Chronic lymphocytic leukaemia genetics overview - Wiley Online Library

review

Chronic lymphocytic leukaemia genetics overview Neil Caporaso,1 Lynn Goldin,1 Christoph Plass,2 George Calin,3 Gerald Marti,4 Steven Bauer,4 Elizabeth Raveche,5 Mary Lou McMaster,1 David Ng,1 Ola Landgren1 and Susan Slager6 1

Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 2Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center at The Ohio State University, Columbus, OH, 3Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH, 4Cellular and Tissue Therapy Branch, Division of Cell and Gene Therapies, Office of Cellular Tissue and Gene Therapies, Center for Biologics Evaluation and Research (CBER), US Food and Drug Administration (FDA), NIH, Bethesda, MD, 5New Jersey Medical School/University of Medicine and Dentistry of New Jersey, Newark, NJ, and 6Mayo Clinic College of Medicine, Division of Biostatistics, Department of Health Sciences Research, Rochester, MN, USA

Summary Although the familial aspect of chronic lymphocytic leukaemia (CLL) has been appreciated for decades, it is only with the recent confluence of improved molecular and gene technologies and world-wide collaborative networks that accelerated progress has become apparent. In this summary we highlight selected themes in the genetics of CLL emphasizing the opportunities and challenges of this malignancy. Keywords: genetic association, linkage, susceptibility, candidate genes, chronic lymphocytic leukaemia, family studies.

some of the key findings of family studies. While the risk of CLL is most prominently increased in relatives of CLL cases, risks are also increased for other lymphoproliferative (LP) malignancies. Based on these types of broad population data we can infer, for example, that the co-aggregation of LP tumours often observed in our families is not due to referral bias but reflects sharing of at least some genes that contribute to the risk for multiple LPs. This means that linkage and association studies in each of these malignancies will need to be closely examined for common elements that might reveal common mechanisms.

Molecular epidemiology Familiality Familial aggregation of a trait is a necessary but not sufficient condition to infer a contribution of heredity, and identifying such families has led to elucidation of the genetic basis for numerous conditions (Risch & Whittemore, 2006). Chronic lymphocytic leukaemia (CLL) exhibits one of the strongest familial tendencies of any malignancy (Bauer et al, 1998; Yuille et al, 2000; Goldin & Caporaso, 2007). CLL kindreds have been extensively described in the literature for decades (Gunz & Veale, 1969). Fraumeni et al (1969) reported one such kindred and since then the National Cancer Institute (NCI) group has continued to accumulate families. Recently, larger studies based on linked registry data from Scandinavia and consortia have provided a much more comprehensive overview. In a review of diverse work in this area Goldin and Caporaso (2007) has summarized

Correspondence: Dr Neil E. Caporaso, Pharmacogenetics Section, Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, EPS 7116, 6120 Executive Blvd., Bethesda, MD 20892, USA. E-mail: [email protected]

doi:10.1111/j.1365-2141.2007.06846.x

The current status of studies looking to implicate chemical, radiation, and immune deficits as risk factors for CLL are reviewed elsewhere in this issue but extrinsic environmental factors in CLL have yet to be clearly implicated. This is relevant to the genetics of CLL, not only because the robustness of the familial tendency suggests the search for genes in CLL should be a high priority, but also because the genes eventually identified may provide etiologic clues to environmental agents, and also because study design will be influenced, i.e. whether to power studies for gene or gene-environment and whether to favour candidate genes or large scale anonymous searches. Perturbations in immune-related phenomenon are plausible as contributing to the genesis of CLL based on strong similarities in the receptors involved in antigen binding in the cell of origin (antigen stimulated B-cell), clinical characteristics, and association between respiratory infections (Landgren et al, 2007a), certain immune-related conditions (Landgren et al, 2006a, 2007b) and CLL. If a limited set of antigens promotes division of lymphocytes destined for malignancy, there is hope that, as with gastric lymphomas and Helicobacter pylori, or mantle cell lymphoma and hepatitis C virus (Mazzaro et al, 1996; Hermine et al, 2002), future studies will identify them (Chiorazzi et al, 2005). Interestingly, familial LP patients were

