teratomas have not been thoroughly investigated. Chromosome 12p abnormalities are the hallmark genetic alterations of germ cell tumors. We studied chromosome 12p abnormalities in the fibrous stroma and other components of pure testicular teratomas from 32 patients using interphase fluorescence in situ hybridization. Overall, 72% (23/32) of pure testicular teratomas had chromosome 12p abnormalities. Isochromosome 12p or 12p overrepresentation independent of isochromosome 12p was detected in the fibrous stroma in 53% (17/32) and 41% (13/32) of cases, respectively. Among the 17 cases positive for isochromosome 12p, 8 (47%) also had 12p overrepresentation. In 31% (10/32) cases, the fibrous stroma showed neither 12p overrepresentation nor isochromosome 12p. Isochromosome 12p and 12p overrepresentation were identified, respectively, in the gastrointestinal-type epithelium of 14/23 (61%) and 15/23 (65%) cases; in the respiratory-type epithelium of 41% (7/17) and 41% (7/17) cases; in the squamous epithelium of 62% (8/13) and 54% (7/13) cases; and in the cartilage of 63% (5/8) and 38% (3/8) cases. Concordant chromosomal 12p abnormalities were observed between the fibrous stroma and epithelial elements of testicular teratomas. Our results indicate that the fibrous stroma of testicular teratomas frequently has genetic abnormalities similar to those of the epithelial components. Concordant chromosome 12p alterations between the fibrous stroma and epithelial elements provide further evidence that both epithelial and fibrous components of teratoma are derived from a common progenitor.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Molecular genetic evidence supporting the neoplastic nature of fibrous stroma in testicular teratoma

et al. 2012

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“…Laser-assisted microdissection of the tumor tissues was performed on the lightly HE-stained sections using a PixCell II Laser Capture Microdissection System (Arcturus Engineering, Mountain View, CA, USA). 6,7 Approximately 600-1000 cells of each tumor were microdissected from the 4-mm histological sections as demonstrated in Figure 1. Microdissected normal tissue from the same patient served as a control.…”

Section: Tumors Samples and Microdissectionmentioning

confidence: 99%

FGFR3 and TP53 mutation analysis in inverted urothelial papilloma: incidence and etiological considerations

et al. 2009

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Urothelial papillomas and low-grade urothelial carcinomas have shown a high incidence of fibroblast growth factor receptor 3 (FGFR3) mutations and are associated with a favorable prognosis. The association of FGFR3 mutations with inverted papillomas is less known. We analyzed 20 cases of inverted papilloma in the urinary tract. Mutations of FGFR3 (exons 7, 10, and 15) and TP53 genes were evaluated by DNA sequencing in these cases. Point mutations of the FGFR3 gene were identified in 45% (9 of 20) of inverted papillomas with four cases exhibiting mutations at multiple exons. Seven cases had exon 7 mutations containing R248C, S249T, L259L, P260P, and V266M. Two cases had exon 10 and 15 mutations including A366D, H412H, E627D, D641N, and H643D; five cases had N653H. The most frequent mutation was identified at R248C. None of the inverted papillomas exhibited mutations in TP53. During a mean follow-up of 78 months, none had recurrence or developed urothelial carcinoma. These findings support the concept that low-grade and low-stage urothelial neoplasms arise in a background of molecular changes that are distinctly different from the molecular changes of high-grade and high-stage urothelial cancers. Modern Pathology ( Keywords: urinary bladder; urinary tract; inverted papilloma; fibroblast growth factor receptor 3; tumorigenesis; TP mutationsThe fibroblast growth factor receptor 3 (FGFR3) is a member of a family of tyrosine kinase receptors and is composed of an extracellular ligand-binding domain, a transmembrane region, and a cytoplasmic domain with tyrosine kinase activity. Ligand binding causes receptor dimerization and subsequent activation of intracellular tyrosines. Activating mutations of FGFR3 gene lead to constitutive activation of the receptor subsequently inducing the downstream molecular pathogenesis. Activating point mutations of FGFR3 have been associated with autosomal dominant dwarfism and severe achondroplasia. An oncogenic role for FGFR3 in human cancer has emerged recently and FGFR3 mutations were reported to be associated with multiple myeloma, urothelial, and cervical cancers.Urothelial carcinomas harboring FGRFR3 mutations, in general, tend to be of low histological grade and of low pathological stage, and consequently are associated with a more favorable clinical outcome.

