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BMC Cancer
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

DNA methylation analysis reveals distinct methylation signatures in pediatric germ cell tumors

Authors: James F Amatruda, Julie A Ross, Brock Christensen, Nicholas J Fustino, Kenneth S Chen, Anthony J Hooten, Heather Nelson, Jacquelyn K Kuriger, Dinesh Rakheja, A Lindsay Frazier, Jenny N Poynter

Published in: BMC Cancer | Issue 1/2013

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Abstract

Background

Aberrant DNA methylation is a prominent feature of many cancers, and may be especially relevant in germ cell tumors (GCTs) due to the extensive epigenetic reprogramming that occurs in the germ line during normal development.

Methods

We used the Illumina GoldenGate Cancer Methylation Panel to compare DNA methylation in the three main histologic subtypes of pediatric GCTs (germinoma, teratoma and yolk sac tumor (YST); N = 51) and used recursively partitioned mixture models (RPMM) to test associations between methylation pattern and tumor and demographic characteristics. We identified genes and pathways that were differentially methylated using generalized linear models and Ingenuity Pathway Analysis. We also measured global DNA methylation at LINE1 elements and evaluated methylation at selected imprinted loci using pyrosequencing.

Results

Methylation patterns differed by tumor histology, with 18/19 YSTs forming a distinct methylation class. Four pathways showed significant enrichment for YSTs, including a human embryonic stem cell pluripotency pathway. We identified 190 CpG loci with significant methylation differences in mature and immature teratomas (q < 0.05), including a number of CpGs in stem cell and pluripotency-related pathways. Both YST and germinoma showed significantly lower methylation at LINE1 elements compared with normal adjacent tissue while there was no difference between teratoma (mature and immature) and normal tissue. DNA methylation at imprinted loci differed significantly by tumor histology and location.

