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

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

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Article number313
JournalBMC Cancer
Volume13
DOIs
StatePublished - Jun 27 2013

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Germ Cell and Embryonal Neoplasms
DNA Methylation
Methylation
Teratoma
Pediatrics
Germinoma
Endodermal Sinus Tumor
Neoplasms
Histology
Environmental Exposure
Epigenomics
Germ Cells
Linear Models
Stem Cells
Demography
Genes

Keywords

  • DNA Methylation
  • Germ Cell Tumor
  • Imprinting
  • Teratoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics
  • Medicine(all)

Cite this

Amatruda, J. F., Ross, J. A., Christensen, B., Fustino, N. J., Chen, K., Hooten, A. J., ... Poynter, J. N. (2013). DNA methylation analysis reveals distinct methylation signatures in pediatric germ cell tumors. BMC Cancer, 13, [313]. https://doi.org/10.1186/1471-2407-13-313

DNA methylation analysis reveals distinct methylation signatures in pediatric germ cell tumors. / Amatruda, James F; Ross, Julie A.; Christensen, Brock; Fustino, Nicholas J.; Chen, Kenneth; Hooten, Anthony J.; Nelson, Heather; Kuriger, Jacquelyn K.; Rakheja, Dinesh; Frazier, A. Lindsay; Poynter, Jenny N.

In: BMC Cancer, Vol. 13, 313, 27.06.2013.

Research output: Contribution to journalArticle

Amatruda, JF, Ross, JA, Christensen, B, Fustino, NJ, Chen, K, Hooten, AJ, Nelson, H, Kuriger, JK, Rakheja, D, Frazier, AL & Poynter, JN 2013, 'DNA methylation analysis reveals distinct methylation signatures in pediatric germ cell tumors', BMC Cancer, vol. 13, 313. https://doi.org/10.1186/1471-2407-13-313
Amatruda, James F ; Ross, Julie A. ; Christensen, Brock ; Fustino, Nicholas J. ; Chen, Kenneth ; Hooten, Anthony J. ; Nelson, Heather ; Kuriger, Jacquelyn K. ; Rakheja, Dinesh ; Frazier, A. Lindsay ; Poynter, Jenny N. / DNA methylation analysis reveals distinct methylation signatures in pediatric germ cell tumors. In: BMC Cancer. 2013 ; Vol. 13.
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AU - Amatruda, James F

AU - Ross, Julie A.

AU - Christensen, Brock

AU - Fustino, Nicholas J.

AU - Chen, Kenneth

AU - Hooten, Anthony J.

AU - Nelson, Heather

AU - Kuriger, Jacquelyn K.

AU - Rakheja, Dinesh

AU - Frazier, A. Lindsay

AU - Poynter, Jenny N.

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N2 - 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.

AB - 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.

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KW - Imprinting

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