DNA Methylation and Somatic Mutations Converge on the Cell Cycle and Define Similar Evolutionary Histories in Brain Tumors

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2015 Sep 17

PMID 26373278

Citations 143

Authors

Tali Mazor

Aleksandr Pankov

Brett E Johnson

Chibo Hong

Emily G Hamilton

Robert J A Bell

Ivan V Smirnov

Gerald F Reis

Joanna J Phillips

Michael J Barnes

Ahmed Idbaih

Agusti Alentorn

Jenneke J Kloezeman

Martine L M Lamfers

Andrew W Bollen

Barry S Taylor

Annette M Molinaro

Adam B Olshen

Susan M Chang

Jun S Song

Joseph F Costello

Affiliations

Soon will be listed here.

Abstract

The evolutionary history of tumor cell populations can be reconstructed from patterns of genetic alterations. In contrast to stable genetic events, epigenetic states are reversible and sensitive to the microenvironment, prompting the question whether epigenetic information can similarly be used to discover tumor phylogeny. We examined the spatial and temporal dynamics of DNA methylation in a cohort of low-grade gliomas and their patient-matched recurrences. Genes transcriptionally upregulated through promoter hypomethylation during malignant progression to high-grade glioblastoma were enriched in cell cycle function, evolving in parallel with genetic alterations that deregulate the G1/S cell cycle checkpoint. Moreover, phyloepigenetic relationships robustly recapitulated phylogenetic patterns inferred from somatic mutations. These findings highlight widespread co-dependency of genetic and epigenetic events throughout brain tumor evolution.

Citing Articles

MGMT epimutations and risk of incident cancer of the colon, glioblastoma multiforme, and diffuse large B cell lymphomas.

Nikolaienko O, Anderson G, Chlebowski R, Jung S, Harris H, Knappskog S Clin Epigenetics. 2025; 17(1):28.

PMID: 39980037 PMC: 11841191. DOI: 10.1186/s13148-025-01835-x.

High-resolution, noninvasive single-cell lineage tracing in mice and humans based on DNA methylation epimutations.

Chen M, Fu R, Chen Y, Li L, Wang S Nat Methods. 2025; 22(3):488-498.

PMID: 39820752 DOI: 10.1038/s41592-024-02567-1.

Epigenomic heterogeneity as a source of tumour evolution.

Laisne M, Lupien M, Vallot C Nat Rev Cancer. 2024; 25(1):7-26.

PMID: 39414948 DOI: 10.1038/s41568-024-00757-9.

Resolving tumor evolution: a phylogenetic approach.

Li L, Xie W, Zhan L, Wen S, Luo X, Xu S J Natl Cancer Cent. 2024; 4(2):97-106.

PMID: 39282584 PMC: 11390690. DOI: 10.1016/j.jncc.2024.03.001.

The evolutionary theory of cancer: challenges and potential solutions.

Laplane L, Maley C Nat Rev Cancer. 2024; 24(10):718-733.

PMID: 39256635 PMC: 11627115. DOI: 10.1038/s41568-024-00734-2.

References

Costello J, Berger M, Huang H, Cavenee W . Silencing of p16/CDKN2 expression in human gliomas by methylation and chromatin condensation. Cancer Res. 1996; 56(10):2405-10. View

Sproul D, Kitchen R, Nestor C, Dixon J, Sims A, Harrison D . Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns. Genome Biol. 2012; 13(10):R84. PMC: 3491412. DOI: 10.1186/gb-2012-13-10-r84. View

Watanabe T, Nobusawa S, Kleihues P, Ohgaki H . IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol. 2009; 174(4):1149-53. PMC: 2671348. DOI: 10.2353/ajpath.2009.080958. View

Rufini A, Agostini M, Grespi F, Tomasini R, Sayan B, Niklison-Chirou M . p73 in Cancer. Genes Cancer. 2011; 2(4):491-502. PMC: 3135637. DOI: 10.1177/1947601911408890. View

Eckhardt F, Lewin J, Cortese R, Rakyan V, Attwood J, Burger M . DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet. 2006; 38(12):1378-85. PMC: 3082778. DOI: 10.1038/ng1909. View

Toyota M, Ahuja N, Herman J, Baylin S, Issa J . CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A. 1999; 96(15):8681-6. PMC: 17576. DOI: 10.1073/pnas.96.15.8681. View

Hunter C, Smith R, Cahill D, Stephens P, Stevens C, Teague J . A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res. 2006; 66(8):3987-91. PMC: 7212022. DOI: 10.1158/0008-5472.CAN-06-0127. View

Witte T, Plass C, Gerhauser C . Pan-cancer patterns of DNA methylation. Genome Med. 2014; 6(8):66. PMC: 4254427. DOI: 10.1186/s13073-014-0066-6. View

Trapnell C, Pachter L, Salzberg S . TopHat: discovering splice junctions with RNA-Seq. Bioinformatics. 2009; 25(9):1105-11. PMC: 2672628. DOI: 10.1093/bioinformatics/btp120. View

10.

Zardo G, Tiirikainen M, Hong C, Misra A, Feuerstein B, Volik S . Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors. Nat Genet. 2002; 32(3):453-8. DOI: 10.1038/ng1007. View

11.

Banine F, Bartlett C, Gunawardena R, Muchardt C, Yaniv M, Knudsen E . SWI/SNF chromatin-remodeling factors induce changes in DNA methylation to promote transcriptional activation. Cancer Res. 2005; 65(9):3542-7. DOI: 10.1158/0008-5472.CAN-04-3554. View

12.

Greaves M, Maley C . Clonal evolution in cancer. Nature. 2012; 481(7381):306-13. PMC: 3367003. DOI: 10.1038/nature10762. View

13.

Desper R, Gascuel O . Fast and accurate phylogeny reconstruction algorithms based on the minimum-evolution principle. J Comput Biol. 2002; 9(5):687-705. DOI: 10.1089/106652702761034136. View

14.

Kerkel K, Spadola A, Yuan E, Kosek J, Jiang L, Hod E . Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation. Nat Genet. 2008; 40(7):904-8. DOI: 10.1038/ng.174. View

15.

Trapnell C, Williams B, Pertea G, Mortazavi A, Kwan G, van Baren M . Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010; 28(5):511-5. PMC: 3146043. DOI: 10.1038/nbt.1621. View

16.

Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B . Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010; 467(7319):1114-7. PMC: 3148940. DOI: 10.1038/nature09515. View

17.

Chen H, Tsai S, Leone G . Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nat Rev Cancer. 2009; 9(11):785-97. PMC: 3616489. DOI: 10.1038/nrc2696. View

18.

Gerlinger M, Rowan A, Horswell S, Math M, Larkin J, Endesfelder D . Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012; 366(10):883-892. PMC: 4878653. DOI: 10.1056/NEJMoa1113205. View

19.

Price M, Cotton A, Lam L, Farre P, Emberly E, Brown C . Additional annotation enhances potential for biologically-relevant analysis of the Illumina Infinium HumanMethylation450 BeadChip array. Epigenetics Chromatin. 2013; 6(1):4. PMC: 3740789. DOI: 10.1186/1756-8935-6-4. View

20.

Wick W, Meisner C, Hentschel B, Platten M, Schilling A, Wiestler B . Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation. Neurology. 2013; 81(17):1515-22. DOI: 10.1212/WNL.0b013e3182a95680. View