Genetic susceptibility to chronic lymphocytic leukemia

Leukemia (2002) 16, 1008–1014  2002 Nature Publishing Group All rights reserved 0887-6924/02 $25.00 www.nature.com/leu REVIEW Genetic susceptibility to chronic lymphocytic leukemia RS Houlston1, D Catovsky2 and MR Yuille2 1 Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK; and 2Academic Department of Haematology and Cytogenetics, Institute of Cancer Research, Sutton, UK There is increasing evidence that a subset of chronic lymphocytic leukemia is caused by an inherited predisposition. Here we review the evidence for an inherited predisposition, the characteristics of familial cases and evidence for the involvement of specific genes. Leukemia (2002) 16, 1008–1014. DOI: 10.1038/sj/leu/2402538 Keywords: inherited susceptibility; chronic lymphocytic leukemia SPOTLIGHT Introduction In Western countries, leukemia affects 1–2% of the population.1 B cell chronic lymphocytic leukemia (CLL) is the most common form of leukemia accounting for around 30% of all cases.2 The incidence rate of CLL increases logarithmically from age 35 with a median age of diagnosis at 65 years.3 A very small number of acute leukemia cases are well documented to occur at a higher frequency in individuals with constitutional chromosome anomalies or are a feature of some Mendelian cancer syndromes. While there is general awareness of these associations, by contrast, CLL and associated B cell lymphoproliferative disorders (LPDs) have not been thought of until recently as having an inherited genetic component. However, evidence from epidemiological studies and family studies suggests that a subset of CLL may also be caused by an inherited predisposition which gives rise to familial forms of the disease. Identification of the gene or genes underlying familial forms of CLL may be useful for diagnosis and treatment of those at high risk, as well as serving as a model for CLL tumorigenesis in general. Evidence for a genetic predisposition to chronic lymphocytic leukemia Epidemiological studies Seven epidemiological studies have systematically examined the risk of CLL and other LPDs in relatives of patients (Table 1). Four of the studies were case–control and three were cohort in design. All of the case–control studies examined the risk of leukemia in relatives of CLL patients. All found risks of leukemia or lymphocytic leukemia in relatives. The three cohort studies were all retrospective in design. The study reported by Gunz et al4 was based on a survey of 909 families ascertained through leukemia cases. The study reported by Giles et al5 made no distinction between type of LPD in their analysis of the family histories of cases diagnosed between 1972 and Correspondence: RS Houlston, Section of Cancer Genetics, Institute of Cancer Research, 15 Cotswold Road, Sutton Surrey SM2 5NG UK; Fax: +44 208 722 4362 Received 4 April 2001; accepted 20 September 2001 1980 in Tasmania. The study reported by Goldgar et al6 was a systematic analysis of clustering of malignancy at 28 distinct sites using the Utah population database. Relatives of lymphoctic leukemia cases were at a 5.7-fold increased risk of the same hematological malignancy. The risk of LPD in relatives reported in the three studies was comparable to that observed in the case–control studies. Although none of these studies has systematically examined the familial risk of leukemia by specific subtype, it is likely that the familial risk of leukemia in relatives of lymphocytic leukemia patients reflects an increased risk of CLL since acute lymphoblastic leukemia is the primary potential confounding diagnosis, but does not display an increased sibling risk.7 A number of inherited susceptibility genes cause cancer at several sites. Therefore any excess of cancer at sites other than CLL in relatives may reflect in part the pleiotropic effects of an inherited predisposition gene. In addition to a possible relationship between CLL and other B cell LPDs, a relationship between lymphocytic leukemia and granulocytic leukemia and rectal cancer was observed in the study reported by Goldgar et al.6 Survey of published familial cases Over 50 pedigrees have been reported which show clustering of CLL (Table 2). It has often been suggested that even very striking familial clusters of common malignancies can be ascribed to ascertainment bias. This is, however, a statistical fallacy. For example, Table 2 identifies reports of 24 families with three or more affected individuals, nine of which were ascertained by the authors yet a family with three affected siblings would be expected to occur by chance about every 1000 years. A few reports of