eISSN: 1897-4309
ISSN: 1428-2526
Contemporary Oncology/Współczesna Onkologia
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vol. 21
Original paper

Comparative genomic analysis of intracranial germ cell tumors – the preliminary study focused on Sonic Hedgehog signaling pathway

Dominika Kuleszo, Magdalena Koczkowska, Beata S. Lipska-Ziętkiewicz, Wiesława Grajkowska, Elżbieta Adamkiewicz-Drożyńska, Bożenna Dembowska-Bagińska, Maciej Ciołkowski, Ewa Iżycka-Świeszewska

Contemp Oncol (Pozn) 2017; 21 (4): 279-284
Online publish date: 2017/12/30
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Aim of the study: Examination of copy number changes in a group of intracranial germ cell tumors (GCTs) with particular focus on putative aberrations of the main genes coding SHh pathway proteins.

Material and methods: The study was performed on DNA isolated from fresh-frozen tumor tissue samples from eight GCTs, including six intracranial GCTs. The intracranial group consisted of three germinomas, two mature teratomas and one mixed germ cell tumor. Comparative genomic profiling analysis was carried out using microarray-CGH method (Cytosure ISCA UPD 4×180k, OGT). The results were analyzed with Feature Extraction (Agilent Technologies) and Nexus Copy Number (BioDiscovery) softwares.

Results and conclusions: Chromosomal aberrations were found in two intracranial germinomas. These tumors were characterized by complex genomic profiles encompassing chromosomes 7, 8, 9, 10, 11, 12, 16, 17 and 19. Common findings were gain at 12p13.33p11.1 of 35 Mbp and gain at 17q11.1q25.3 of 55 Mbp. In one tumor, also SHh (7q36.3), SMO (7q32.1) and GLI3 (7p14.1) copy gains occurred together with 9q21.11q34.3 loss, including PTCH1, all being elements of SHh signaling pathway. Moreover, both tumors showed various copy gain of genes being ligands, regulators, receptors or target genes of SHh (MTSS1; PRKACA and FKBP8) as well as gain of genes of SHh coopting WNT pathway (WNT3, WNT5B, WNT9B in both tumors; WNT16, WNT2 in pineal lesion). Further studies on larger group are needed to characterize SHh-related gene alterations in intracranial GCTs and for searching genotype-phenotype relations.

