Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Neurology
Published in: BMC Neurology 1/2020

Open Access 01-12-2020 | Research article

Molecular exploration of paediatric intracranial germinomas from multi-ethnic Singapore

Authors: Sharon Yin Yee Low, He Cheng, Ruiyang Zou, Lee Ping Ng, Chik Hong Kuick, Nurfarhanah Bte Syed Sulaiman, Kenneth Tou En Chang, David Chyi Yeu Low, Lihan Zhou, Wan Tew Seow

Published in: BMC Neurology | Issue 1/2020

Login to get access

Abstract

Background

Germinomas (IG) account for up to 50% of all intracranial germ cell tumours. These tumours are reputed to be more prevalent in Oriental populations in comparison to Western cohorts. Biological characteristics of IG in other ethnic groups are unknown. Singapore is a multi-ethnic country with diverse cultures. Owing to inter-racial heterogeneity, the authors hypothesize there are molecular differences between paediatric IG patients in our local population. The aims of this study are exploratory: firstly, to identify molecular characteristics in this tumour type and circulating CSF unique to different racial cohorts; and next, to corroborate our findings with published literature.

Methods

This is a single-institution, retrospective study of prospectively collected data. Inclusion criteria encompass all paediatric patients with histologically confirmed IG. Excess CSF and brain tumour tissues are collected for molecular analysis. Tumour tissues are subjected to a next generation sequencing (NGS) targeted panel for KIT and PDGRA. All CSF samples are profiled via a high-throughput miRNA multiplexed workflow. Results are then corroborated with existing literature and public databases.

Results

In our cohort of 14 patients, there are KIT exon variants in the tumour tissues and CSF miRNAs corroborative with published studies. Separately, there are also KIT exon variants and miRNAs not previously highlighted in IG. A subgroup analysis demonstrates differential CSF miRNAs between Chinese and Malay IG patients.

