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

BMC Cancer

James F Amatruda⁴  Julie A Ross¹  Brock Christensen³  Nicholas J Fustino⁴  Kenneth S Chen⁴  Anthony J Hooten¹  Heather Nelson⁶  Jacquelyn K Kuriger⁶  Dinesh Rakheja⁵  A Lindsay Frazier²  Jenny N Poynter¹ 

[1] Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA

[2] Dana Farber Cancer Institute, Boston 02115MA, USA

[3] Department of Community and Family Medicine, Section of Biostatistics and Epidemiology, Dartmouth Medical School, Hanover, NH 03755, USA

[4] Center for Cancer and Blood Disorders, Children’s Medical Center, Dallas, TX 75390, USA

[5] Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA

[6] Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 55455, USA

关键词: Imprinting;    DNA Methylation;    Teratoma;    Germ Cell Tumor;   

Others  :  1079677
DOI  :  10.1186/1471-2407-13-313

 received in 2012-10-25, accepted in 2013-06-14,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Amatruda et al.; licensee BioMed Central Ltd.

【 图 表 】

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