From genomic variation to personalized medicine

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From genomic variation to personalized medicine

Wesolowska, Agata; Schmiegelow, Kjeld

偵扬楣慴楯渠摡瑥㨀

2012

䑯捵浥湴⁖敲獩潮
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Wesolowska, A., & Schmiegelow, K. (2012). From genomic variation to personalized medicine. Department of
Systems Biology, Technical University of Denmark.

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From genomic variation to personalized medicine

Agata Wesołowska-Andersen

14th December, 2012
iii

Variability is the law of life, and as no two faces are the same,
so no two bodies are alike, and no two individuals react alike and
behave alike under the abnormal conditions we know as disease.
Sir William Osler (1849-1919)
PREFACE v

Preface

This thesis was prepared at the Center for Biological Sequence Analysis
(CBS), Department of Systems Biology, at the Technical University of Denmark (DTU) in partial fulfilment of the requirements for acquiring the Ph.D.
degree. The Ph.D. was funded by the Childhood Cancer Foundation, Danish
Cancer Research Foundation (KB) and DTU.

All the work was carried out at the Center for Biological Sequence Analysis under the supervision of Associate Professor Ramneek Gupta, Professor
Søren Brunak and Professor Kjeld Schmiegelow from Rigshospitalet.
Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Dansk resumé . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . .
Papers included in the thesis . . . . . . . . . . . . . . . . . . . . .
Papers not included in the thesis . . . . . . . . . . . . . . . . . . . v
vii
x
xi
xiii
xv
xvi

I Introduction 1
1 Genomic variation
1.1 Genotype to phenotype . . . . . . . . . . . . . . . . . . . . .
1.2 GWAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3 Identifying disease variants with NGS . . . . . . . . . . . . .
1.4 Personal genomes . . . . . . . . . . . . . . . . . . . . . . . . . 3
4
5
7
9
2 Childhood acute lymphoblastic leukaemia
2.1 Epidemiology and aetiology . . . . . . . . . . . . . . . . . . .
2.2 ALL classification . . . . . . . . . . . . . . . . . . . . . . . . .
2.3 Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . 11
11
12
13
3 Pharmacogenomics
3.1 Pharmacogenetics in ALL . . . . . . . . . . . . . . . . . . . .
3.2 Drugs in childhood ALL . . . . . . . . . . . . . . . . . . . . .
3.2.1 Glucocorticoids . . . . . . . . . . . . . . . . . . . . . .
3.2.2 Vincristine . . . . . . . . . . . . . . . . . . . . . . . .
3.2.3 Anthracyclines . . . . . . . . . . . . . . . . . . . . . .
3.2.4 Asparaginase . . . . . . . . . . . . . . . . . . . . . . .
3.2.5 Methotrexate . . . . . . . . . . . . . . . . . . . . . . .
3.2.6 Mercaptopurine . . . . . . . . . . . . . . . . . . . . . .
3.2.7 Cytarabine . . . . . . . . . . . . . . . . . . . . . . . . 15
16
17
17
18
18
18
18
19
19

vii
viii

3.2.8
3.2.9

CONTENTS

Cyclophosphamide . . . . . . . . . . . . . . . . . . . .
Epipodophyllotoxins . . . . . . . . . . . . . . . . . . . 19
20

II Methods 21
4 Predicting SNP effects
4.1 SNP effect on transcript . . . . . . . . . . . . . . . . . . . . .
4.2 Protein-coding changes . . . . . . . . . . . . . . . . . . . . . .
4.3 Non-coding variations . . . . . . . . . . . . . . . . . . . . . .
4.4 Paper I- Protein annotation in the era of personal genomics . 23
23
23
25
26
5 Variant calling with NGS
5.1 Raw read quality control . . . . . . . . . . . . . . . . . . . . .
5.2 Alignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3 SNP calling . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4 CNV calling . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5 Other challenges . . . . . . . . . . . . . . . . . . . . . . . . . 35
35
36
37
38
40
6 Hypothesis-driven SNP selection and assay
6.1 SNP selection . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2 Available genotyping methods review . . . . . . . . . . . . . .
6.3 Multiplexing - pilot study . . . . . . . . . . . . . . . . . . . .
6.4 Paper II - Multiplexing before capture . . . . . . . . . . . . . 41
41
42
44
49
7 Integrative variation analysis
7.1 Single SNP associations . . . . . . . . . . . . . . . . . . . . .
7.2 Rare variant accumulation . . . . . . . . . . . . . . . . . . . .
7.3 Pathways analysis . . . . . . . . . . . . . . . . . . . . . . . .
7.4 Individual disease risk . . . . . . . . . . . . . . . . . . . . . .
7.5 Subgrouping patients . . . . . . . . . . . . . . . . . . . . . . . 57
57
58
60
62
64
IIISNP profiling of treatment efficacy in childhood ALL 69
8 Paper III - Extensive targeted SNP profiling predicts early
treatment response and risk of relapse in 864 childhood
ALL patients 71
IVInfections during induction therapy 91
9 Paper IV - Variation in host genetics and infections during induction treatment in childhood acute lymphoblastic
leukaemia 93
CONTENTS

V Cytogenetic aberrations in t(12;21) childhood ALL

ix

109

10 Paper V - Genome-wide analysis of cytogenetic aberrations
in ETV6/RUNX1-positive childhood acute lymphoblastic
leukaemia 111

VIEpilogue 121

11 Summary and perspectives 123
11.1 Functional variations . . . . . . . . . . . . . . . . . . . . . . . 124
11.2 Personalized medicine . . . . . . . . . . . . . . . . . . . . . . 125

Bibliography 127