The Genetic Basis of Haematological Cancers

Dr Sabrina Tosi graduated in Biological Sciences at the University of Milan (Italy) in 1989 and then attained her post-graduate degree in Human Cytogenetics at the University of Pavia (Italy) in 1992. Her interest in leukaemia dates back to 1989, when she started to work as a research scientist in the Department of Paediatric Haematology, Ospedale San Gerardo, Monza (Italy). In 1991-1992  Dr Tosi spent a year in the Oncogenetic Laboratory, Children's Hospital, University of Giessen (Germany) as a visiting research scientist. After another two years in Monza, Dr Tosi moved to the University of Oxford at the Weatherall Institute of Molecular Medicine, where she attained her DPhil in 1999 and spent altogether 12 years in leukaemia research. In 2005 she was appointed as Lecturer in Biosciences at Brunel University London, where she continues to work on the contribution of chromosomal abnormalities to leukaemia, with particular interest towards paediatric leukaemia. Dr Alistair Reid graduated in Genetics from the University of Newcastle upon Tyne in 1995, and trained as a diagnostic genetic scientist in the UK heath service. He obtained his PhD in Cambridge in 2003 based on the characterization of novel genetic prognosticators in myeloid leukemia. Since then he has held positions at several clinical academic haematology centres including Royal Free, London and University Children’s Hospital, Zurich, and has also spent time as a consultant in the genetic diagnostics industry. In 2006 he was appointed Consultant Clinical Scientist in Molecular Pathology at Imperial College Healthcare Trust in London. He has an active laboratory-based translational research program focused on the genetics of myeloid leukemia and holds an honorary senior clinical lectureship for the development of novel methods of personalized genetic management in malignancy. Dr Reid has contributed to over 60 papers on malignancy genetics and was awarded fellowship of the Royal College of Pathologists in 2011.

List of contributors xi

Preface xiii

1 The myelodysplastic syndromes 1
Cristina Mecucci, Valeria Di Battista and Valeria Nofrini

Introduction 1

Predisposing conditions 2

Familial platelet disorder with propensity to myeloid malignancy (FPD/AML) 2

Severe congenital neutropenia (SCN) 5

Poikiloderma with neutropenia 6

Familial MDS/AML 6

Shwachman–Diamond syndrome (SDS) 7

Dyskeratosis congenita (DKC) and telomere syndromes 8

Fanconi anaemia (FA) 11

Down syndrome 12

Cytogenetics 12

Loss of Y chromosome (–Y) and del(11q) 13

Del(20q) 15

idic(X)(q13) 15

Del(17)(p13)/i(17q) 15

Del(12p) 16

Trisomy 8 16

Rare trisomies: +6, +13, +14, +15, +16, +19, +21 16

Monosomy 7 and del(7q) 17

Rare monosomies 19

Unbalanced translocations involving 1q 19

t(17;18)(p10;q10) 20

Rare or sporadic balanced translocations 20

Complex karyotypes 22

Chromosome 5q deletions 23

Somatic mutations 31

Oncogenes and tumour suppressor genes 31

Mutations of genes involved in epigenetic modulation 39

Mutations of genes involved in the spliceosome machinery 45

Rare gene mutations in myelodysplastic syndromes 48

Epigenetics 49

DNA methylation 50

Histone modifications 52

RNA 53

Conclusion 54

References 54

2 Molecular genetics of the myeloproliferative neoplasms 80
Philip A. Beer

Introduction 80

Overview of the different types of mutation found in MPN patients 80

Acquired mutations in cytokine signalling pathways 82

Acquired mutations in pathways controlling transcriptional regulation 84

Acquired mutations associated with transformation to advanced-phase disease 87

Inherited predisposition to clonal MPNs 87

Inherited non-clonal disorders that phenocopy distinct MPNs 87

Polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) 88

Acquired mutations in cytokine signalling pathways (Table 2.3) 89

Acquired mutations in pathways controlling transcriptional regulation (Table 2.4) 95

Acquired mutations associated with progression to advanced and blastic-phase disease 101

Inherited predisposition to clonal MPNs 103

Inherited non-clonal disorders that phenocopy distinct MPNs 104

Principles and clinical utility of laboratory testing 107

Chronic eosinophilic leukaemia 109

Acquired mutations in cytokine signalling pathways 109

Acquired mutations in pathways controlling transcriptional regulation 113

Acquired mutations associated with progression to advanced and blastic-phase disease 113

Inherited predisposition to clonal MPNs 113

Inherited non-clonal disorders that phenocopy distinct MPNs 114

Principles and clinical utility of laboratory testing 114

Neoplastic mast cell disease 115

Acquired mutations in cytokine signalling pathways 116

Acquired mutations in pathways controlling transcriptional regulation 118

Acquired mutations associated with progression to advanced and blastic-phase disease 118