Journal Compilation ª 2007 Blackwell Publishing Ltd No claim to original US government works, British Journal of Haematology, 139, 630–634

Review recently reported to have enhanced risk of selected secondary tumours, consistent with genes, environmental factors, or their interaction (Landgren et al., 2006b). The malignant cell that characterizes CLL is unique in that it can be obtained in quantity via simple blood collection. In contrast to this, obtaining tissue from solid tumours is involved and typically involves co-ordination of liquid nitrogen storage capacity with surgical schedules and the co-operation of multiple experts (surgeon, pathologist, technicians, transport team, etc) to obtain samples suitable for the eventual application of advanced technologies. For CLL, obtaining malignant and ‘normal’ cells from blood requires only routine phlebotomy and can be exploited to conduct studies to identify the unique characteristics of this cell. There are some limitations. The role of stroma is increasingly appreciated as being vital to B-cell development and so examining the specific ‘‘CLL cell’’ in isolation may be deceptive (Kay et al 2007; Dave et al, 2004). As in all the haematological/ LP malignancies there are daunting classification issues, i.e. CLL versus small lymphocytic lymphoma. Newer studies based on larger case-control (Slager et al, 2007) and consortia studies (Sellick et al, 2007) will provide new opportunities to test aetiological and genetic hypotheses, and mechanism. Molecular epidemiology may provide unique tools to enhance progress. First, high technology approaches to assaying minute quantities of key exposures adducted to protein or DNA may help to identify key heretofore unsuspected chemicals. Second, Mendelian randomization is a technique whereby the genes implicated in anonymous study may implicate exposures that are processed/metabolized by those genes (Minelli et al, 2004). Using this approach, emerging large scale genetic studies may contribute to the search for elusive environmental cofactors.

Molecular lesions and prognosis While the initial goal of genetics studies of germline DNA is the identification of specific genes/mutations that influence susceptibility to CLL, equally important is the identification of molecular characteristics that define outcome. A stated general goal of the redefinition of medicine based on the new molecular understanding of disease in general, and cancer in particular, is the refinement of disease categories based on molecularly defined treatment and prognostic subgroups. For CLL, this is a reality as heavy chain mutation status defines virtually equal groups with sharply differing prognostic categories. For CLL, IGHV mutation status is mechanistically plausible and independently adds information to the many other traditional factors documented to influence CLL prognosis: lymphocyte doubling time, morphology, immunophenotype characteristics, CD23 expression, Beta-2-microglobulin, cytogenetics, ZAP-70, pattern of bone marrow involvement, and traditional staging according to Rai or Binet (Muntanola et al, 2007). ‘New’ prognostic factors continue to appear in the literature, i.e., smudge cells (Nowakowski et al, 2007), ‘abnormalities on

abdominal computed tomography scan’ and combining traditional clinical/morphological factors with new molecular/ genetic markers is a key challenge. Improved prognostic understanding should accelerate the development of riskadapted treatment strategies that take into account clinical factors, traditional prognostic factors (lymphocyte doubling time, clinical features presence of autoimmune haemolytic anaemia, percentage of atypical cells, bone marrow involvement, etc.) and treatment-related factors (Montserrat, 2001).

Ethnic differences There are important differences in CLL incidence by racial/ ethnic group, best illustrated by the strikingly lower incidence in Asians. In general however, studies of CLL are sparse in other ethnic groups (such as African-Americans). In contrast to studies conducted with breast and colon cancer, where migrant studies show that individuals acquire the rates of new host countries (suggesting environmental factors are determinant in aetiology), migrant studies in CLL support the hereditary component in that low rates of CLL in Asians appear to be stable with migration to western countries (Pang et al, 2002). This underscores the hereditary component of risk and suggests that a future priority can be investigation of mixed ethnicity samples where admixture mapping might efficiently identify susceptibility loci (Seldin, 2007).