relatively large kindreds clearly show vertical transmission of CLL and other LPDs, suggesting that predisposition to CLL and other LPD is caused by the inheritance of a dominantly acting gene (or genes) with incomplete penetrance and pleiotropic effects. Although most of the families reported are nuclear rather than multigenerational, it is conceivable that many family members may have subclinical disease as CLL generally has an indolent course. Such a notion is supported by the obervation that in some of the families reported apparently unaffected family members had a persistent lymphocytosis.8 It is relatively difficult to determine the proportion of CLL cases that have a family history of the disease because much disease goes undetected. However, in a recent systematic survey of CLL, 6% of patients reported a family history of CLL and another 5% a family history of a LPD.9 Published CLL pedigrees appear to be characterized by an earlier onset than sporadic forms of the disease, suggesting a more aggressive clonal expansion. One intriguing feature seen Genetic susceptibility to CLL RS Houlston et al 1009 Familial risks of CLL and other LPDs Study Diagnosis in index case Cohort studies Giles et al5 Gunz et al4 LPD Leukemia Goldgar et al6 Lymphocytic leukemia Case–control studies Cartwright et al46 47 Linet et al CLL CLL Pottern et al48 CLL 49 Radovanovic et al CLL Relative Observed Expected Risk (95% CI) LPD in first-degree relatives Leukemia in first-degree relatives Lymphocytic leukemia in firstdegree relatives 35 16 10.3 6.61 3.4 (2.4–4.7) 2.4 (1.9–3.9) 18 3.6 5.7 (2.6–10.0) Lymphocytic leukemia in blood relatives Leukemia in parents and siblings Leukemia in parents and siblings Leukemia in first- and seconddegree relatives 5/330 2/559 4.3 (0.9–19.5) 25/342 10/342 2.6 (1.2–5.5) 13/237 30/1207 2.3 (1.2–4.4) 7/130 0/130 — in the expression of CLL in many of the families reported is anticipation, the phenomenon of earlier onset and more severe phenotype in successive generations.10–14 This phenomenon is observed in other Mendelian diseases, where it is known to have a specific molecular basis. Anticipation in familial CLL may have a similar basis, although other possibilities exist, such as a cohort effect in relation to viral or other environmental exposures, which act as risk factors. Molecular genetics of familial chronic lymphocytic leukemia Molecular studies of neoplastic disease have shown that multiple genetic alterations are an essential feature of the tumorigenic process. These alterations involve two broad classes of genes: tumor suppressor genes, whose products normally directly inhibit neoplastic development by negatively regulating growth and differentiation; and oncogenes which positively contribute to the neoplastic transformation when activated. Inactivation of tumor suppressor genes coupled with activation of oncogenes leads to malignancy. Genetic alterations involved in the transformation of normal cells to the malignant state can be both inherited in the germline and arise somatically in the tissue in which the cancer arises. The genetics of CLL are conceivably similar to the genetics of breast and colon cancers, in which a subset of the disease occurs in individuals who possess in their germline one or more of the causal genetic alterations required for the neoplastic transformation. In the majority of cases, these genes are altered at the tissue level by random errors in cellular processes. According to the multistep model of carcinogenesis, the development of the full neoplastic phenotype in both inherited and non-inherited forms of CLL depends upon multiple genetic alterations. The genetic basis of CLL is largely unknown. Cytogenetic abnormalities appear, probably for technical reasons, to be less frequent in CLL than in many other hematological malignancies.15 A number of chromosome breakage syndromes have been known for many years to be associated with an increased risk of leukemia,16 including the recessive disease, ataxia telangiectasia (A-T). A-T maps to chromosome 11q23.17 A-T patients have an increased risk of lymphomas and leukemias, while A-T heterozygotes may have a significantly increased risk of breast cancer.18,19 CLL has also been reported in A-T families20 suggesting that A-T heterozygotes may be at an increased risk. In a retrospective study of the cancer incidence in 110 A-T families the risk of hematological and lymphoid malignancies was increased in blood relatives of AT patients and CLL accounted for all but one of the leukemias seen in adult blood relatives. However, these observations did not attain statistical significance. It has been demonstrated