Inherited predisposition to clonal MPNs 119

Inherited non-clonal disorders that phenocopy distinct MPNs 119

Principles and clinical utility of laboratory testing 120

References 121

3 Acute myeloid leukaemia 133
Matthew L. Smith and Thomas McKerrell

Introduction 133

AML classification 134

Cytogenetic aberrations 135

Fusion genes arising from structural rearrangements 135

Monosomies 148

Complex and monosomal karyotypes 148

Trisomies 148

Double minute chromosomes 151

Normal karyotype – is it really normal? 151

Altered gene expression 152

EVI1 152

BAALC 153

MN1 153

ERG 154

SET 154

BRE 154

WT1 154

miRNA genes 154

Diagnosis and classification of AML 155

Current risk stratification of AML patients: European LeukemiaNet (ELN) guidelines 156

Therapeutic regimens in AML 158

Management of younger adults aged 18–60 years 159

Older AML patients (aged >60 years) 159

Novel agents 160

Monitoring response to therapy (MRD) 160

The genomics of AML 161

Clonal evolution of AML 161

Established recurrent mutations in AML 163

Novel recurrent mutations in AML 173

Emerging concepts and future directions 179

Age-related clonal haematopoiesis (ARCH) 179

Application of genomic technologies to the diagnosis of AML 179

Conclusion 181

Mini-glossary 183

References 184

4 Molecular genetics of paediatric acute myeloid leukaemia 203
Marry van den Heuvel-Eibrink, Jasmijn D.E. de Rooij and Christian Michel Zwaan

Clinical introduction 203

Epidemiology of AML 203

Diagnostic approach 204

Treatment and outcome 205

Relevant molecular and genetic aberrations in paediatric AML 206

Type I/II aberrations and their non-random associations 206

Relevance of type I/II aberrations for outcome and stratification of paediatric AML treatment 209

Epigenetic modifiers and hydroxymethylation pathway mutations 212

Further strategies 213

Further genomic approaches to unravelling the biology of paediatric AML 213

Molecularly targeted therapy 214

Conclusion 215

References 215

5 Acute lymphoblastic leukaemia 223
Anna Andersson, Anthony V. Moorman, Christine J. Harrison and Charles Mullighan

Introduction 223

Chromosomal aberrations in BCP-ALL 224

High hyperdiploidy 227

t(12;21)(p13;q22)/ETV6-RUNX1 232

t(1;19)(q23;p13)/TCF3-PBX1 233

t(17;19)(q22;p13)/TCF3-HLF 234

Hypodiploidy 234

11q23/KMT2A (MLL) gene rearrangements 236

t(9;22)(q34;q11.1)/BCR-ABL1 237

Intrachromosomal amplification of chromosome 21 (iAMP21) 238

Complex karyotype 239

Submicroscopic genetic alterations in BCP-ALL 240

Alteration of transcription factors in BCP-ALL 241

CRLF2 rearrangements and Janus kinase mutations in ALL 242

BCR-ABL1-like or Ph-like ALL 243

ERG-altered ALL 245

Genetic rearrangements in T-lineage ALL 245

TAL1/LMO2 rearranged T-ALL 247

TLX1/TLX3 rearranged T-ALL 248

Early T-cell precursor ALL 249

Other T-ALL genetic subtypes: MLL rearranged and PICALM-MLLT10 250

Relapsed ALL 251

Future directions 252

References 252

6 The genetics of mature B-cell malignancies 265
Jonathan C. Strefford, Jude Fitzgibbon, Matthew J.J. Rose-Zerilli and Csaba Bödör

Introduction 265

Chronic lymphocytic leukaemia 266

Immunoglobulin heavy-chain variable region gene mutational status 267

Chromosomal banding and interphase molecular cytogenetics 268

Copy number alterations 269

Deletions of 13q14 269

Trisomy 12 272

Deletions of 11q24 and mutations of ATM 273

Deletions of 17p13 and mutations of TP53 275

Other copy number alterations in CLL 276

Genome complexity and chromothripsis 277

Novel mutations in patients with CLL 279

NOTCH1 280

SF3B1 281

Other genes 282

Novel genetic mutations in clinical practice 282

Germinal centre lymphomas 284

Follicular lymphoma 286

Diffuse large B-cell lymphoma 293

Conclusions and future perspectives 296

Acknowledgements 299

References 299

7 The genetics of chronic myelogenous leukaemia 312
Philippa C. May, Jamshid S. Khorashad, Mary Alikian, Danilo Perrotti and Alistair G. Reid

Introduction 312

Clinical features 313

The structure and physiological function of BCR and ABL1 316

The structure of the BCR-ABL1 fusion gene 317

Mechanisms of BCR-ABL1-induced oncogenesis 319

Potential mechanisms underlying the genesis of CML 320

CML blast crisis transformation 321

Tyrosine kinase inhibitor (TKI) therapy 325

The genetic basis of TKI resistance 326

Novel therapeutic approaches 330

Genetics in patient management 332

Cytogenetic and molecular cytogenetic monitoring 332

Quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) 334

BCR-ABL1 mutation analysis 337

Conclusion 338

References 339

Index 359