The precursor condition (Monoclonal B-Cell Lymphocytosis, MBL) A key goal of this Workshop has been to advance the morphological, population, molecular and familial understanding of the precursor condition Monoclonal B-Cell Lymphocytosis (MBL) (Marti et al, 2005). MBL is described in accompanying reports and the needs to better define the natural history, consider ethical aspects, and conduct studies in diverse groups by age, ethnicity and gender are emphasized. One clear theme in the literature is that MBL is more frequently observed in CLL kindreds (Rawstron et al, 2002; Marti et al, 2003; De Tute et al, 2006). This feature suggests that the condition may offer the opportunity to identify some of the earliest changes in CLL and that taking this condition into account will reduce misclassification in future genetic studies. Although MBL appears to share the age and gender distribution of CLL, little is known about possible etiologic factors. Importantly, we need to know whether CLL is always preceded by the precursor. It is possible that indolent (IGHV mutated) CLL occurs after MBL, while aggressive (IGHV unmutated CLL) has an alternative pathway that develops rapidly and bypasses any precursor state. In familial CLL some kindreds display abnormal clonally expanded B-cells in the background of polyclonal, perhaps normal cells. Comparisons of the normal and abnormal B-cells from such sources could yield insight precursor states and lesions involved in progression. Further refinement in the definition of the precursor state


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Chromosome abnormalities Chromosome abnormalities in CLL are well documented, the most common being an interstitial deletion in13q14 in about 50% of cases (by interphase fluorescence in situ hybridization) followed by del 11q22–q23 (20%), trisomy 12 (15%), del 6q21 (10%) and del 17p13 (5–10%) (Stilgenbauer et al, 1993). Unlike closely related lymphomas, where chromosomal translocations involving oncogenes are common, no single unifying mutation has been identified, although the recent observation that 13q and 11q share a common syntenic ancestral region in the zebrafish suggests a possible explanation for involvement of both these regions (Auer et al, 2007). In spite of extensive work in the last decade as Liu et al (1997) identified the most common deletion at 13q14 in B-CLL, the relationship of 13q deletions to disease is incompletely understood. NCI conducted an initial linkage study involving 94 individuals from 18 families (Goldin et al, 2003) and followed with fine mapping studies in four CLL families that shared a 3.7 Mb region (13q21.33– q22.2). However, no new mutations associated with disease were identified (Ng et al, 2007). Recent work identifying a homologous region to 13q in the New Zealand Black mouse model (Phillips et al, 1992; Raveche et al, 2007) suggests the fundamental importance of this chromosome deficit. The observation that the most common (13q14.3) chromosome abnormality observed in CLL is associated with a favourable prognosis, while less common (11q, tris12, 17p13) abnormalities result in adverse clinical outcomes is not well understood (Dohner et al, 2000). One possible explanation for the favourable prognosis associated with monoalleleic 13q14 deletion is that this is not the initiating event in CLL tumorigenesis, rather it is a by product of oncogenesis and the genes in the deleted region are modifiers of CLL progression. This hypothesis is supported by the finding that deletion 13q14 wan not present in all CD5+/CD19+ purified cells in a subset of CLL patients with deletion 13q14 (Dewald et al, 2003). The observation that regulatory micro-RNA (miRs) genes located at 13q14 are deleted in CLL cells may provide clues as to how this deletion confers a selective advantage to B-cells, possibly by predisposing to additional mutations via regulatory changes involving key oncogenes, i.e. TCL1A via miR29 (Calin et al, 2004; Pekarsky et al, 2006; Nicoloso et al, 2007).