that the ATM gene is mutant in approximately 20% of samples from CLL patients and that some patients have heterozygous germline mutations.21–24 The ATM gene specifies a 12 kb mRNA encoding an approximate 350 kDa.25 The 3′ end of the gene has some homology to phosphinositide 3-kinases and to S. cerevisiae TEL1 that controls telomere length and maintenance of genome integrity.26 Homozygous germline mutations in ATM are associated with radiosensitivity and genomic instability: the mutation rate is increased; double strand breaks are misrepaired; there is a high frequency of cytogenetic rearrangements; homologous recombination is increased and error-prone. A-T cells also show defects in cell cycle checkpoints. These defects underlie a model,27 in which the Atm protein functions to survey the genome for radiation damage. This and the prevalence of leukemia in relatives of patients with A-T led a number of researchers to question whether germline ATM mutations are involved in familial cases of CLL. Stankovic et al21 observed two germline ATM mutations in 32 cases (6.3%) of CLL (P = 0.04; 95% CI: 1–21%). We recently assessed the role of ATM in familial CLL through a linkage analysis of 28 families.28 The observed distribution of sharing of ATM haplotypes between affected individuals did not lend support to the notion that ATM is involved in familial CLL. However, the study was not sufficiently large to preclude that ATM might account for up to a two-fold sibling relative risk. Multigenerational families are characteristic of highly penetrant susceptibility genes, it is therefore conceivable that genes conferring susceptibility to CLL are associated with more modest risks. Assuming that approximately 6% of CLL is caused by ATM,21 mutations in this gene should only confer a sibling relative risk of 1.1. ATM therefore represents a credible candidate predisposition locus for CLL. While ATM is an attractive CLL predisposition gene candidate, there is currently insufficient evidence to show unambiguously that ATM acts as a susceptibility locus. The established relationship between HLA and Hodgkin’s SPOTLIGHT Table 1 Leukemia Genetic susceptibility to CLL RS Houlston et al 1010 Table 2 Published familial CLL cases Reference Affected family members* Guasch 195450 Sibs, M, M Parent F, offspring M Sibs M, M Sibs M, M, M, F Sibs M, M, M Sibs M, M Sibs M, M Sibs M, M Sibs M, M, F Parent F, offspring F MZ twins M, M Parent M, offspring M Parent M, offspring M Sibs M, M Sibs M, M Uncle, nephew Sibs M, M; Sibs M, M Sibs F, M, M Brem et al 195551 Videbaek 195852 Hudson et al 196053 SPOTLIGHT Gunz et al 196254 Fitzgerald et al55 Furbetta et al 196356 Wisniewski 196657 Rigby 196658 Ardizzone et al 196859 Magaraggia et al 196860 McPhedran et al 196961 Fraumeni et al;62 Blattner et al 196963 Gunz et al 196964 65 Undritz et al 1971 Potolosky et al 197166 Schweitzer et al 197367 Blattner et al;68 Neuland et al;69 Shen et al;70 Caporaso et al 199171 Gunz 197572 Petzholdt 197673 Fazekas et al 197874 Branda et al 197875 Conley et al 198076 Alfinito et al 198277 Vanni et al 198378 Brok-Simoni et al79 Hakim et al 198780 Eriksson et al 198781 Shah et al 199282 Cuttner 199383 Fernhout et al 199784 Yuille et al 20009 Grandparent M, parent F, offspring F Parent M, offspring M 2 half-sibs Sibs M, M Sibs M, M Sibs F, M, F, cousins F, M, M Sibs F, M, M Sibs M, F Sibs M, M Sibs M, M, M, F Sibs F, F Additional information Sib M LK Sib CGL Sib LY, sib LY, sib acute LK Sibs F, M, M, F, F Parent M, offspring M, M, F, F 3 first degree; 3 others Sibs M, M, M Sibs, M, M, M Parent F; offspring M Sibs F, F Sibs M, M Nephew, maternal aunt; Nephew M; greataunt Sibs F, F Sibs F, F MZ twins F, F, sib F Sibs M, M; Sibs M, F; Sibs M, F; MZ twins M; Parent M, offspring M; Parent M, offspring M Sibs F, M, F Sibs M, M; Parent M, offspring M; MZ twins M, M Sibs F, F, F, F Parent M, offspring M, pat cousin F; Parent F, offspring M; Parent F, offspring M; Parent F, offspring F; Parent M, offspring M; Parent F, offspring M; Sibs M, F; Sibs M, M; Parent M, offspring M; Parent F, offspring M; Parent F, offspring F; Sibs M, M Parent F, offspring M; Parent M, offspring M Sib M NHL Nephew NHL Sib F LK Offspring F LK Offspring M HL CGL, chronic granulocytic leukemia; HL, Hodgkin’s lymphoma; LK, leukemia; LY, lymphoma; NHL, non-Hodgkin’s leukemia. Leukemia Genetic susceptibility to CLL RS Houlston et al Somatic changes in familial CLL Investigation of somatic genetic changes in familial cancer tumor samples can, in principle, provide information on the etiology of the disease. Two types of investigation on familial CLL samples have been conducted that have used this