Conclusion

This is the first in-depth molecular study of a mixed ethnic population of paediatric IGs from a Southeast Asian cohort. Validation studies are required to assess the relevance of novel findings in our study.
Appendix
Available only for authorised users
Literature
1.
Sato K, Takeuchi H, Kubota T. Pathology of intracranial germ cell tumors. Progress in neurological surgery. 2009;23:59–75.PubMedCrossRef
2.
Aker FV, Berkman ZM, Aydingoz I, Hakan T, Toksoy G. Pineal germinoma associated with multiple congenital melanocytic nevi: a unique presentation. Neuropathology. 2005;25(4):336–40.PubMedCrossRef
3.
Report of Brain Tumor Registry of Japan (1984-2000). Neurol Med Chir (Tokyo). 2009;49 Suppl:PS1-96. PMID: 23914398.
4.
Nomura K. Epidemiology of germ cell tumors in Asia of pineal region tumor. J Neuro-Oncol. 2001;54(3):211–7.CrossRef
5.
Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors: natural history and pathogenesis. J Neurosurg. 1985;63(2):155–67.PubMedCrossRef
6.
Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803–20.CrossRefPubMed
7.
Lin IJ, Shu SG, Chu HY, Chi CS. Primary intracranial germ-cell tumor in children. Zhonghua Yi Xue Za Zhi (Taipei). 1997;60(5):259–64.
8.
Matsutani M, Sano K, Takakura K, Fujimaki T, Nakamura O, Funata N, et al. Primary intracranial germ cell tumors: a clinical analysis of 153 histologically verified cases. J Neurosurg. 1997;86(3):446–55.PubMedCrossRef
9.
Huang X, Zhang R, Mao Y, Zhou LF, Zhang C. Recent advances in molecular biology and treatment strategies for intracranial germ cell tumors. World J Pediatr. 2016;12(3):275–82.PubMedCrossRef
10.
Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, Dull TJ, et al. Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J. 1987;6(11):3341–51.PubMedPubMedCentralCrossRef
11.
Murray MJ, Nicholson JC, Coleman N. Biology of childhood germ cell tumours, focussing on the significance of microRNAs. Andrology. 2015;3(1):129–39.PubMedCrossRef
12.
Wang L, Yamaguchi S, Burstein MD, Terashima K, Chang K, Ng HK, et al. Novel somatic and germline mutations in intracranial germ cell tumours. Nature. 2014;511(7508):241–5.PubMedPubMedCentralCrossRef
13.
Murray MJ, Bell E, Raby KL, Rijlaarsdam MA, Gillis AJ, Looijenga LH, et al. A pipeline to quantify serum and cerebrospinal fluid microRNAs for diagnosis and detection of relapse in paediatric malignant germ-cell tumours. Br J Cancer. 2016;114(2):151–62.PubMedCrossRef
14.
Matsutani M. Japanese pediatric brain tumor study G. combined chemotherapy and radiation therapy for CNS germ cell tumors--the Japanese experience. J Neuro-Oncol. 2001;54(3):311–6.CrossRef
15.
Chen YW, Huang PI, Hu YW, Ho DM, Chang KP, Guo WY, et al. Treatment strategies for initially disseminated intracranial germinomas: experiences at a single institute. Childs Nerv Syst. 2012;28(4):557–63.PubMedCrossRef
16.
Phua J, Kee AC, Tan A, Mukhopadhyay A, See KC, Aung NW, et al. End-of-life care in the general wards of a Singaporean hospital: an Asian perspective. J Palliat Med. 2011;14(12):1296–301.PubMedCrossRef
17.
18.
Wong LL, Zou R, Zhou L, Lim JY, Phua DCY, Liu C, et al. Combining circulating MicroRNA and NT-proBNP to detect and categorize heart failure subtypes. J Am Coll Cardiol. 2019;73(11):1300–13.PubMedCrossRef
19.
Saw WY, Tantoso E, Begum H, Zhou L, Zou R, He C, et al. Establishing multiple omics baselines for three southeast Asian populations in the Singapore integrative Omics study. Nat Commun. 2017;8(1):653.PubMedPubMedCentralCrossRef
20.
Ying L, Du L, Zou R, Shi L, Zhang N, Jin J, et al. Development of a serum miRNA panel for detection of early stage non-small cell lung cancer. Proc Natl Acad Sci U S A. 2020;117(40):25036–42.PubMedCrossRefPubMedCentral
21.
Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I. Controlling the false discovery rate in behavior genetics research. Behav Brain Res. 2001;125(1–2):279–84.PubMedCrossRef
22.
Benjamini Y, Yekutieli D. The control of the false discovery rate in multiple testing under dependency. Ann Stat. 2001;29:1165–88.CrossRef
23.
Wang HW, Wu YH, Hsieh JY, Liang ML, Chao ME, Liu DJ, et al. Pediatric primary central nervous system germ cell tumors of different prognosis groups show characteristic miRNome traits and chromosome copy number variations. BMC Genomics. 2010;11:132.PubMedPubMedCentralCrossRef
