Does childhood leukaemia develop in cells which are pre- primed by - - PowerPoint PPT Presentation

Does childhood leukaemia develop in cells which are pre- primed by the presence of aberrant patterns of DNA methylation?

Sanne van Otterdijk Northern Institute of Cancer Research

CpG Island Exon

Aims

• Understand how abnormal methylation develops in and

contributes to haematological malignancies – Quantify the extent and variability of DNA methylation in healthy populations at different ages – Quantify the extent and variability of DNA methylation in childhood and adult ALL patients at different stages of the disease – Examine the overlap between methylation patterns in healthy individuals and ALL patients – Assess the potential of differential methylation in apparently healthy samples for leukaemia risk assessment or detection of early disease – Assess the potential of differential methylation in ALL remission samples for prediction of outcome

DNA methylation is increasing with age

Similar patterns observed in 4 other leukaemia related genes; TWIST2, HOXD4, EphA10 and HAND2

N33 methylation with age 5 10 15 20 25 30 35 40 20 40 60 80 100 Age (years) Methylation levels (%) Patient Mean

* A significant difference in methylation levels is observed # A significant difference in variance of methylation is observed

*# *# *# *#

N33 methylation during ALL remission 5 10 15 20 25 30 20 40 60 80 100 Age (years) M ethylation levels (%)

Childhood ALL patient Adult ALL patient M ean Controls

DNA methylation during ALL remission

Similar patterns observed in 4 other leukaemia related genes; TWIST2, HOXD4, EphA10 and HAND2

“Leukaemia-like” features are already present in healthy individuals

Gene TWIST2 HOXD4 EphA10 N33 TWIST2 HOXD4 R Value = 0.51 p value = 0.0002 EphA10 R value = 0.55 p value = 0.00004 R value = 0.36 p value = 0.01 N33 R value = 0.49 p value = 0.0003 R value = 0.72 p value = 5.0E-09 R value = 0.31 p value = 0.03 HAND2 R value = 0.43 P value = 0.001 R value = 0.64 p value = 7.0E-07 R value = 0.38 p value = 0.006 R value = 0.64 p value = 0.000002

CpG Site

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

TWIST2

CIMP Highly methylated alleles

Pre-existing methylation may underlie susceptibility to cancer

Densely hypermethylated alleles Several genes methylated Genes are unmethylated Partial methylation in all cells

Acknowledgements

Supervisors Dr Gordon Strathdee Professor John Matters Professor Iokim Spyridopoulos Crucible Team Hannah Gautry Shabnam Thathia Stefano Tonin Fadhel Lafta Newcastle biobank Newcastle 85+ study Newcastle 85+ Study Core Team The Newcastle Thousand Families study Dr Mark Pearce North Cumbria Community Genetics Project (NCCGP) Dr Caroline Relton Funding Newcastle NIHR Biomedical Research Centre Newcastle Healthcare Charity and Newcastle upon Tyne hospitals NHS Charity