Epigenetics and miRNA Epigenetic changes alter gene expression without changing nucleotide sequence and include DNA methylation and histone modifications (Boultwood & Wainscoat, 2007). Extensive promoter methylation has now been described in CLL with malignancy-specific as well as subgroup-specific distribution patterns. For example, Plass et al (2007) identified nonrandom patterns of methylation in CLL and identified 632

a candidate gene, Death-Associated Protein Kinase 1 (DAPK1), that exhibits a mechanism consistent with known pathophysiology of CLL (i.e. mediator of apoptosis), silencing by epigenetic mechanism in multiple human malignancies including sporadic CLL and downregulation of expression due to a single nucleotide change segregating with disease in a large CLL kindred. Although DAPK down-regulation is associated with a variation in a regulatory single nucleotide polymorphism from a conserved upstream regulatory area, further studies in other kindreds are needed, as the region does not appear in linkage studies conducted to date. MicroRNAs (miRs) are small endogenously expressed translational-repressor RNAs that regulate cellular pathways and are often aberrantly expressed in haematological malignancies (Lawrie, 2007). The location of many human miRNAs at cancer-associated genomic sites underscores their importance in malignancy (Calin et al, 2004). Nicoloso et al (2007) have identified two miRNAs (MIRN15A and MIRN16-1) in the minimally deleted region of 13q14 and observed reduced expression of these miRNAs in a series of CLL cases (41/60, 68%) in comparison with CD5+ B cells. These findings require confirmation in other samples including familial series, but clearly suggest the potential of this approach to supplement traditional methods and identify promising non-coding genes and are a key theme for future investigation. We advocate an integrative approach (Caporaso, 2007) to the investigation of susceptibility. That is, concurrent studies in families and populations, and the application of diverse molecular techniques supplemented with informatics to provide evidence to identify precise genes (from a region of interest) and suggest mechanisms whereby gene mutations alter function. Where possible, investigation of both miRNAs and epigenetic alterations should be included as these types of alterations may provide critical clues to unravel the aetiology of this and other complex traits.

Consortia Two published linkage analyses (Goldin et al, 2003; Sellick et al, 2005) and numerous candidate gene studies have yet to identify a clear group of susceptibility genes that characterize CLL (Slager et al, 2007). A larger combined study including a combined analysis on 206 families has identified new potential regions for disease loci (2q21.2, 6p22.1 and 18q21.1) (Sellick et al, 2007). A key insight emerging from this meeting is that consortial efforts, such as this linkage study, will greatly extend our ability to extract genetic information from families and need to be strongly endorsed. It is clear that many more such families can be identified and optimally utilized for advanced studies through increased participation in consortia and that these consortia also optimize the opportunities for collaborations between mechanistic and population scientists. Moreover, application of advanced molecular approaches that identify new candidates will yield most rapid benefits if they are able to access


Review population and family samples for verification studies. Consortia that allow those investigators already interested in families to pool resources, samples, techniques, etc. are the most promising approaches to advance our understanding. Existing consortia with substantial numbers of subjects for population and family analyses have provided opportunities for high quality studies and are likely to provide the substrate for large-scale investigations in the future, i.e. INTERLYMPH (International Lymphoma Epidemiology Consortium), GEC (Genetic Epidemiology of CLL), and IFCLL (International Familial CLL Consortium). Web based resources will be increasingly utilized. For example, recruitment of families could be supplemented using patient web sites, such as the CLL List Serve. To date, no population-based whole genome study has been conducted on CLL (or other haematological malignancy) but it is certain that such studies will emerge in the near future. Recent successful scans (Gundmundsson et al, 2007) for other malignancies have used high density arrays, large samples (allowing statistical thresholds appropriate for genome-wide searches) and designs that take into account potential bias (i.e. population substructure and genotyping error) and allow for replication in independent samples (Alshuler & Daly, 2007). The consortia approach will be key to incorporating these design features into future CLL studies.

Disclaimer This work does not represent the official position of the Food and Drug Administration.