approach. One type of investigation is to look for a region of recurrent genomic loss in tumor cells from familial cases. Such a region may harbor a CLL tumor suppressor gene. The technique of comparative genomic hybridization (CGH) permits this type of investigation by examining the whole genome for regions of chromosomal loss or gain. We have applied CGH to 24 familial cases of CLL (unpublished data). The data indicated that three regions of the genome may harbor predisposition genes: Xp11.2-p21, Xq21-qter, 2p12-p14 and 4q11-q21. Considerable caution is called for in extrapolating from CGH data and only detailed investigation of these regions of the genome by linkage analysis or by closer delineation of regions of shared loss between affected family members may permit candidate familial CLL gene identification. A second line of investigation has characterized immunoglobulin variable regions in familial CLL. This type of study may characterize familial CLL as genetically homogeneous or genetically heterogenous. During the B cell response to T celldependent antigens, B cells undergo a rapid proliferative phase in the germinal center. This is accompanied by the introduction of mutations into the immunoglobulin (Ig) variable region (V) genes. The B cells are then selected according to the affinity of the encoded immunoglobulin for antigen, resulting in affinity maturation of the response. It is now apparent that there are two subsets of CLL, one with a low load of mutations and poor prognosis and one with a heavy load of mutations with a much more favorable prognosis. Between 20% and 50% of all CLL cases have IgV mutations.41,42 Two investigations have assessed IgV status in familial CLL.43,44 In 23 CLL families, 66% of 48 affected family members had IgV mutations. This frequency is significantly higher for familial CLL than sporadic CLL (assuming a mutation frequency of approximately 50%, significance levels are ⬍0.001 in Pritsch et al43 and 0.04 in Sakai et al44). Using the data from these studies it is also possible to assess whether there is intra-familial concordance for IgV status. Table 3 shows the number of concordant and discordant pairs in each of these studies. To formally assess the significance, the observed distribution is compared with the random distribution predicted on the basis of the observed prevalence of the mutated phenotype. Whilst the distribution of phenotypes in the families reported study by Pritsch et al43 is not significantly different from that expected, the distribution in the families reported by Sakai et al44 shows a clear deviation. Combining data from the two studies, the concordance is significant within families (␹2 = 11.2, 1 df, P ⬍ 0.001). This strongly suggests that determining IgV status will be helpful in subgroup analyses of linkage data and future meta-analyses. 1011 SPOTLIGHT lymphoma, another B cell disorder and the association between autoimmune disease and CLL raises the possibility that genes within the MHC region may be determinants of CLL susceptibility. Hodgkin’s lymphoma shows strong linkage to HLA.29,30 The underlying basis of linkage is not through a common haplotype, but it appears that certain HLA-DPB1 alleles may affect susceptibility and resistance to specific subtypes of Hodgkin’s lymphoma.31,32 Patients with CLL frequently share common HLA haplotypes with relatives with autoimmune disease. The majority of B cell CLL is CD5+ and B cells are implicated in autoimmunity. Hence genetic determinants of CD5+ B cell proliferation or differentiation are likely to be involved in both B-CLL and autoimmune disease. The notion of a relationship between CLL and autoimmune disease is supported by animal studies using congenic New Zealand mouse strains.33,34 In Hodgkin’s disease, the allele sharing probabilities between affected siblings suggest that the HLA locus is likely to explain a two-fold sibling relative risk with more than half of all cases arising in susceptible individuals. There is no evidence that such a situation exists with respect to familial CLL. In the linkage study reported by Bevan et al35 there was no evidence for linkage in an analysis of 27 families. However, the 95% confidence limit for the estimate of the sibling relative risk ascribable to the HLA did not preclude that variation within HLA or the MHC is a determinant of CLL susceptibility in some instances. The B cell antigen receptor (BCR) comprises membrane Igs (mIgs) and a heterodimer of Ig (CD79a) and Ig (CD79b) transmembrane proteins, encoded by the mb-1 and B29 genes, respectively. These accessory proteins are necessary for surface expression of mIg and BCR signaling.36 