The Genetic Basis of Haematological Cancers

Sabrina Tosi, Alistair G. Reid, Sabrina Tosi, Alistair G. Reid

• Publisher: Wiley-Blackwell
• Year: 2016
• Print ISBN: 9780470979389
• eBook ISBN: 9781118528051
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Genetics & Genomics
• Index: Biological Sciences

Written by a team of international experts, this book provides an authoritative overview and practical guide to the molecular biology and genetic basis of haematologic cancers including leukemia. Focusing on the importance of cytogenetics and related assays, both as diagnostic tools and as a basis for translational research, this is an invaluable guide for basic and clinical researchers with an interest in medical genetics and haemato-oncology.

The Genetic Basis of Haematological Cancers reviews the etiology and significance of genetic and epigenetic defects that occur in malignancies of the haematopoietic system. Some of these chromosomal and molecular aberrations are well established and already embedded in clinical management, while many others have only recently come to light as a result of advances in genomic technology and functional investigation. The book includes seven chapters written by clinical and academic leaders in the field, organised according to haematological malignancy sub-type. Each chapter includes a background on disease pathology and the genetic abnormalities most commonly associated with the condition. Authors present in-depth discussions outlining the biological significance of these lesions in pathogenesis and progression, and their use in diagnosis and monitoring response to therapy. The current or potential role of specific abnormalities as novel therapeutic targets is also discussed. There is also a full colour section containing original FISH, microarrays and immunostaining images. 

Chapter 1
The myelodysplastic syndromes

Cristina Mecucci, Valeria Di Battista and Valeria Nofrini

Introduction

Myelodysplastic syndromes (MDS) define neoplastic disorders with bone marrow dysplasia and insufficiency leading to one or more cytopenia in the peripheral blood. Bone marrow differentiation, although abnormal, is maintained. Despite the reduced amount of circulating blood cells, bone marrow cellularity is increased in the majority of cases. Less frequently, the bone marrow is hypoplastic, particularly in children and young adults with a predisposing genetic condition. The large majority of MDS cases affect individuals over the age of 60 years. Blast count, by definition, is less than 20%, although a minority of cases (10–20%) eventually transform to acute myeloid leukaemia (AML), defined by a blast count of 20% or more.

As bone marrow dysplasia may be induced from a variety of non-neoplastic conditions, including vitamin deficiencies, viral infections, smoking or medication, the identification of clonal genetic aberrations detected by chromosome banding or higher throughput genomic technologies plays a key role in achieving the correct diagnosis. Conventional cytogenetic analysis is able to detect abnormalities in around 40–50% of cases of de novo MDS, increasing to around 70–80% when integrated with whole-genome analysis detecting copy-number variations, uniparental disomy and acquired mutations.^1–3 Cytogenetic abnormalities involving partial or complete chromosome loss are more frequent than reciprocal translocations. This is in contrast to AML, which is partly subcategorized according to the presence of typical reciprocal chromosome translocations, such as t(8;21), t(15;17) and inv(16). Importantly, the latter are consistent with a diagnosis of AML, even in the presence of morphological evidence of less than 20% bone marrow blasts.⁴

The incidence of chromosome aberrations is much higher in MDS arising after chemo- or radiotherapy, including bone marrow transplantation procedures, for a prior neoplastic or non-neoplastic disease. A complex abnormal karyotype is found in more than 80% of treatment-induced MDS.

The critical role of clonal cytogenetic defects at diagnosis is underlined by the hierarchical clonal evolution and acquisition of additional chromosomal defects that often accompany disease progression. In addition to chromosomal rearrangements, newly acquired gene mutations may also mark clonal evolution and disease progression.^5–7 These changes may contribute to the development of a higher risk MDS or AML by conveying growth advantage, decreased apoptosis or avoidance of immune control.⁸ The identification of driver gene mutations might also help define distinctive entities within myelodysplastic syndromes, improving classification and clinical management.⁹ This chapter summarizes the current understanding of the genetic and epigenetic landscape of MDS and known predisposing conditions.

Predisposing conditions

Several inherited or congenital conditions have been associated with a predisposition to develop myelodysplasia. These conditions are characterized by the presence of inherited genetic defects and the development of MDS is often linked to additional genetic mistakes that are acquired and confined to the myeloid lineage. Table 1.1 summarizes the conditions described in this section and includes a list of constitutional genetic defects associated with the disorders.

Table 1.1 Inherited or congenital conditions predisposing to MDS and leukaemia

...

Disease	Inheritance	Gene	Locus	Other features	Incidence of MDS/AML (%)
Severe congenital neutropenia	AD	ELANE	19q13	None	10
AD	GFI1	1p22	Monocytosis Lymphopenia
AR	GSPC3	17q24	Cardiac and urogenital malformations
AR	HAX1	1q21	Neuropsychological defects
XL	WAS	Xp11	Monocytopenia Low NK cells
Shwachman–Diamond syndrome	AR	SBDS	7q11	Exocrine pancreatic insufficiency, bone marrow failure, skeletal abnormalities	10
Poikiloderma with neutropenia	AR	C16orf57	16q21	Poikiloderma, pachyonychia, chronic neutropenia
Dyskeratosis congenita	XL	DKC1	Xq28	Mucocutaneous abnormalities, aplastic anaemia	3–5
Fanconi anaemia	AR	FANC/BRCA	Xp22	Multiple congenital abnormalities	50
XL	FANCB
Bloom syndrome	AR	BLM	15q26	Short stature, photosensitivity reactions	25
Familial platelet disorder with propensity to myeloid malignancy	AD	RUNX1	21q22	Dysmorphic features, intellectual disability (in cases with RUNX1 deletions)	20–60
Familial MDS/AML with GATA2 mutations	?	GATA2	3q21	Monocytopenia, B, NK and dendritic cell lymphopenia
Down syndrome	N/A	HMGN1	21q22.2	Delayed development, learning disabilities, heart defects, vision problems, hearing loss, hypotonia	10–20-fold higher than general population
SCN	AD	ELANE	19q13	None	10
AD	GFI1	1p22	Monocytosis Lymphopenia
AR	GSPC3	1p34	Cardiac and urogenital malformations
AR	HAX1	1q21	Neuropsychological defects
XL	WAS	Xp11	Monocytopenia Low NK cells
SDS	AR	SBDS	7q11	Exocrine pancreatic insufficiency and skeletal abnormalities	10
PN	AR	C16orf57	16q21	Poikiloderma, pachyonychia, chronic neutropenia
DC	XL	DKC1	Xq28	Mucocutaneous abnormalities, aplastic anaemia	3–5
FA	AR	FANC/BRCA			50
	XL

Table of contents

• Cover
• Title Page
• Copyright
• Table of Contents
• List of contributors
• Preface
• Chapter 1: The myelodysplastic syndromes
• Chapter 2: Molecular genetics of the myeloproliferative neoplasms
• Chapter 3: Acute myeloid leukaemia
• Chapter 4: Molecular genetics of paediatric acute myeloid leukaemia
• Chapter 5: Acute lymphoblastic leukaemia
• Chapter 6: The genetics of mature B-cell malignancies
• Chapter 7: The genetics of chronic myelogenous leukaemia
• Index
• End User License Agreement