Conclusion

Understanding methylation patterns may identify the developmental stage at which the GCT arose and the at-risk period when environmental exposures could be most harmful. Further, identification of relevant genetic pathways could lead to the development of new targets for therapy.
Appendix
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Literature
1.
Smiraglia DJ, Szymanska J, Kraggerud SM, Lothe RA, Peltomaki P, Plass C: Distinct epigenetic phenotypes in seminomatous and nonseminomatous testicular germ cell tumors. Oncogene. 2002, 21 (24): 3909-3916. 10.1038/sj.onc.1205488.CrossRefPubMed
2.
Netto GJ, Nakai Y, Nakayama M, Jadallah S, Toubaji A, Nonomura N, Albadine R, Hicks JL, Epstein JI, Yegnasubramanian S, et al: Global DNA hypomethylation in intratubular germ cell neoplasia and seminoma, but not in nonseminomatous male germ cell tumors. Mod Pathol. 2008, 21 (11): 1337-1344. 10.1038/modpathol.2008.127.CrossRefPubMedPubMedCentral
3.
Bussey KJ, Lawce HJ, Himoe E, Shu XO, Heerema NA, Perlman EJ, Olson SB, Magenis RE: SNRPN methylation patterns in germ cell tumors as a reflection of primordial germ cell development. Genes Chromosomes Cancer. 2001, 32 (4): 342-352. 10.1002/gcc.1199.CrossRefPubMed
4.
Wermann H, Stoop H, Gillis AJ, Honecker F, Van Gurp RJ, Ammerpohl O, Richter J, Oosterhuis JW, Bokemeyer C, Looijenga LH: Global DNA methylation in fetal human germ cells and germ cell tumours: association with differentiation and cisplatin resistance. J Pathol. 2010, 221 (4): 433-442.PubMed
5.
Furukawa S, Haruta M, Arai Y, Honda S, Ohshima J, Sugawara W, Kageyama Y, Higashi Y, Nishida K, Tsunematsu Y, et al: Yolk sac tumor but not seminoma or teratoma is associated with abnormal epigenetic reprogramming pathway and shows frequent hypermethylation of various tumor suppressor genes. Cancer Sci. 2009, 100 (4): 698-708. 10.1111/j.1349-7006.2009.01102.x.CrossRefPubMed
6.
Kato N, Shibuya H, Fukase M, Tamura G, Motoyama T: Involvement of adenomatous polyposis coli (APC) gene in testicular yolk sac tumor of infants. Hum Pathol. 2006, 37 (1): 48-53. 10.1016/j.humpath.2005.09.008.CrossRefPubMed
7.
Kato N, Tamura G, Fukase M, Shibuya H, Motoyama T: Hypermethylation of the RUNX3 gene promoter in testicular yolk sac tumor of infants. Am J Pathol. 2003, 163 (2): 387-391. 10.1016/S0002-9440(10)63668-1.CrossRefPubMedPubMedCentral
8.
Rathi A, Virmani AK, Harada K, Timmons CF, Miyajima K, Hay RJ, Mastrangelo D, Maitra A, Tomlinson GE, Gazdar AF: Aberrant methylation of the HIC1 promoter is a frequent event in specific pediatric neoplasms. Clin Cancer Res. 2003, 9 (10 Pt 1): 3674-3678.PubMed
9.
Jeyapalan JN, Noor DA, Lee SH, Tan CL, Appleby VA, Kilday JP, Palmer RD, Schwalbe EC, Clifford SC, Walker DA, et al: Methylator phenotype of malignant germ cell tumours in children identifies strong candidates for chemotherapy resistance. Br J Cancer. 2011, 105 (4): 575-585. 10.1038/bjc.2011.218.CrossRefPubMedPubMedCentral
10.
Schneider DT, Schuster AE, Fritsch MK, Hu J, Olson T, Lauer S, Gobel U, Perlman EJ: Multipoint imprinting analysis indicates a common precursor cell for gonadal and nongonadal pediatric germ cell tumors. Cancer Res. 2001, 61 (19): 7268-7276.PubMed
11.
Sievers S, Alemazkour K, Zahn S, Perlman EJ, Gillis AJ, Looijenga LH, Gobel U, Schneider DT: IGF2/H19 imprinting analysis of human germ cell tumors (GCTs) using the methylation-sensitive single-nucleotide primer extension method reflects the origin of GCTs in different stages of primordial germ cell development. Genes Chromosomes Cancer. 2005, 44 (3): 256-264. 10.1002/gcc.20237.CrossRefPubMed