References Alshuler, D. & Daly, M. (2007) Guilt beyond a reasonable doubt. Nature Genetics, 39, 813–814. Auer, R.L., Riaz, S. & Cotter, F.E. (2007) The 13q and 11q B-cell CLL associated regions derive from a common ancestral region in the zebrafish. British Journal of Haematology, 137, 444–453. Bauer, S.R., Ruiz-Hidalgo, M.J., Rudikoff, E.K., Goldstein, J. & Laborda, J. (1998) Modulated expression of the epidermal growth factor-like homeotic protein dlk influences stromal-cell-Pre-B cell interactions, stromal cell adipogenesis, and the pre-B-Cell interleukin-7 requirements. Molecular and Cellular Biology, 18, 5247–5255. Boultwood, J. & Wainscoat, J.S. (2007) Gene silencing by DNA methylation in haematological malignancies. British Journal of Haematology, 138, 3–11. Calin, G.A., Liu, C.G., Sevignani, C., Ferracin, M., Felli, N., Dumitru, C.D., Shimizu, M., Cimmino, A., Zupo, S., Dono, M., Dell’Aquila, M.L., Alder, H., Rassenti, L., Kipps, T.J., Bullrich, F., Negrini, M. & Croce, C.M. (2004) MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. PNAS USA, 101, 11755–11760. Caporaso, N. (2007) Integrative study designs – next step in the evolution of molecular epidemiology. Cancer Epidemiology, Biomarkers & Prevention, 16, 365–366. Chiorazzi, N., Rai, K. & Ferrarini, M. (2005) Chronic lymphocytic leukemia. New England Journal of Medicine, 352, 804–815. Dave, S.S., Wright, G., Tan, B., Rosenwald, A., Gascoyne, R.D., Chan, W.C., Fisher, R.I., Braziel, R.M., Rimsza, L.M., Grogan, T.M., Miller,

