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

Liu, Cheng; Zhang, Shaobo; Eble, John N.; Beck, Stephen D.W.; Foster, Richard S.; Wang, Mingsheng; Ulbright, Thomas M.

doi:10.1038/modpathol.2012.99

Cited by 25 publications

(13 citation statements)

References 41 publications

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“…This leads us to assume that amplification of 12p seems to play an important role in germinomas. In the last years, several reports already highlighted the importance of chromosome 12p in testicular GCTs, especially of amplification at 12p11.2-p12.1 [28] and describing it as a genetic hallmark of germ cell tumors [29]. Our results strongly confirm these findings for germinomas.…”

Section: Discussionsupporting

confidence: 89%

CNS germinomas are characterized by global demethylation, chromosomal instability and mutational activation of the Kit-, Ras/Raf/Erk- and Akt-pathways

et al. 2016

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CNS germinomas represent a unique germ cell tumor entity characterized by undifferentiated tumor cells and a high response rate to current treatment protocols. Limited information is available on their underlying genomic, epigenetic and biological alterations. We performed a genome-wide analysis of genomic copy number alterations in 49 CNS germinomas by molecular inversion profiling. In addition, CpG dinucleotide methylation was studied by immunohistochemistry for methylated cytosine residues. Mutational analysis was performed by resequencing of candidate genes including KIT and RAS family members. Ras/Erk and Akt pathway activation was analyzed by immunostaining with antibodies against phospho-Erk, phosho-Akt, phospho-mTOR and phospho-S6. All germinomas coexpressed Oct4 and Kit but showed an extensive global DNA demethylation compared to other tumors and normal tissues. Molecular inversion profiling showed predominant genomic instability in all tumors with a high frequency of regional gains and losses including high level gene amplifications. Activating mutations of KIT exons 11, 13, and 17 as well as a case with genomic KIT amplification and activating mutations or amplifications of RAS gene family members including KRAS, NRAS and RRAS2 indicated mutational activation of crucial signaling pathways. Co-activation of Ras/Erk and Akt pathways was present in 83% of germinomas. These data suggest that CNS germinoma cells display a demethylated nuclear DNA similar to primordial germ cells in early development. This finding has a striking coincidence with extensive genomic instability. In addition, mutational activation of Kit-, Ras/Raf/Erk- and Akt- pathways indicate the biological importance of these pathways and their components as potential targets for therapy.

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Section: Discussionsupporting

confidence: 89%

CNS germinomas are characterized by global demethylation, chromosomal instability and mutational activation of the Kit-, Ras/Raf/Erk- and Akt-pathways

et al. 2016

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“…22 Although low case numbers precluded a definite analysis, patients with i12p appeared to do poorly with higher likelihood of incomplete response to therapy, recurrence or death than the counterparts without the chromosomal aberration. The authors of that work and other studies 23,24 indicate the presence of i12p as a hallmark finding diagnostic of midline germ cell tumors and i12p positivity as a factor in carcinogenesis, including the evolving understanding of the stroma 23 and invasive growth. 24 In addition, testicular teratomas can metastize to the sacrum and retroperitoneum, whereas primary testicular sites can regress or involute.…”

Section: Discussionmentioning

confidence: 93%

Sacrococcygeal teratomas: clinico-pathological characteristics and isochromosome 12p status

et al. 2014

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The biological behavior of teratomas is highly variable, and morphologic features alone are insufficient to predict their clinical course. Prognostic factors that influence behavior include the following: patient sex, age, anatomic site, coincident neoplasm, and cytogenetic abnormalities. Gonadal teratomas have been wellcharacterized; postpubertal testicular teratomas are commonly associated with isochromosome 12p (i12p) and considered to nearly always carry a potential for malignant behavior, whereas ovarian and prepubertal testicular teratomas are i12p negative and predominantly benign in behavior. For extragonadal sites, such as sacrum and coccyx, clinical characteristics and i12p status are yet to be adequately characterized. As part of this study, we identified 19 sacrococcygeal teratomas in our surgical pathology archives from 1990 to 2012. Clinical records and slides were reviewed to confirm the original diagnosis. Gains in chromosome 12p, including i12p status were assessed in representative paraffin sections by fluorescence in situ hybridization. Our cases included 16 mature sacrococcygeal teratomas (11 prepubertal and 5 postpubertal) and three immature saccrococygeal teratomas (all prepubertal). Among mature teratomas, the average tumor size was larger in adults compared with prepubertal patients. A higher number of adult cases were recurrences (80% vs 21%), but only pediatric recurrences were managed with postoperative chemotherapy. All examined tumors were negative for i12p. 100% survival was documented in our cohort with a median follow-up of 6 years. We present a large series of sacrococcygeal teratomas and the first series to examine postpubertal adults at this anatomic site. All tumors lacked chromosome 12p gains, including i12p. Both pre-and postpubertal sacrococcygeal teratomas had a favorable outcome regardless of age or sex.

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“…A specific chromosome change, isochromosome 12p, is observed in 86% of germ cell tumors and all of their histologic components . Similarly, it has been demonstrated that the molecular profiles of the various histologic components, primary and metastatic tumors, stromal and epithelial compartments, and teratomatous and somatically transformed constituents are highly concordant . Because the various histologic components of NSGCT have a similar genetic signature, the discovery of a specific driver mutation in a particular NSGCT subtype seems both rational and feasible.…”

Section: Introductionmentioning

confidence: 99%

Intratumoral heterogeneity: Role of differentiation in a potentially lethal phenotype of testicular cancer

Bilen

Hess

et al. 2016

Cancer

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BACKGROUNDIntratumoral heterogeneity presents a major obstacle to the widespread implementation of precision medicine. The authors assessed the origin of intratumoral heterogeneity in nonseminomatous germ cell tumor of the testis (NSGCT) and identified distinct tumor subtypes and a potentially lethal phenotype.METHODSIn this retrospective study, all consecutive patients who had been diagnosed with an NSGCT between January 2000 and December 2010 were evaluated. The histologic makeup of primary tumors and the clinical course of disease were determined for each patient. A Fine and Gray proportional hazards regression analysis was used to determine the prognostic risk factors, and the Gray test was used to detect differences in the cumulative incidence of cancer death. In a separate prospective study, next‐generation sequencing was performed on tumor samples from 9 patients to identify any actionable mutations.RESULTSSix hundred fifteen patients were included in this study. Multivariate analysis revealed that the presence of yolk sac tumor in the primary tumor (P = .0003) was associated with an unfavorable prognosis. NSGCT could be divided into 5 subgroups. Patients in the yolk sac‐seminoma subgroup had the poorest clinical outcome (P = .0015). These tumors tended to undergo somatic transformation (P < .0001). Among the 9 NSGCTs that had a yolk sac tumor phenotype, no consistent gene mutation was detected.CONCLUSIONSThe current data suggest that intratumoral heterogeneity is caused in part by differentiation of pluripotent progenitor cells. Integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of NSGCT. Cancer 2016;122:1836–43. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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

Cited by 25 publications

References 41 publications

CNS germinomas are characterized by global demethylation, chromosomal instability and mutational activation of the Kit-, Ras/Raf/Erk- and Akt-pathways

CNS germinomas are characterized by global demethylation, chromosomal instability and mutational activation of the Kit-, Ras/Raf/Erk- and Akt-pathways

Sacrococcygeal teratomas: clinico-pathological characteristics and isochromosome 12p status

Intratumoral heterogeneity: Role of differentiation in a potentially lethal phenotype of testicular cancer

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