Familial aspects of haematological malignancy



Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria



The study of inherited predisposition to cancer provides the unique opportunity to identify key driver genes in oncogenesis that are likely to play important roles in the more common sporadic forms of disease. Inherited predisposition to malignancies, such as colon, breast and ovarian cancer have been well established. It has also long been accepted that several inherited syndromes, such as Fanconi Anaemia, are associated with an increased risk for haematological malignancy. However, inherited predisposition to a purely haematological malignancy, without associated syndromic features, has only recently become widely accepted. To date, only three genes have been shown to be causative of these predispositions, however in the majority of families studied, the causative mutation remains elusive. The Australian Familial Haematological Cancer Study is strategically identifying and collecting Australian families with inherited predisposition to a specific haematological malignancy. The identification and study of these families is integral to the study of haematological malignancy, as knowledge of the gene/s mutated and the subsequent disease progression in affected individuals will provide important insight into the mechanisms of leukemogenesis in the more common sporadic cases. This review will primarily discuss the familial aspects of pure haematological malignancy, however the syndromic causes will also be briefly addressed.

Cancer results from an accumulation of genetic mutations in genes involved in regulating cell differentiation and proliferation, leading to aberrant control of these processes. These mutations generally occur as somatic mutations due to intrinsic errors in DNA replication and ineffective repair mechanisms. However, in some rare cases, a mutation in one of these genes may occur in the germline and become a heritable mutation. It is likely that these genes, through their ability to predispose to cancer, play a key role in the development of cancer sporadically. Their identification will provide insight into the more common sporadic cases.

Familial clustering of cancer, including haematological malignancies, has been recognised by some and argued over by others for more than 50 years. Two doctors on different sides of the world, Henry T Lynch in Nebraska, United States and Frederick W Gunz, in Christchurch, New Zealand, were among the early supporters of a strong familial genetic component to cancers in the 1960s. The underlying genetic causes have subsequently been identified in a number of familial cancers, in particular the mismatch repair genes eg. MLH1 and MSH2 in colorectal cancer, and BRCA1 and BRCA2 in breast and ovarian cancer. Indeed, Lynch syndrome is a commonly used synonym for hereditary non-polyposis colorectal cancer. Many colon and breast cancer families used in the identification of these genes were collected by the ever active Dr Lynch.1

Fred Gunz will be well known to readers of Cancer Forum as the director of medical research at the Kanematsu Institute in Sydney from 1967 until 1980 and, until his death in 1990, an active contributor to Cancer Forum. Fred Gunz is the first author on one of the few papers online today from the period and summarises the early arguments in the medical literature about a hereditary component to haematological malignancies.2 Familial clustering of purely haematological malignancies has also been described, including a beautiful description by Fred Gunz and colleagues of the largest ever published family with a predisposition to develop leukaemia, with 17 affected family members from Sydney.3

However, only three genes have been definitively identified as playing a role in these haematological malignancy predispositions. The difficulty in identifying haematological malignancy predisposition genes partially results from an inability toperform linkage studies. This is due to relatively small family sizes, the high mortality rate, incomplete penetrance, relatively late age of onset and potential for sporadic phenocopies. A greater number of genes has been identified in bone marrow failure syndromes or other syndromes where an increased risk for haematological malignancy exists, however a number of nonhaematological diseases/phenotypes are also observed.

Pure familial leukaemia

A large number of families has been described in the literature, where aggregation of a greater than expected number of individuals diagnosed with a particular type of haematological malignancy has been observed. Lowenthal et al documented a series of over 200 pedigrees with two or more cases of haematological malignancies between 1972 and1980.4,5 Some of these pedigrees are large, with 12 or more affected individuals in the one family. It has also been observed that there is a propensity for individuals within the same family to be afflicted with a disease showing similar clinical phenotype. For example, families exist where predominantly acute myeloid leukaemia (AML) is observed, whereas others exist where only chronic lymphocytic leukaemia (CLL) is found, suggesting that the gene/s affected are distinct between the different families. Inheritance patterns also suggest many families have monogenic disorders displaying autosomal dominant inheritance, with varying penetrance.