T.P., LeBlanc, M., Greiner, T.C., Weisenburger, D.D., Lynch, J.C., Vose, J., Armitage, J.O., Smeland, E.B., Kvaloy, S., Holte, H., Delabie, J., Connors, J.M., Lansdorp, P.M., Ouyang, Q., Lister, T.A., Davies, A.J., Norton, A.J., Muller-Hermelink, H.K., Ott, G., Campo, E., Montserrat, E., Wilson, W.H., Jaffe, E.S., Simon, R., Yang, L., Powell, J., Zhao, H., Goldschmidt, N., Chiorazzi, M. & Staudt, L.M. (2004) Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. New England Journal of Medicine, 351, 2159–2169. De Tute, R., Yuille, M., Catovsky, D., Houlston, R.S., Hillman, P. & Rawston, A.C. (2006) Monoclonal B-cell lymphocytosis (MBL) in CLL families: substantial increase in relative risk for young adults. Leukemia, 20, 728–729. Dewald, G.W., Brockman, S.R., Paternoster, S.F., Bone, N.D., O’Fallon, J.R., Allmer, C., James, C.D., Jelinek, D.F., Tschumper, R.C., Hanson, C.A., Pruthi, R.K., Witzig, T.E. & Kay, N.E. (2003) Chromosome anomalies detected by interphase fluorescence in situ hybridization: correlation with significant biological features of B-cell chronic lymphocytic leukemia. British Journal of Haematology, 121, 287–295. Dohner, H., Stilgenbauer, S., Benner, A., Leupolt, E., Krober, A., Bullinger, L., Dohner, K., Bentz, M. & Lichter, P. (2000) Genomic aberrations and survival in chronic lymphocytic leukemia. New England Journal of Medicine, 343, 1910–1916. Fraumeni, J.F., Jr. Vogel, C.L. & DeVita, V.T. (1969) Familial chronic lymphocytic leukemia. Annals of Internal Medicine, 71, 279–284. Goldin, L. & Caporaso, N.E. (2007) Family studies in chronic lymphocytic leukaemia and other lymphoproliferative tumours. British Journal of Haematology, 139, 774–779. Goldin, L.R., Ishibe, N., Sgambati, M., Marti, G.E., Fontaine, L., Lee, M.P., Kelley, J.M., Scherpbier, T., Buetow, K.H. & Caporaso, N.E. (2003) A genome scan of 18 families with chronic lymphocytic leukemia. British Journal of Haematology, 121, 866–873. Gundmundsson, J., Sulem, P., Gudmundsson, J., Sulem, P., Steinthorsdottir, V., Bergthorsson, J.T., Thorleifsson, G., Manolescu, A., Rafnar, T., Gudbjartsson, D., Agnarsson, B.A., Baker, A., Sigurdsson, A., Benediktsdottir, K.R., Jakobsdottir, M., Blondal, T., Stacey, S.N., Helgason, A., Gunnarsdottir, S., Olafsdottir, A., Kristinsson, K.T., Birgisdottir, B., Ghosh, S., Thorlacius, S., Magnusdottir, D., Stefansdottir, G., Kristjansson, K., Bagger, Y., Wilensky, R.L., Reilly, M.P., Morris, A.D., Kimber, C.H., Adeyemo, A., Chen, Y., Zhou, J., So, W.Y., Tong, P.C., Ng, M.C., Hansen, T., Andersen, G., BorchJohnsen, K., Jorgensen, T., Tres, A., Fuertes, F., Ruiz-Echarri, M., Asin, L., Saez, B., van Boven, E., Klaver, S., Swinkels, D.W., Aben, K.K., Graif, T., Cashy, J., Suarez, B.K., van Vierssen Trip, O., Frigge, M.L., Ober, C., Hofker, M.H., Wijmenga, C., Christiansen, C., Rader, D.J., Palmer, C.N., Rotimi, C., Chan, J.C., Pedersen, O., Sigurdsson, G., Benediktsson, R., Jonsson, E., Einarsson, G.V., Mayordomo, J.I., Catalona, W.J., Kiemeney, L.A., Barkardottir, R.B., Gulcher, J.R., Thorsteinsdottir, U., Kong, A. & Stefansson, K. (2007) Two variants on chromosome 17 confer prostate cancer risk, and the one on TCF2 protects against type 2 diabetes. Nature Genetics, 39, 1–7. Gunz, F.W. & Veale, A.M.O. (1969) Leukemia in close relatives – accident or predisposition. Journal National Cancer Institute, 42, 517–524. Hermine, O., Lefrere, F., Bronowicki, J.P., Mariette, X., Jondeau, K., Eclache-Saudreau, V., Delmas, B., Valensi, F., Cacoub, P., Brechot, C., Varet, B. & Troussard, X. (2002) Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C infection. New England Journal of Medicine, 347, 89–94.