24.
Spiegel AM, Di Chiro G, Gorden P, Ommaya AK, Kolins J, Pomeroy TC. Diagnosis of radiosensitive hypothalamic tumors without craniotomy: endocrine and neuroradiologic studies of intracranial atypical teratomas. Ann Intern Med. 1976;85(3):290–3.PubMedCrossRef
25.
Inoue Y, Takeuchi T, Tamaki M, Nin K, Hakuba A, Nishimura S. Sequential CT observations of irradiated intracranial germinomas. AJR Am J Roentgenol. 1979;132(3):361–5.PubMedCrossRef
26.
27.
Ono M, Ono M, Rhoton AL Jr, Barry M. Microsurgical anatomy of the region of the tentorial incisura. J Neurosurg. 1984;60(2):365–99.PubMedCrossRef
28.
Shinoda J, Sakai N, Yano H, Hattori T, Ohkuma A, Sakaguchi H. Prognostic factors and therapeutic problems of primary intracranial choriocarcinoma/germ-cell tumors with high levels of HCG. J Neuro-Oncol. 2004;66(1–2):225–40.CrossRef
29.
Vaquero J, Martinez R, Manrique M. Stereotactic biopsy for brain tumors: is it always necessary? Surg Neurol. 2000;53(5):432–7 discussion 7-8.PubMedCrossRef
30.
Lindsay H, Huang Y, Du Y, Braun FK, Teo WY, Kogiso M, et al. Preservation of KIT genotype in a novel pair of patient-derived orthotopic xenograft mouse models of metastatic pediatric CNS germinoma. J Neuro-Oncol. 2016;128(1):47–56.CrossRef
31.
Kim JY, Park J. Understanding the treatment strategies of intracranial germ cell tumors: focusing on radiotherapy. J Korean Neurosurg Soc. 2015;57(5):315–22.PubMedPubMedCentralCrossRef
32.
33.
Poynter JN, Fonstad R, Tolar J, Spector LG, Ross JA. Incidence of intracranial germ cell tumors by race in the United States, 1992-2010. J Neuro-Oncol. 2014;120(2):381–8.CrossRef
34.
Bhoo-Pathy N, Hartman M, Yip CH, Saxena N, Taib NA, Lim SE, et al. Ethnic differences in survival after breast cancer in South East Asia. PLoS One. 2012;7(2):e30995.PubMedPubMedCentralCrossRef
35.
36.
Wang H, Seow A, Lee HP. Trends in cancer incidence among Singapore Malays: a low-risk population. Ann Acad Med Singap. 2004;33(1):57–62.PubMed
37.
Cheo ST, Lim GH, Lim KH. Glioblastoma multiforme outcomes of 107 patients treated in two Singapore institutions. Singap Med J. 2017;58(1):41–5.CrossRef
38.
Chiang PP, Lamoureux EL, Cheung CY, Sabanayagam C, Wong W, Tai ES, et al. Racial differences in the prevalence of diabetes but not diabetic retinopathy in a multi-ethnic Asian population. Invest Ophthalmol Vis Sci. 2011;52(10):7586–92.PubMedCrossRef
39.
Kurtz JE, Asmane I, Voegeli AC, Neuville A, Dufresne A, Litique V, et al. A V530I mutation in c-KIT exon 10 is associated to Imatinib response in Extraabdominal aggressive Fibromatosis. Sarcoma. 2010;2010:458156.PubMedPubMedCentralCrossRef
40.
Yim E, An HJ, Cho U, Kim Y, Kim SH, Choi YG, et al. Two different KIT mutations may lead to different responses to imatinib in metastatic gastrointestinal stromal tumor. Korean J Intern Med. 2018;33(2):432–4.PubMedCrossRef
41.
Strohmeyer T, Reese D, Press M, Ackermann R, Hartmann M, Slamon D. Expression of the c-kit proto-oncogene and its ligand stem cell factor (SCF) in normal and malignant human testicular tissue. J Urol. 1995;153(2):511–5.PubMedCrossRef
42.
Goddard NC, McIntyre A, Summersgill B, Gilbert D, Kitazawa S, Shipley J. KIT and RAS signalling pathways in testicular germ cell tumours: new data and a review of the literature. Int J Androl. 2007;30(4):337–48 discussion 49.PubMedCrossRef
43.
Ichimura K, Fukushima S, Totoki Y, Matsushita Y, Otsuka A, Tomiyama A, et al. Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy. Acta Neuropathol. 2016;131(6):889–901.PubMedCrossRef
44.
Fukushima S, Otsuka A, Suzuki T, Yanagisawa T, Mishima K, Mukasa A, et al. Mutually exclusive mutations of KIT and RAS are associated with KIT mRNA expression and chromosomal instability in primary intracranial pure germinomas. Acta Neuropathol. 2014;127(6):911–25.PubMedCrossRef
45.
Kamakura Y, Hasegawa M, Minamoto T, Yamashita J, Fujisawa H. C-kit gene mutation: common and widely distributed in intracranial germinomas. J Neurosurg. 2006;104(3 Suppl):173–80.PubMed
46.
Sakuma Y, Sakurai S, Oguni S, Satoh M, Hironaka M, Saito K. C-kit gene mutations in intracranial germinomas. Cancer Sci. 2004;95(9):716–20.PubMedCrossRef
47.
Bruno A, Boisselier B, Labreche K, Marie Y, Polivka M, Jouvet A, et al. Mutational analysis of primary central nervous system lymphoma. Oncotarget. 2014;5(13):5065–75.PubMedPubMedCentralCrossRef