Familial chronic lymphocytic leukaemia (CLL)

CLL is the most common form of sporadic leukaemia in western countries, representing approximately 30% of all cases. CLL also appears to show a relatively common familial aggregation, with some epidemiological studies suggesting a three-to-seven fold increased risk in first degree relatives of a CLL patient.6,7 More than 80 families showing CLL aggregation have been reported.8 This includes an Australian family with at least 12 affected members over four generations, ascertained by James Wiley, Professor of Haematology, University of Sydney and at least partially responsible for a linkage signal on chromosome 11p11.9 In 1975, Gunz and colleagues reported on a study of 909 families in respect to familial leukaemia.10 They reported that first degree relatives with leukaemia were much more frequent in families of patients with chronic lymphocytic, than in those of patients with chronic granulocytic leukaemia. The incidence of leukaemia among first degree relatives was established to be 2.8 – 3.0 times, among more distant relatives about 2.3 times and overall about 2.5 times that expected. Subsequently, a 1984 Tasmanian study found that 11.8% of CLL cases had at least one affected first degree relative.4

Several large association studies have been performed on cohorts of CLL families leading to the identification of several candidate loci, including 11p11,9 13q21.33- q22.211 and 6p21,3,12 however no genes in these regions have been implicated to date. Regions of consistent chromosomal rearrangement in sporadic CLL have also been suggested, such as consistent deletion of 13p14.3, implying the presence of a tumour suppressor gene.13 No genes within these regions have been implicated, although recently a common nonsense polymorphism in the ARLTS1 ADP-ribosylation factor gene in the 13p14.3 commonly deleted region was found to be associated with familial CLL.14 However, several groups have since been unable to confirm this result in their own familial cohorts.15,16

In a paper recently published in Cell, an epigenetic and genetic mechanism for CLL predisposition in a family ascertained by Henry Lynch with seven affected individuals was proposed.17 The authors found significant linkage to 9q21-22 in this family and sequencing of the region identified a novel regulatory sequence change in the death-associated protein kinase, DAPK1 gene, in all affected members analysed.17 This sequence change correlated with significant down-regulation of DAPK1 expression in these individuals. The same authors demonstrated that DAPK1 is epigenetically silenced in 89% of sporadic CLL, thus reduced expression of this gene appears to be a potent promoter of CLL formation.17 While it has not been definitively proven that DAPK1, or this sequence variation, is causative of CLL in this family, the data signifies the potential for regulatory mutations to play a role in familial cancer. It also shows that DAPK1, like the other two known familial haematological malignancy genes, RUNX1 and CEBPA, is important in both familial and sporadic haematological malignancies (see below).

Lymphoproliferative disorders – non-Hodgkin lymphoma and Hodgkin lymphoma

Several studies utilising large Swedish and Danish cancer registries have identified significant familial aggregation of the lympho-proliferative disorders, non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL).18-20 The 1984 Tasmanian study by Giles et al identified 13 potential families (at least two affected first degree relatives) with NHL and found that the overall risk for first degree relatives of an affected individual was 3.15-3.61.4 However, no chromosomal regions or candidate genes have yet been implicated.

Acute leukaemia

Families with acute lymphocytic leukaemia (ALL) have been reported21,22 and a significant number of families with predisposition to AML have been described.23 Families with aggregation of AML can be broadly segregated into those with a pre-leukaemic familial platelet disorder (FPD-AML), those with a pre-leukaemic early onset myelodysplasia (MDS-AML) and those with no obvious pre-leukaemic phenotype (AML). Clinically, this pre-leukaemic phase allows identification of “potentially unaffected” siblings for genetic testing and allogeneic bone marrow donation. The gene responsible for most, if not all cases of FPD-AML, has been identified as has one gene for familial AML. No gene has been identified for a number of other familial AML cases, or for MDS-AML cases, however one region on 16q22 has been implicated in MDS-AML.

The FPD-AML gene, RUNX1, is present on 21q22.1 and is one of the most frequent targets of chromosomal aberrations in sporadic AML and point mutations, deletions and amplifications have also been identified.24,25 Germline RUNX1 mutations have been found in 12 families with FPD-AML.26-31

The other identified familial AML gene, CEBPA, lies on 19q13.1 and is mutated in approximately 9% of sporadic AML.32 Germline mutations were recently identified in two families with AML and accompanying eosinophilia, but with no obvious pre-leukaemic phenotype.33,34 These two germline mutations affecting the same polyC string, appear to cause a truncation of the normal 42kDa protein resulting in increased formation of the 30kDa dominant negative isoform, which inhibits DNA binding and transactivation by wild-type CEBPA.33,34 We have recently identified (unpublished data) similar mutations in the Sydney pedigree described by Fred Gunz et al.3 An unexpected observation in this pedigree is that affected carriers of the mutation have an extremely poor clinical outcome compared to the two other published pedigrees, in which some patients were treated in the 1960s and clinical outcome was excellent.