CLL B cells frequently express low to undetectable surface Ig, as well as CD79b protein and show abnormal B29 expression and/or function. The possibility that these abnormalities might be caused by B29 gene mutations has been assessed recently in a study of 10 CLL families.36 While a few silent or replacement mutations were observed, none led to a truncated CD79b protein, furthermore there was no evidence of co-segregation of mutation with disease strongly implying that germline mutations in B29 are not implicated in familial CLL. Linkage of Hodgkin’s disease to the pseudo-autosomal region of the genome has recently been proposed Horwitz and Wiernik37 on the basis of an excess of sex concordance among affected siblings. The common lineage of Hodgkin’s and CLL prompted us to examine whether familial CLL also shows pseudo-autosomal linkage. An analysis of published CLL and families shows that the frequency of sex-concordant sibling pairs is skewed beyond random expectation, however it is impossible to preclude publication bias and so the implicated pseudo-autosomal linkage in CLL is questionable.38 In a number of Mendelian diseases, anticipation has been shown to be indicative of a dynamic mutation mechanism involving expansion of a triplet repeat motifs.39 If the genetic basis of familial CLL involves a similar mechanism this offers a novel method of identifying a predisposition locus for the disease, since specialized methods exist specifically for cloning genes associated with such expansions.40 Conclusions Chronic lymphocytic leukemia has not generally been considered to have an inherited genetic basis. However, there is Table 3 Frequency of IgV concordancy IgV mutation status familial phenotype N/N N/Mut Mut/Mut Pritsch et al43 Sakai et al44 Combined 1 2 11 5 2 6 6 4 17 Mut, IgV mutation present; N, no IgV mutation present. Leukemia Genetic susceptibility to CLL RS Houlston et al 1012 SPOTLIGHT indirect evidence that a subset of CLL cases may be ascribed to the inheritance of an autosomal dominant gene. It is therefore desirable not to restrict the collection of family histories to hematology patients with the rare inherited cancer syndromes. Furthermore, there is some evidence that familial forms of CLL may warrant more attentive clinical management, owing to a more aggressive phenotype. Identification of the genes involved in inherited forms of CLL should provide insights into the pathogenesis of CLL in general. At present there is no convincing evidence that any specific gene acts as a susceptibility locus and identification of these genes for CLL awaits future linkage studies. Genetic heterogeneity severely reduces the power of any linkage analysis to detect disease genes. Since subcategorization of a disease provides a strategy to mitigate the impact of heterogeneity on linkage, IgV43,44 and BCL-645 status may achieve this for familial CLL. The identification of a CLL predisposition gene through genetic linkage is clearly contingent on the acquisition of a large series of informative families. Experience in other fields of cancer research has shown that such family collections are only readily achievable through the establishment on large pan-country collaborations. Therefore to expedite the ascertainment and collection of families we have established an International CLL Linkage consortium. We invite interested parties who identify families segregating CLL with or without an associated LPDs to contribute to the initiative we have established. 9 10 11 12 13 14 15 16 17 18 Acknowledgements 19 The authors’ work is supported by the Leukaemia Research Fund. We thank all the families and their clinicians that have contributed to our research. 20 21 Editor’s note We are very indebted to Dr Peter Daniel who recruited and evaluated all the Reviews published in this Spotlight. Authors who are interested in contributing a Review for this Spotlight are invited to contact the Editor-in-Chief, Dr Muller Bérat. 22 23 24 References 1 Miller BA, Ries LAG, Hankey BF, Kosary CL, Harras A, Devesa SS (eds). Cancer Statistics Review 1973–90. National Cancer Institute, NIH 1993, Pub. No. 93–2789. 2 Gale RP, Foon KA. Biology of chronic lymphocytic leukemia Semin Haematol 1987; 24: 209–229. 3 Linet MS, Blattner WA. The epidemiology of chronic lymphocytic leukemia in: Polliack A, D Catovsky D (eds). Chronic Lymphocytic Leukemia Harwood Academic: Chur, 1988, pp 110–120. 4 Gunz FW, Gunz JP, Veale AM, Chapman CJ, Houston IB. familial leukemia: a study of 909 families. Scand J Haematol 1975; 15: 117–31. 5 Giles GG, Lickiss JN, Baikie MJ, Lowenthal RM, Panton JJ. 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