12.
Kawakami T, Zhang C, Okada Y, Okamoto K: Erasure of methylation imprint at the promoter and CTCF-binding site upstream of H19 in human testicular germ cell tumors of adolescents indicate their fetal germ cell origin. Oncogene. 2006, 25 (23): 3225-3236. 10.1038/sj.onc.1209362.CrossRefPubMed
13.
Gobel U, Schneider DT, Calaminus G, Haas RJ, Schmidt P, Harms D: Germ-cell tumors in childhood and adolescence. GPOH MAKEI and the MAHO study groups. Ann Oncol. 2000, 11 (3): 263-271. 10.1023/A:1008360523160.CrossRefPubMed
14.
Norris HJ, Zirkin HJ, Benson WL: Immature (malignant) teratoma of the ovary: a clinical and pathologic study of 58 cases. Cancer. 1976, 37 (5): 2359-2372. 10.1002/1097-0142(197605)37:5<2359::AID-CNCR2820370528>3.0.CO;2-Q.CrossRefPubMed
15.
Ulbright TM: Gonadal teratomas: a review and speculation. Adv Anat Pathol. 2004, 11 (1): 10-23. 10.1097/00125480-200401000-00002.CrossRefPubMed
16.
Epelman M, Chikwava KR, Chauvin N, Servaes S: Imaging of pediatric ovarian neoplasms. Pediatr Radiol. 2011, 41 (9): 1085-1099. 10.1007/s00247-011-2128-x.CrossRefPubMed
17.
Park SB, Cho KS, Kim JK: CT findings of mature cystic teratoma with malignant transformation: comparison with mature cystic teratoma. Clin Imaging. 2011, 35 (4): 294-300. 10.1016/j.clinimag.2010.08.016.CrossRefPubMed
18.
Bibikova M, Lin Z, Zhou L, Chudin E, Garcia EW, Wu B, Doucet D, Thomas NJ, Wang Y, Vollmer E, et al: High-throughput DNA methylation profiling using universal bead arrays. Genome Res. 2006, 16 (3): 383-393. 10.1101/gr.4410706.CrossRefPubMedPubMedCentral
19.
Woodfine K, Huddleston JE, Murrell A: Quantitative analysis of DNA methylation at all human imprinted regions reveals preservation of epigenetic stability in adult somatic tissue. Epigenetics Chromatin. 2011, 4 (1): 1-10.1186/1756-8935-4-1.CrossRefPubMedPubMedCentral
20.
Bollati V, Baccarelli A, Hou L, Bonzini M, Fustinoni S, Cavallo D, Byun HM, Jiang J, Marinelli B, Pesatori AC, et al: Changes in DNA methylation patterns in subjects exposed to low-dose benzene. Cancer Res. 2007, 67 (3): 876-880. 10.1158/0008-5472.CAN-06-2995.CrossRefPubMed
21.
22.
Christensen BC, Marsit CJ, Houseman EA, Godleski JJ, Longacker JL, Zheng S, Yeh RF, Wrensch MR, Wiemels JL, Karagas MR, et al: Differentiation of lung adenocarcinoma, pleural mesothelioma, and nonmalignant pulmonary tissues using DNA methylation profiles. Cancer Res. 2009, 69 (15): 6315-6321. 10.1158/0008-5472.CAN-09-1073.CrossRefPubMedPubMedCentral
23.
Houseman EA, Christensen BC, Yeh RF, Marsit CJ, Karagas MR, Wrensch M, Nelson HH, Wiemels J, Zheng S, Wiencke JK, et al: Model-based clustering of DNA methylation array data: a recursive-partitioning algorithm for high-dimensional data arising as a mixture of beta distributions. BMC Bioinforma. 2008, 9: 365-10.1186/1471-2105-9-365.CrossRef
24.
Christensen BC, Kelsey KT, Zheng S, Houseman EA, Marsit CJ, Wrensch MR, Wiemels JL, Nelson HH, Karagas MR, Kushi LH, et al: Breast cancer DNA methylation profiles are associated with tumor size and alcohol and folate intake. PLoS Genet. 2010, 6 (7): e1001043-10.1371/journal.pgen.1001043.CrossRefPubMedPubMedCentral
25.
Benjamini Y, Hochberg Y: Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Statist Soc B. 1995, 57: 289-300.
26.
Tost J, Jammes H, Dupont JM, Buffat C, Robert B, Mignot TM, Mondon F, Carbonne B, Simeoni U, Grange G, et al: Non-random, individual-specific methylation profiles are present at the sixth CTCF binding site in the human H19/IGF2 imprinting control region. Nucleic Acids Res. 2007, 35 (2): 701-PubMed
27.
Rescorla FJ, Breitfeld PP: Pediatric germ cell tumors. Clin Imaging. 1999, 23 (6): 257-303.