The chromosomal region 16q22 was found through candidate region linkage analysis to be linked with disease in two families with MDS-AML.35-37 The gene for the integral cofactor of RUNX1 and CBFB lies within this region, however pathogenic mutations in this gene and several other neighbouring candidate genes have been ruled out in both families.38,39 There still remains a large number of families reported in the literature in which no causative mutation has been identified.

Syndromic predisposition to leukaemia

Several inherited syndromes also confer an increased risk of haematological malignancy, however a number of other disease characteristics are also present. These syndromes result from mutations in genes whose key functions are not confined to the haematopoietic system, and are thus less likely to represent key haematological malignancy driver genes in sporadic cases. However, insight into oncogenesis may still be gained through identifying how these genes lead to an increased risk of haematological malignancy. Specific syndromes are outlined in table 1, however a general overview of the different groups of syndromes is given below.

Table 1

DNA repair syndromes

Autosomal recessive mutations leading to DNA repair deficiency have been shown to predispose to cancer, particularly haematological malignancies. Such syndromes include Ataxia Telangiectasia, Fanconi Anaemia and Li Fraumeni syndrome.

Bone marrow failure syndromes

Bone marrow failure syndromes show defects in several hematopoietic lineages and include Kostmann syndrome of severe congenital neutropenia, Shwachman Diamond syndrome, dyskeratosis congenital and Diamond-Blackfan anaemia. All of these syndromes strongly increase the risk of acquiring MDS and leukaemia.40

Immuno-deficiency syndromes

Some immuno-deficiency syndromes have also been linked to an increased risk of haematological malignancy, however it is still unknown how these syndromes predispose to malignancy. These syndromes include severe combined immunodeficiency disease, Wiskott-Aldrich syndrome and Xlinked lymphoproliferative syndrome. All have been shown to predispose to B-cell lymphomas.

Australian Familial Haematological Cancer Study (AFHCS)

The only systematic familial collection of haematological malignancies is being performed by Henry Lynch in the US, whose collection has many families with multiple myeloma, and Richard Houlston at the Institute of Cancer Research in the United Kingdom, whose collection of families with at least one case of CLL and other haematological malignancies is being utilised to identify familial CLL genes. The AFHCS was established to systematically collect Australian families with all types of haematological malignancies.

The AFHCS represents a powerful collaboration between researchers, nurses, haematologists and oncologists, enabling families to be identified, pedigrees assessed and relevant affected and unaffected samples to be efficiently collected. Collection criteria includes affected sibling pairs, parent child transmission and/or three first degree relatives. This approach has already identified 24 families with apparent predisposition to haematological malignancy. Calculations based on this rate of collection within South Australia alone have suggested that at least 200 such families may exist within Australia. The families collected thus far include CLL, AML, HL and NHL families, as well as mixed haematological malignancy families.

Our preliminary data does not support the fact that familial haematological malignancies are rare. Indeed, similar to other cancers, we would propose that 5-25% of haematological malignancies will be caused by either highly penetrant germline mutations (5-10%), or will show ‘familial’ clustering due to lower penetrance germline mutations and/or gene–environment interactions (10–15%). Our database shows 124 Australians with familial haematological malignancies and we have identified RUNX1 and CEBPA mutations in 36 Australian patients from three families, including many at-risk individuals. This information has already been used in the choice of bone marrow donors.

The power of this approach is the ability to identify families and subsequently recruit a large number of relatives of the pro-band, both affected and unaffected, into the study. Close collaboration with the admitting hospitals also enables collection of affected pathology samples, which reduces the confounding effect of the high mortality of these diseases on linkage power. Linkage remains the most powerful method for monogenic disease gene identification and the AFHCS provides a unique opportunity to obtain enough samples to allow powerful linkage to be performed.


The prevalence of familial predisposition to haematological malignancy is becoming increasingly apparent. To date, it has not been properly studied. Whilst many syndromes increase the risk of leukaemia or lymphoma, there are increasing numbers of purely haematological familial predispositions being identified due to increased awareness among clinicians. The variety of haematological malignancies represented by these families, for example AML, CLL and HL, suggests that a number of distinct haematological malignancy driver genes await discovery.

Currently, disease gene identification in families with haematological malignancy predisposition is confounded by an inability to perform linkage analyses. Collaborative efforts such as the AFHCS represent a potential solution to this problem through their systematic and efficient collection of families, where samples from a number of affected and unaffected individuals are available (including pathology samples).

It is hoped that identification of these familial haematological malignancy genes will identify novel players in the more common sporadic forms of the disease. Subsequent studies on the downstream events occurring during disease progression in these families, will aid in the elucidation of the mechanisms of both familial and sporadic haematological malignancy, as well as the discovery of novel therapeutics and diagnostics.


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