intracranial germ cell tumors, germinoma, array-CGH, Sonic Hed­ge­hog signaling

Horton Z, Schlatter M, Schultz S. Pediatric germ cell tumors. Surg Oncol 2007; 16: 205-13.
Echevarría ME, Fangusaro J, Goldman S. Pediatric central nervous system germ cell tumors: a review. Oncologist 2008; 13: 690-9.
Ruiz I Altaba A, Stecca B, Sánchez P. Hedgehog-Gli signaling in brain tumors: stem cells and paradevelopmental programs in cancer. Cancer Lett 2004; 20: 145-57.
Richardson BE, Lehmann R. Mechanisms guiding primordial germ cell migration: strategies from different organisms. Nat Rev Mol Cell Biol 2010; 11: 37-49.
Cohen M, Kicheva A, Ribeiro A, Blassberg R, Page KM, Barnes CP, Briscoe J. Ptch1 and Gli regulate Shh signaling dynamics via multiple mechanisms. Nature Com 2015. 2015; 6:6709.
Shagufta TM, Awatif J. Primary intracranial germ cell tumors. Asian J Neurosurg 2012; 7: 197-202.
Okada Y, Nishikawa R, Matsutani M, Louis DN. Hypomethylated X chromosome gain and rare isochromosome 12p in diverse intracranial germ cell tumors. J Neuropathol Exp Neurol 2002; 61: 531-8.
Schneider DT, Zahn S, Sievers S, et al. Molecular genetic analysis of central nervous system germ cell tumors with comparative genomic hybridization. Mod Pathol 2006; 19: 864-73.
Terashima K, Yu A, Chow W, et al. Genome-wide analysis of DNA copy number alterations and loss of heterozygosity in intracranial germ cell tumors. Pediatr Blood Cancer 2014; 61: 593-600.
Fukushima S, Yamashita S, Kobayashi H, et al. Genome-wide methylation profiles in primary intracranial germ cell tumors indicate a primordial germ cell origin for germinomas. Acta Neuropathol 2017; 133: 445-62.
Iwato M, Tachibana O, Tohma Y, Arakawa Y, Nitta H, Hasegawa M, Yamashita J, Hayashi Y. Alterations of the INK4a/ARF locus in human intracranial germ cell tumors. Cancer Res 2000; 60: 2113-5.
Sakuma Y, Sakurai S, Oguni S, Satoh M, Hironaka M, Saito K. C-kit gene mutations in intracranial germinomas. Cancer Sci 2004; 95: 716-20.
Guo X, Wang XF. Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Res 2009; 19: 71-88.
Petrova R, Joyner AL. Roles for Hedgehog signaling in adult organ homeostasis and repair. Development 2014; 141: 3445-57.
Daya-Grosjean L, Couvé-Privat S. Sonic hedgehog signaling in basal cell carcinomas. Cancer Lett 2005; 225: 181-92.
Briscoe J, Thérond PP. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol 2013; 14: 416-29.
Lum L, Beachy PA. The Hedgehog response network: sensors, switches, and routers. Science 2004; 304: 1755-9.
Taipale J, Beachy PA. The Hedgehog and Wnt signalling pathways in cancer. Nature 2001; 411: 349-54.
Zhou X, Qiu W, Sathirapongsasuti JF, et al. Gene expression analysis uncovers novel hedgehog interacting protein (HHIP) effects in human bronchial epithelial cells. Genomics 2013; 101: 263-72.
Zhu H, Lo HW. The Human Glioma-Associated Oncogene Homolog 1 (GLI1) Family of Transcription Factors in Gene Regulation and Diseases. Curr Genomics 2010; 11: 238-45.
Milla LA, González-Ramírez CN, Palma V. Sonic Hedgehog in cancer stem cells: a novel link with autophagy. Biol Res 2012; 45: 223-30.
Katoh Y, Katoh M. Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation. Curr Mol Med 2009; 9: 873-86.
Xie J, Bartels CM, Barton SW, Gu D. Targeting hedgehog signaling in cancer: research and clinical developments. Onco Targets Ther 2013; 6: 1425-35.
Aszterbaum M, Rothman A, Johnson RL, et al. Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. J Invest Dermatol 1998; 110: 885-8.
Murray MJ, Nicholson JC. Germ cell tumours in children and adolescents. Paediatrics and Child Health 2009; 20: 109-16.
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 1215.
MacDonald JR, Ziman R, Yuen RK, Feuk L, Scherer SW. The database of genomic variants: a curated collection of structural variation in the human genome. Nucleic Acids Res 2014; 42(Database issue): D986-92.
Forbes SA, Beare D, Boutselakis H. COSMIC: somatic cancer genetics at high-resolution. Nucleic Acids Res 2017; 45 (D1): D777-83.
Liu H, Gu D, Xie J. Clinical implications of hedgehog signaling pathway inhibitors. Chin J Cancer 2011; 30: 13-26.
Lin TL, Matsui W. Hedgehog pathway as a drug target: Smoothened inhibitors in development. Onco Targets Ther 2012; 5: 47-58.
Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, Scott MP, Beachy PA. Effects of oncogenic mutations in smoothened and patched can be reversed by cyclopamine. Nature 2000; 406: 1005-9.
Litchfield K, Levy M, Huddart RA, Shipley J, Turnbull C. The genomic landscape of testicular germ cell tumours: from susceptibility to treatment. Nat Rev Urol 2016; 13: 409-19.
Sheikine Y, Genega E, Melamed J, Lee P, Reuter VE, Ye H. Molecular genetics of testicular germ cell tumors. Am J Cancer Res 2012; 2: 153-67.
Dessen P, Huret JL. Chromosomal band 17q. Atlas Genet Cytogenet Oncol Haematol. July 2012.
Dimova I, Orsetti B, Negre V, et al. Genomic markers for ovarian cancer at chromosomes 1, 8 and 17 revealed by array CGH analysis. Tumori 2009; 95: 357-66.
Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002; 20: 719-26.
Shimkets R, Gailani MR, Siu VM, et al. Molecular analysis of chromosome 9q deletions in two Gorlin syndrome patients. Am J Hum Genet 1996; 59: 417-22.
Firth HV, Richards SM, Bevan AP. Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Am J Hum Genet 2009; 84: 524-33.
Callahan CA, Ofstad T, Horng L, Wang JK, Zhen HH, Coulombe PA, Oro AE. MIM/BEG4, a Sonic hedgehog-responsive gene that potentiates Gli-dependent transcription. Genes Dev 2004; 18: 2724-9.
Jia J, Tong C, Wang B, Luo L, Jiang J. Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I. Nature 2004; 432: 1045-50.
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