28.
Oosterhuis JW, Looijenga LH: Testicular germ-cell tumours in a broader perspective. Nat Rev Cancer. 2005, 5 (3): 210-222. 10.1038/nrc1568.CrossRefPubMed
29.
Koul S, Houldsworth J, Mansukhani MM, Donadio A, McKiernan JM, Reuter VE, Bosl GJ, Chaganti RS, Murty VV: Characteristic promoter hypermethylation signatures in male germ cell tumors. Mol Cancer. 2002, 1: 8-10.1186/1476-4598-1-8.CrossRefPubMedPubMedCentral
30.
Lind GE, Skotheim RI, Fraga MF, Abeler VM, Esteller M, Lothe RA: Novel epigenetically deregulated genes in testicular cancer include homeobox genes and SCGB3A1 (HIN-1). J Pathol. 2006, 210 (4): 441-449. 10.1002/path.2064.CrossRefPubMed
31.
Manton KJ, Douglas ML, Netzel-Arnett S, Fitzpatrick DR, Nicol DL, Boyd AW, Clements JA, Antalis TM: Hypermethylation of the 5' CpG island of the gene encoding the serine protease Testisin promotes its loss in testicular tumorigenesis. Br J Cancer. 2005, 92 (4): 760-769. 10.1038/sj.bjc.6602373.CrossRefPubMedPubMedCentral
32.
Cheung HH, Lee TL, Davis AJ, Taft DH, Rennert OM, Chan WY: Genome-wide DNA methylation profiling reveals novel epigenetically regulated genes and non-coding RNAs in human testicular cancer. Br J Cancer. 2010, 102 (2): 419-427. 10.1038/sj.bjc.6605505.CrossRefPubMedPubMedCentral
33.
De Smet C, Loriot A: DNA hypomethylation in cancer: Epigenetic scars of a neoplastic journey. Epigenetics. 2010, 5: 3-CrossRef
34.
Looijenga LH, Verkerk AJ, Dekker MC, Van Gurp RJ, Gillis AJ, Oosterhuis JW: Genomic imprinting in testicular germ cell tumours. APMIS. 1998, 106 (1): 187-195. discussion 196–187CrossRefPubMed
35.
Miura K, Obama M, Yun K, Masuzaki H, Ikeda Y, Yoshimura S, Akashi T, Niikawa N, Ishimaru T, Jinno Y: Methylation imprinting of H19 and SNRPN genes in human benign ovarian teratomas. Am J Hum Genet. 1999, 65 (5): 1359-1367. 10.1086/302615.CrossRefPubMedPubMedCentral
36.
Ueda T, Abe K, Miura A, Yuzuriha M, Zubair M, Noguchi M, Niwa K, Kawase Y, Kono T, Matsuda Y, et al: The paternal methylation imprint of the mouse H19 locus is acquired in the gonocyte stage during foetal testis development. Genes Cells. 2000, 5 (8): 649-659. 10.1046/j.1365-2443.2000.00351.x.CrossRefPubMed
37.
Kerjean A, Dupont JM, Vasseur C, Le Tessier D, Cuisset L, Paldi A, Jouannet P, Jeanpierre M: Establishment of the paternal methylation imprint of the human H19 and MEST/PEG1 genes during spermatogenesis. Hum Mol Genet. 2000, 9 (14): 2183-2187. 10.1093/hmg/9.14.2183.CrossRefPubMed
38.
Ross JA, Schmidt PT, Perentesis JP, Davies SM: Genomic imprinting of H19 and insulin-like growth factor-2 in pediatric germ cell tumors. Cancer. 1999, 85 (6): 1389-1394. 10.1002/(SICI)1097-0142(19990315)85:6<1389::AID-CNCR24>3.0.CO;2-V.CrossRefPubMed
39.
Riley PA, Sutton PM: Why are ovarian teratomas benign whilst teratomas of the testis are malignant?. Lancet. 1975, 1 (7921): 1360-1362.CrossRefPubMed
40.
Eppig JJ, Wigglesworth K, Varnum DS, Nadeau JH: Genetic regulation of traits essential for spontaneous ovarian teratocarcinogenesis in strain LT/Sv mice: aberrant meiotic cell cycle, oocyte activation, and parthenogenetic development. Cancer Res. 1996, 56 (21): 5047-5054.PubMed
Metadata
Title
DNA methylation analysis reveals distinct methylation signatures in pediatric germ cell tumors
Authors
James F Amatruda
Julie A Ross
Brock Christensen
Nicholas J Fustino
Kenneth S Chen
Anthony J Hooten
Heather Nelson
Jacquelyn K Kuriger
Dinesh Rakheja
A Lindsay Frazier
Jenny N Poynter
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-313

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