Background

Approximately 1.3% of males and 1% of females in Europe and North Americadevelop leukaemia. CLL is the most common of its subtypes, constitutingabout 30% of all cases. Its incidence rate increases logarithmically fromage 35 and has a median age of onset of 64 years. No single cytogeneticabnormality or gene mutation is found in all CLL cases. However, activation ofeach of the oncogenes BCL1, BCL2 and BCL3 has been reported in some cases afterdetection of cytogenetic abnormalities, as has mutation in tumour suppressorgenes including those associated with the mutator phenotype and p53 . Aputative tumour suppressor locus has been identified on chromosome 13q14.

A number of case-control and cohort studies have examined the cancer risksassociated with a family history of lymphoproliferative disorders, includingCLL (Table 1). These studies showed an elevated risk of lymphoproliferativedisorders in relatives. Although no study has systematically examined theincidence of leukaemia by specific subtype in cases and relatives, there isevidence suggesting that the familial risk of leukaemia is greater than therisk of all lymphoproliferative disorders. In the cohort study reported byGoldgar et al using the Utah population database, a 6-fold increase in riskwas seen in relatives of patients with lymphocytic leukaemia. This databasecomprises over 1.4 million records on a population with normal levels ofinbreeding that is genetically representative of a Northern Europeanpopulation.

Table 1: Familial leukaemia risks

Case reports

There is no doubt from literature reports over 7 decades that multiple cases ofCLL do occur in families. Two of these are illustrated in Figures 1 and 2. Bothare consistent explicitly or implicitly with vertical transmission of anautosomal trait over three generations. In Figure 1, the absence of recordedCLL in the first two generations is consistent with incomplete penetrance.

Figure 1. Adapted from McPhedran et al - filled symbols indicate adiagnosis of CLL

Figure 2. Adapted from Furbetta et al - filled symbols indicate adiagnosis of CLL

Although early reports on familial CLL were published before B-cells had beendescribed, most of the diagnoses are likely to be accurate. This is because thespecific morphology of mature B-cell CLL makes diagnosis comparatively easy andthe generally indolent course of the disease contrasts markedly with the otherleukaemias. We have identified reports that describe over 80 pedigrees whichshow clustering of CLL and, sometimes, other lymphoproliferative disorders.Some of this literature has been reviewed . Of these 80 pedigrees,over a quarter are multigenerational CLL families with up to four generations,thus illustrating vertical transmission of CLL consistent with an autosomaldominant mode of inheritance. The majority of families comprise sibs. This isnot surprising: CLL usually has an indolent course and may be asymptomatic formany years, yet it also has a late onset. It has been suggested that evenstriking clusters of common cancers could be due to ascertainment bias. Thisis, however, statistical fallacy. For example, we have identified reports of 10sibships with three of more affecteds, yet a family with 3 affected sibs wouldbe expected to occur by chance about every 1,000 years.

Analysis of these reports [26] has also indicated a mean decline in age ofonset of 21 years (SE = 4.1y) (P = 0.001) between the affected in the parentalgeneration and the affected offspring as well as a reduced cumulativedisease-free survival period for the offspring. Anticipation is now known toarise in a dozen instances from single gene defects associated, variously, withdominant or recessive modes of inheritance.

Identification of a familial CLL gene would significantly help research intothe molecular pathology and aetiology of CLL. Earlier diagnosis of CLL and newapproaches to therapy should also follow identification of a gene or genes.

Current progress

In 1996 we began collecting detailed family histories from 130 patients withCLL registered at the Royal Marsden Hospital under the care of D.C. In order toextend the study, the MRC Adult Leukaemia Working Party gave us permission toidentify CLL patients in MRC trials and contact their consultants (DC is theMRC trials co-ordinator). Of the 1402 patients with CLL registered in the CLLtrials, we have contacted and collected family history information on 250 (June1997). We have identified 20 families with at least two CLL cases. In most ofthe potentially informative families, the affecteds are siblings. We arepursuing a further 39 families.

We initiated this spring an International Co-operative Group on Familial CLLunder the auspices of the International Workshop on CLL with a successfulsatellite meeting of IWCLL. All members of IWCLL in 32 nations overseas havebeen contacted and many have expressed an interest in contributing. So far,around 20 overseas CLL families have been identified and blood samples arebeing collected.

We have confirmed the finding of anticipation in our families and we havepublished data that does not support the claim that germline mutationsin the Ataxia Telangiectasia confer a particular risk of CLL.

The identification of sufficient CLL families to be able successfully to perform a genetic linkage study to find the CLL gene is a major task. With support from the Medical Research Council in the UK and from the International Workshop on CLL, the Co-ordinating Centre based at the Institute of Cancer Research and the Royal Mrsden NHS Trust Hospital in London has been able to accrue families from around the world on a collaborrative basis. For example, haematologists from 9 countries contributed families to a paper testing a candidate gene, ATM. More detailed genetic approaches will become possible as the numbers of families contributed increases.
Clinicians who identify CLL families (i.e. families with more than one affected individual) are encouraged to advise the Co-ordinating Centre.

Contact:
M. R. Yuille MA PhD
Academic Department of Haematology and Cytogenetics
Institute of Cancer Research
15 Cotswold Road
SUTTON Surrey SM2 5NG UK

Telephone: 020 8 722 4666
Fax:E-mail: [email protected]

OR

Prof Daniel Catovsky DSc(Med) FRCPath FRCP FMedSci
Academic Department of Haematology and Cytogenetics
Royal Marsden NHS Trust Hospital
Fulham road
London SW3 6JJ

Telephone: 020 7 808 2880/2875
Fax: 020 7 351 6420

Bibliography

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