Genome‐wide analysis of DNA copy number alterations and loss of heterozygosity in intracranial germ cell tumors

Terashima, Keita; Yu, Alexander; Chow, Wing Yuk; Hsu, Jim; Chen, Peikai; Wong, Stephen T.C.; Hung, Y. S.; Suzuki, Tomonari; Nishikawa, Ryo; Matsutani, Masao; Nakamura, Hideo; Ng, Ho Keung; Allen, Jeffrey C.; Aldape, Kenneth; Su, Jack M.; Adesina, Adekunle M.; Leung, Hon Chiu Eastwood; Man, Tsz-Kwong; Lau, Ching C.

doi:10.1002/pbc.24833

Cited by 45 publications

(28 citation statements)

References 29 publications

(39 reference statements)

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“…Recent molecular studies of GCT have identified several potential therapeutic targets expressed on individual GCT components . These molecular markers may serve as both prognostic indicators of outcome and therapeutic targets for newly developed targeted therapies.…”

Section: Future Directionsmentioning

confidence: 99%

Critical review of the management of primary central nervous nongerminomatous germ cell tumors

Arja

Bouffet

Finlay

et al. 2019

Pediatric Blood & Cancer

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Multimodal strategies have significantly improved the outcomes for patients with central nervous system nongerminomatous germ cell tumors. Two large cooperative group studies have recently reported much improved outcomes compared with historical series. However, a substantial proportion of patients still attain inadequate responses to initial chemotherapy prior to irradiation, with adverse impact upon survival; optimal induction chemotherapy regimens and radiotherapy strategies are as yet unidentified. Outcomes for patients with relapsed disease remain poor. There is an obvious need to incorporate molecular studies within prospective clinical trials that will likely lead to the incorporation of targeted, more effective future treatment strategies.

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Section: Future Directionsmentioning

confidence: 99%

Critical review of the management of primary central nervous nongerminomatous germ cell tumors

Arja

Bouffet

Finlay

et al. 2019

Pediatric Blood & Cancer

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“…An embryonic cell theory has been proposed for the PIGCTs, which postulates misplacement of embryonic germ cells in the brain due to aberrantly aborted migration of the germ cell precursors during early embryonic development (Teilum, 1965). More recent analyses of various germ cell markers as well as the spectra of tumorigenic defects largely support the notion that gonadal and intracranial GCTs share the origin from germ cell precursors (Hoei-Hansen et al, 2006;Oosterhuis et al, 2007;Rajpert-De Meyts et al, 2003;Terashima et al, 2014). The PIGCTs occur primarily in children and adolescents, and account for approximately 0.5% of malignant pediatric tumors (Gobel et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Patterns of DNA damage response in intracranial germ cell tumors versus glioblastomas reflect cell of origin rather than brain environment: Implications for the anti‐tumor barrier concept and treatment

et al. 2014

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The DNA damage response (DDR) machinery becomes commonly activated in response to oncogenes and during early stages of development of solid malignancies, with an exception of testicular germ cell tumors (TGCTs). The active DDR signaling evokes cell death or senescence but this anti-tumor barrier can be breached by defects in DDR factors, such as the ATM-Chk2-p53 pathway, thereby allowing tumor progression. The DDR barrier is strongly activated in brain tumors, particularly gliomas, due to oxidative damage and replication stress. Here, we took advantage of rare human primary intracranial germ cell tumors (PIGCTs), to address the roles of cell-intrinsic factors including cell of origin, versus local tissue environment, in the constitutive DDR activation in vivo. Immunohistochemical analysis of 7 biomarkers on a series of 21 PIGCTs (germinomas and other subtypes), 20 normal brain specimens and 20 glioblastomas, revealed the following: i) The overall DDR signaling (γH2AX) and activation of the ATM-Chk2-p53 pathway were very low among the PIGCTs, reminiscent of TGCTs, and contrasting sharply with strong DDR activation in glioblastomas; ii) Except for one case of embryonal carcinoma, there were no clear aberrations in the ATM-Chk2-p53 pathway components among the PIGCT cohort; iii) Subsets of PIGCTs showed unusual cytosolic localization of Chk2 and/or ATM. Collectively, these results show that PIGCTs mimic the DDR activation patterns of their gonadal germ cell tumor counterparts, rather than the brain tumors with which they share the tissue environment. Hence cell-intrinsic factors and cell of origin dictate the extent of DDR barrier activation and also the ensuing pressure to select for DDR defects. Our data provide conceptually important insights into the role of DNA damage checkpoints in intracranial tumorigenesis, with implications for the differential biological responses of diverse tumor types to endogenous stress as well as to genotoxic treatments such as ionizing radiation or chemotherapy.

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“…About 10% of germinomas and most NGGCTs remain refractory to multimodality therapy 4 . Previously the biology of these tumors is largely unknown except for gain-of-function mutations of KIT reported in ~25% of pure germinomas 5,6 and a few chromosomal abnormalities revealed by comparative genomic hybridization (CGH) 7–9 . Through an international multicenter collaboration, we have conducted an in-depth analysis of the genetic abnormalities of IGCTs.…”

mentioning

confidence: 99%

Novel somatic and germline mutations in intracranial germ cell tumours

Wang

Yamaguchi

Burstein

et al. 2014

Nature

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186

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Intracranial germ cell tumors (IGCTs) are a group of rare heterogeneous brain tumors which are clinically and histologically similar to the more common gonadal GCTs. IGCTs show great variation in their geographic and gender distribution, histological composition and treatment outcomes. The incidence of IGCTs is historically 5–8 fold greater in Japan and other East Asian countries than in Western countries1 with peak incidence near the time of puberty2. About half of the tumors are located in the pineal region. The male-to-female incidence ratio is approximately 3–4:1 overall but even higher for tumors located in the pineal region3. Due to the scarcity of tumor specimens available for research, little is currently known about this rare disease. Here we report the analysis of 62 cases by next generation sequencing, SNP array and expression array. We find the KIT/RAS signaling pathway frequently mutated in over 50% of IGCTs including novel recurrent somatic mutations in KIT, its downstream mediators KRAS and NRAS, and its negative regulator CBL. Novel somatic alterations in the AKT/mTOR pathway included copy number gain of the AKT1 locus at 14q32.33 in 19% of patients, with corresponding upregulation of AKT1 expression. We identified loss-of-function mutations in BCORL1, a transcriptional corepressor and tumor suppressor. We report significant enrichment of novel and rare germline variants in JMJD1C, a histone demethylase and coactivator of the androgen receptor, among Japanese IGCT patients. This study establishes a molecular foundation for understanding the biology of IGCTs and suggests potentially promising therapeutic strategies focusing on the inhibition of KIT/RAS activation and the AKT1/mTOR pathway.

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Genome‐wide analysis of DNA copy number alterations and loss of heterozygosity in intracranial germ cell tumors

Cited by 45 publications

References 29 publications

Critical review of the management of primary central nervous nongerminomatous germ cell tumors

Critical review of the management of primary central nervous nongerminomatous germ cell tumors

Patterns of DNA damage response in intracranial germ cell tumors versus glioblastomas reflect cell of origin rather than brain environment: Implications for the anti‐tumor barrier concept and treatment

Novel somatic and germline mutations in intracranial germ cell tumours

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