48.
Lee JY, Park K, Lim SH, Kim HS, Yoo KH, Jung KS, et al. Mutational profiling of brain metastasis from breast cancer: matched pair analysis of targeted sequencing between brain metastasis and primary breast cancer. Oncotarget. 2015;6(41):43731–42.PubMedPubMedCentralCrossRef
49.
Wang Y, Springer S, Zhang M, McMahon KW, Kinde I, Dobbyn L, et al. Detection of tumor-derived DNA in cerebrospinal fluid of patients with primary tumors of the brain and spinal cord. Proc Natl Acad Sci U S A. 2015;112(31):9704–9.PubMedPubMedCentralCrossRef
50.
Seoane J, De Mattos-Arruda L, Le Rhun E, Bardelli A, Weller M. Cerebrospinal fluid cell-free tumour DNA as a liquid biopsy for primary brain tumours and central nervous system metastases. Ann Oncol. 2019;30(2):211–8.PubMedCrossRef
51.
Xiao F, Lv S, Zong Z, Wu L, Tang X, Kuang W, et al. Cerebrospinal fluid biomarkers for brain tumor detection: clinical roles and current progress. Am J Transl Res. 2020;12(4):1379–96.PubMedPubMedCentral
52.
McEwen AE, Leary SES, Lockwood CM. Beyond the blood: CSF-derived cfDNA for diagnosis and characterization of CNS tumors. Front Cell Dev Biol. 2020;8:45.PubMedPubMedCentralCrossRef
53.
Watanabe M, Kawaguchi T, Isa S, Ando M, Tamiya A, Kubo A, et al. Ultra-sensitive detection of the pretreatment EGFR T790M mutation in non-small cell lung Cancer patients with an EGFR-activating mutation using droplet digital PCR. Clin Cancer Res. 2015;21(15):3552–60.PubMedCrossRef
54.
Lynam-Lennon N, Maher SG, Reynolds JV. The roles of microRNA in cancer and apoptosis. Biol Rev Camb Philos Soc. 2009;84(1):55–71.PubMedCrossRef
55.
56.
Gonzalez-Gomez P, Sanchez P, Mira H. MicroRNAs as regulators of neural stem cell-related pathways in glioblastoma multiforme. Mol Neurobiol. 2011;44(3):235–49.PubMedCrossRef
57.
58.
Yang W, Lee DY, Ben-David Y. The roles of microRNAs in tumorigenesis and angiogenesis. Int J Physiol Pathophysiol Pharmacol. 2011;3(2):140–55.PubMed
59.
Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 2008;18(10):997–1006.PubMedCrossRef
60.
Adlakha YK, Saini N. Brain microRNAs and insights into biological functions and therapeutic potential of brain enriched miRNA-128. Mol Cancer. 2014;13:33.PubMedPubMedCentralCrossRef
61.
Knutsen E, Fiskaa T, Ursvik A, Jorgensen TE, Perander M, Lund E, et al. Performance comparison of digital microRNA profiling technologies applied on human breast Cancer cell lines. PLoS One. 2013;8(10):e75813.PubMedPubMedCentralCrossRef
62.
Schmittgen TD, Lee EJ, Jiang J, Sarkar A, Yang L, Elton TS, et al. Real-time PCR quantification of precursor and mature microRNA. Methods. 2008;44(1):31–8.PubMedPubMedCentralCrossRef
63.
Kang K, Peng X, Luo J, Gou D. Identification of circulating miRNA biomarkers based on global quantitative real-time PCR profiling. J Animal Sci Biotechnology. 2012;3(1):4.CrossRef
64.
Wan G, Lim QE, Too HP. High-performance quantification of mature microRNAs by real-time RT-PCR using deoxyuridine-incorporated oligonucleotides and hemi-nested primers. Rna. 2010;16(7):1436–45.PubMedPubMedCentralCrossRef
Metadata
Title
Molecular exploration of paediatric intracranial germinomas from multi-ethnic Singapore
Authors
Sharon Yin Yee Low
He Cheng
Ruiyang Zou
Lee Ping Ng
Chik Hong Kuick
Nurfarhanah Bte Syed Sulaiman
Kenneth Tou En Chang
David Chyi Yeu Low
Lihan Zhou
Wan Tew Seow
Publication date
01-12-2020
Publisher
BioMed Central
Published in
BMC Neurology / Issue 1/2020
Electronic ISSN: 1471-2377
DOI
https://doi.org/10.1186/s12883-020-01981-0

Other articles of this Issue 1/2020

BMC Neurology 1/2020 Go to the issue

Case report

Stanford type a aortic dissection with cerebral infarction: a rare case report

Research Article

Machine learning analysis of motor evoked potential time series to predict disability progression in multiple sclerosis

Research article

The Filum disease and the Neuro-Cranio-vertebral syndrome: definition, clinical picture and imaging features

Research article

Characteristics of acute ischemic stroke in hospitalized patients in Tibet: a retrospective comparative study

Research article

T2 mapping of molecular subtypes of WHO grade II/III gliomas

Case report

Neurolisteriosis in a previously asymptomatic patient with serum IgM deficiency: a case report