6. Historically,
Cancer Was Considered
to be Driven Mostly by Genetic Changes
Example:
Replication errors
GENETIC
Altered
DNA/mRNA/proteins
Altered
DNA sequence
X X
Oncogenesis
Tumor
Mutations in p53
Activating mutations in RAS
Mutations or amplifications of the
HER-2 gene
Chromosomal translocations in
myeloid cells and the generation of
the BCR-ABL fusion protein
7. Epigenetic Changes are
Important in Causing Cancer
Example:
Replication errors
GENETIC EPIGENETIC
Example:
Chromatin modification errors
Altered
DNA/mRNA/proteins
Altered
DNA sequence
Altered levels of
mRNA/proteins
Altered
chromatin structure
X X
Oncogenesis
Tumor
8. Source: Schuebel et al 2007
0
20
40
60
80
100
120
Methylated Mutated
76-100 51-75 21-50 1-20
Dx
CDx
Example of Methylation
vs Mutation: Colon & Breast Cancer
9. MGMT Biology
O6 Methyl-Guanine
Methyl Transferase
Essential DNA Repair Enzyme
Removes alkyl groups from damaged
guanine bases
Healthy individual:
- MGMT is an essential DNA repair enzyme
Loss of MGMT activity makes individuals susceptible
to DNA damage and prone to tumor development
Glioblastoma patient on alkylator chemotherapy:
- Patients with MGMT promoter methylation show
have longer PFS and OS with the use of alkylating
agents as chemotherapy
10. MGMT Promoter
Methylation Predicts
Benefit form DNA-Alkylating Chemotherapy
Post-hoc subgroup analysis of Temozolomide Clinical trial with primary
glioblastoma patients show benefit for patients with MGMT promoter methylation
0
5
10
15
20
25
Median Overall Survival
21.7 months
12.7 months
radiotherapy
plus
temozolomide
Methylated
MGMT Gene
Non-Methylated
MGMT Gene
radiotherapy
Adapted from Hegi et al.
NEJM 2005
352(10):1036-8.
Study with 207 patients
38. Sequencing
Deep
Seq
Molecular Unification
107 106 105 104 103 102 101 1108109
Full genome bp
Whole-genome
Bisulphite seq
RUO Clinical
E
P
I
G
E
N
E
T
I
C
Whole-genome
sequencing
Enrichment seq
(MBD, RRBS)
Enrichment seq
(Exome)
Probes
(450-27K)
Enrichment
Targeted Panels
Enrichment
Targeted Panels
Ultra
Deep
43. Sequencing
Deep
Seq
Molecular Unification
107 106 105 104 103 102 101 1108109
Full genome bp
Whole-genome
Bisulphite seq
RUO Clinical
E
P
I
G
E
N
E
T
I
C
Whole-genome
sequencing
Enrichment seq
(MBD, RRBS)
Enrichment seq
(Exome)
Probes
(450-27K)
Enrichment
Targeted Panels
Enrichment
Targeted Panels
Ultra
Deep
44. Acknowledgments
44
Geert Trooskens
Simon Denil
Klaas Mensaert
Jean-Pierre Renard
Sarah De Keulenaer
Ellen De Meester
Tim De Meyer
Olivier Thas
Wim van den Berghe
Manon Van Engeland
Jurgen Veeck
Monika Hegi
Pierre Bady
Sebastian Kurscheid