633

Review Kay, N.E., Shanafelt, T.D., Strege, A.K., Lee, Y.K., Bone, N.D. & Raza, A. (2007) Bone biopsy derived marrow stromal elements rescue chronic lymphocytic leukemia B-cells from spontaneous and drug induced cell death and facilitates an ‘‘aniogenic switch’’. Leukemia Research, 31, 899–906. Landgren, O., Engels, E.A., Caporaso, N.E., Gridley, G., Mellemkjaer, L., Hemminki, K., Linet, M.S. & Goldin, L.R. (2006a) Patterns of autoimmunity and subsequent chronic lymphocytic leukemia in Nordic countries. Blood, 108, 292–296. Landgren, O., Pfeiffer, R.M., Stewart, L., Gridley, G., Mellemkjaer, L., Hemminki, K., Goldin, L. & Travis, L.B. (2006b) Risk of second mallignant neoplasms among lymphoma patients with a family history of cancer. International Journal of Cancer, 120, 1099–1102. Landgren, O., Rapkin, J.S., Caporaso, N.E., Mellemkjaer, L., Gridley, G., Goldin, L.R. & Engels, E.A. (2007a) Respiratory tract infections and subsequent risk of CLL. Blood, 109, 2198–2201. Landgren, O., Gridley, G., Check, D., Caporaso, N.E. & Brown, L.M. (2007b) Acquired immune-related and inflammatory conditions and subsequent CLL. British Journal of Haematology, current issue. Lawrie, C.H. (2007) MicroRNAs and haematology: small molecules big function. British Journal of Haematology, 137, 503–512. Liu, Y., Corcoran, M., Rasool, O., Ivanova, G., Ibbotson, R., Grander, D., Iyengar, A., Baranova, A., Kashuba, V., Merup, M., Wu, X.S., Gardiner, A., Mullenbach, R., Poltaraus, A., Hultstrom, A.L., Juliusson, G., Chapman, R., Tiller, M., Cotter, F., Gahrton, G., Yankovsky, N., Zabarovsky, E., Einhorn, S. & Oscier, D. (1997) Cloning of two candidate tumor suppressor genes within a 10kb region on chromosome 13q14, frequently deleted in chronic lymphocytic leukemia. Oncogene, 15, 63–73. Marti, G.E., Carter, P., Abbasi, F., Washington, G.C., Jain, N., Zenger, V.E., Ishibe, N., Goldin, L., Fontaine, L., Weissman, N., Sgambati, M., Fauget, G., Bertin, P., Vogt, R.F., Jr. Slade, B., Noguchi, P.D., Stetler-Stevenson, M.A. & Caporaso, N. (2003) B-cell monoclonal lyphocytosis and B-cell abnormalities in the setting of familial B-cell CLL. Cytometry, 52B, 1–12. Marti, G.E., Rawstron, A.C., Ghia, P., Hillmen, P., Houlston, R.S., Kay, N., Schleinitz, T.A., Caporaso, N. & The International Familial CLL Consortium (2005) Diagnostic criteria for monoclonal B-cell lymphocytosis. British Journal of Haematology, 130, 325–332. Mazzaro, C., Franzin, F., Tulissi, P., Pussini, E., Crovatto, M., Carniello, G.S., Efremov, D.G., Burrone, O., Santini, G. & Pozzato, G. (1996) Regression of monoclonal B- cell expansion in patients affected by mixed cryoglobulinemia responsive to alpha interferon therapy. Cancer, 77, 2604–2613. Minelli, C., Thompson, J.R., Tobin, M.D. & Abrams, K.R. (2004) An integrated approach to the meta-analysis of genetic association studies using mendelian randomization. American Journal of Epidemiology, 160, 445–452. Montserrat, E. (2001) Developing risk-adapted treatment strategies for CLL. In: Chronic Lymphocytic Leukemia (ed. B.D. Cheson), 2nd edn, pp. 377–392. Marcel Dekker Inc., New York. Muntanola, A., Bosch, F., Arguis, P., Arellano-Rodrigo, E., Ayuso, C., Gine, E., Crespo, M. & Abrisquieta, P. (2007) Abdominal Computer Tomography predicts progression in patients with Rai stage 0 chronic lymphocytic leukemia. Journal of Clinical Oncology, 25, 1576–1580. Ng, D., Toure, O., Wei, M.-H., Arthur, D.C., Abbasi, F., Fontaine, L., Marti, G.E., Fraumeni, J.F., Jr. Goldin, L.R., Caporaso, N. & Toro, J.R. (2007) Identification of a novel chromosome region 13q21.33-