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“…14 Tissues were microdissected and DNA was extracted as previously described. 9,15 This research was approved by the Indiana University Institutional Review Board.…”

Section: Sample Selection and Preparationmentioning

confidence: 99%

Hypermethylation of tumor-suppressor gene CpG islands in small-cell carcinoma of the urinary bladder

et al. 2008

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Small-cell carcinoma of the urinary bladder (SCBC) is a rare tumor, which shows a common clonal origin with urothelial carcinoma. It bears a high metastatic potential, even when discovered in a localized state. Identifying the molecular underpinnings of this disease may elucidate useful clinical information regarding prevention, diagnosis, prognosis, treatment, and surveillance. As DNA methylation is widely recognized as having a pivotal role in the process of carcinogenesis, we analyzed the DNA methylation status of four frequently hypermethylated tumor suppressors in small-cell and transitional-cell carcinoma (TCC) arising concomitantly in 13 patients. Fourteen cases of pure TCC were also included in the analysis. We identified frequent methylation of RASSF1 and MGMT and infrequent methylation of MLH1 and DAPK1 in cases of concomitant TCC and SCBC. Similar rates of methylation were found in pure and concomitant histopathologies, with the exception of MGMT, which was much less frequently methylated in pure TCC. These findings suggest that SCBC and TCC have common origins, establish DNA methylation of some tumor suppressors as frequent occurrences in both histopathologies, and suggest that MGMT methylation may be an SCBC-specific epimutation. Modern Pathology (2008) 21, 355-362; doi:10.1038/modpathol.3801012; published online 11 January 2008Keywords: urinary bladder; small-cell carcinoma; DNA methylation; epigenetics DNA methylation-induced silencing of gene expression is now recognized as an important contributor in all stages of carcinogenesis. 1 Methylation of CpGdense regions, or CpG islands (CpGIs), associated with the first exons of many genes, serves to recruit transcriptional silencing machinery, including methyl-CpG-binding proteins, histone deacetylases and methyltransferases, and ATP-dependent chromatin-remodeling enzymes. 2,3 Silencing of key tumor and metastasis suppressors, 4,5 drug-metabolizing enzymes, 6 and DNA-repair proteins 7 is an event that contributes to carcinogenesis, acquisition of invasiveness and metastatic potential, angiogenesis, and therapy refractoriness. DNA methylation is a target for both therapeutic and biomarker purposes. 8 Importantly, the study of DNA methylation in clinical samples may provide useful and novel insights into the pathobiology of disease processes such as cancer.Transitional-cell carcinoma (TCC) arises from urothelium, which lines the bladder, as well as the renal pelvis, ureter, and portions of the urethra. Although infrequent in occurrence, small-cell bladder cancer (SCBC) may evolve or co-evolve from pre-existing TCC. 9 We hypothesized that DNA methylation of specific genes may underlie the pathogenesis of SCBC. In this study, we quantitatively analyzed the methylation status of RASSF1,

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Molecular genetic evidence supporting the neoplastic nature of stromal cells in ‘fibrosis’ after chemotherapy for testicular germ cell tumours

Cited by 43 publications

References 50 publications

Molecular genetic evidence supporting the neoplastic nature of fibrous stroma in testicular teratoma

Molecular genetic evidence supporting the neoplastic nature of fibrous stroma in testicular teratoma

FGFR3 and TP53 mutation analysis in inverted urothelial papilloma: incidence and etiological considerations

Hypermethylation of tumor-suppressor gene CpG islands in small-cell carcinoma of the urinary bladder

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