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q22.2 for susceptibility genes in familial chronic lymphocytic leukemia. Blood, 109, 916–925. Nicoloso, M.S., Kipps, T.J., Croce, C.M. & Calin, G.A. (2007) MicroRNAs in the pathogeny of chronic lymphocytic leukaemia. British Journal of Haematology, 139, 709–716. Nowakowski, G.S., Hoyer, J.D., Shanafelt, T.D., Geyer, S.M., LaPlant, B.R., Call, T.G., Jelinek, D.F., Zent, C.S. & Kay, N.E. (2007) Using smudge cells on routine blood smears to predict clinical outcome in CLL: a universally available prognostic test. Mayo Clinic Proceedings, 82, 449–453. Pang, J.W.Y., Cook, L.S., Schwartz, S.M. & Weiss, N.S. (2002) Incidence of leukemia in Asian migrants to the United States and their descendents. Cancer Causes and Control, 13, 791–795. Pekarsky, Y., Santanam, U., Cimmino, A., Palamarchuk, A., Efanov, A., Maximov, V., Volinia, S., Alder, H., Liu, C.G., Rassenti, L., Calin, G.A., Hagan, J.P., Kipps, T. & Croce, C.M. (2006) Tcl1 expression in CLL is regulated by mir-29 and miR-181. Cancer Research, 66, 11590–11593. Phillips, J.A., Mehta, K., Fernandez, C. & Raveche´, E.S. (1992) The NZB mouse as a model for CLL. Cancer Research, 52, 437–443. Plass, C., Byrd, J.C., Raval, A., Tanner, S.M. & de la Chapelle, A. (2007) Molecular profiling of chronic lymphocytic leukaemia: genetics meets epigenetics to identify predisposing genes. British Journal of Haematology, 139, 744–752. Raveche, E.S., Salerno, E., Scaglione, B.J., Manohar, V., Abbasi, F., Lin, Y.C., Fredrickson, T., Landgraf, P., Ramachandra, S., Huppi, K., Toro, J.R., Zenger, V.E., Metcalf, R.A. & Marti, G.E. (2007) Abnormal microRNA-16 locus synteny to human 13q14 linked to CLL in NZB mice. Blood, 109, 5079–5086. Rawstron, A.C., Yuille, M.R., Fuller, J., Cullen, M., Kennedy, B., Richards, S.J., Jack, A.S., Matutes, E., Catovsky, D., Hillmen, P. & Houlston, R.S. (2002) Inherited predisposition to CLL is detectable as sub-clinical monoclonal B-cell expansion. Blood, 100, 2289–2291. Risch, N.J. & Whittemore, A.S. (2006) Genetic concepts and methods in epidemiologic research. In: Cancer Epidemiology and Prevention (ed. by D. Schottenfeld & J.F. Fraumeni Jr), pp. 89–98. 3rd edn. Oxford University Press, Inc., New York. Seldin, M.F. (2007) Admixture mapping as a tool in gene discovery. Current Opinion in Genetics & Development, 17, 177–181. Sellick, G.S., Webb, E.L., Allinson, R., Matutes, E., Dyer, M.J., Jonsson, V., Langerak, A.W., Mauro, F.R., Fuller, S., Wiley, J., Lyttelton, M., Callea, V., Yuille, M., Catovsky, D. & Houlston, R.S. (2005) A high-density SNP genomewide linkage scan for chronic lymphocytic leukemiasusceptibility loci. American Journal of Human Genetics, 77, 420–429. Sellick, G.S., Goldin, L.R., Wild, R.W., Slager, S.L., Ressenti, L., Strom, S.S., Dyer, M.J., Mauro, F.R., Marti, G.E., Fuller, S., Lyttelton, M., Kipps, T.J., Keating, M.J., Call, T.G., Catovsky, D., Caporaso, N. & Houlston, R.S. (2007) A high-density SNP genome-wide linkage search of 206 families identifies susceptibility loci for chronic lymphocytic leukemia. Blood, (E-pub ahead of print) doi:10.1182/blood2007-05-091561 Slager, S.L., Kay, N.E., Fredericksen, Z.S., Wang, A.H., Liebow, M., Cunningham, J.M., Call, T.G. & Cerhan, J.R. (2007) Susceptibility Genes in B-CLL. British Journal of Haematology, 139, 762–771. Stilgenbauer, S., Dohner, H. & Lichter, P. (1993) Genomic aberrations in B-cell chronic lymphocytic leukemia, Chap 16. In: CLL (ed. by B. Cheson), pp. 353–376. 2nd edn, Marcel Dekker, NY. Yuille, M.R., Matutes, E., Marossy, A., Hilditch, B., Catovsky, D. & Houlston, R.S. (2000) Familial Chronic lymphocytic leukemia: a survey and review of published studies. British Journal of Haematology, 109, 794–799.
