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Spotlight on Chronic Lymphocytic Leukemia

Genetic susceptibility to chronic lymphocytic leukemia

Leukemia volume 16, pages 1008–1014 (2002)Cite this article

Abstract

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.

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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

    Google Scholar 

  2. Gale RP, Foon KA . Biology of chronic lymphocytic leukemia Semin Haematol 1987 24: 209–229

    CAS  Google Scholar 

  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

    Google Scholar 

  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

    CAS  PubMed  Google Scholar 

  5. Giles GG, Lickiss JN, Baikie MJ, Lowenthal RM, Panton JJ . Myeloproliferative and lymphoproliferative disorders in Tasmania, 1972–80: occupational and familial aspects Natl Cancer Inst 1984 72: 1233–1240

    CAS  Google Scholar 

  6. Goldgar DE, Easton DF, Cannon-Albright LA, Skolnick MH . Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands J Natl Cancer Inst 1994 86: 1600–1608

    CAS  PubMed  Google Scholar 

  7. Miller RW . Deaths from childhood leukemia and solid tumours among twins and other sibs in the United States, 1960–67 J Natl Cancer Inst 1971 46: 203–209

    CAS  PubMed  Google Scholar 

  8. Thiersch JB . Aspects of leuchaemia: a leuchaemic family in South Australia Proc R Aust Coll Phys 1947 2: 35–38

    Google Scholar 

  9. Yuille MR, Matutes E, Marossy A, Hilditch B, Catovsky D, Houlston RS . Familial chronic lymphocytic leukemia: a survey and review of published studies Br J Haematol 2000 109: 794–799

    CAS  PubMed  Google Scholar 

  10. Penrose LS . The problem of anticipation in pedigrees of dyostrophica myotonica Ann Eugenics 1949 14: 124–132

    Google Scholar 

  11. Yuille MR, Houlston RS, Catovsky D . Anticipation in familial chronic lymphocytic leukemia families Leukemia 1998 12: 1696–1698

    CAS  PubMed  Google Scholar 

  12. Horwitz M, Goode EL, Jarvik GP . Anticipation in familial leukemia Am J Hum Genet 1996 59: 990–998

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Goldin LR, Sgambati M, Marti GE, Fontaine L, Ishibe N, Caporaso N . Anticipation in familial chronic lymphocytic leukemia Am J Hum Genet 1999 65: 265–269

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Pritsch O, Troussard X, Magnac C, Mauro FR, Davi F, Payelle-Brogard B, Dumas G, Pulik M, Clerget F, Mandelli F, Chiorazzi N, Schroeder HW, Leporrier M, Dighiero G . VH gene usage by family members affected with chronic lymphocytic leukaemia Br J Haematol 1999 107: 616–624

    CAS  PubMed  Google Scholar 

  15. Wierda WG, Kipps TJ . Chronic lymphocytic leukemia Curr Opin Hematol 1999 6: 253–261

    CAS  PubMed  Google Scholar 

  16. German J . Chromosome-breakage syndromes: different genes, different treatments, different cancers Basic Life Sci 1980 15: 429–439

    CAS  PubMed  Google Scholar 

  17. Gatti RA, Berkel I, Boder E, Braedt G, Charmley P, Concannon P, Ersoy F, Foroud T, Jaspers NGJ, Lange K, Lathrop GM, Leppert M, Nakamura Y, O'Connell P, Paterson M, Salser W, Sanal O, Silver J, Sparkes RS, Susi E, Weeks DE, Wei S, White R, Yoder F . Localization of an ataxia-telangiectasia gene to chromosome 11q22–23 Nature 1988 336: 577–578

    CAS  PubMed  Google Scholar 

  18. Taylor AMR, Metcalfe JA, Thick J, Mak Y-F . Leukemia and lymphoma in ataxia telangiectasia Blood 1996 87: 423–428

    CAS  PubMed  Google Scholar 

  19. Athma P, Rappaport R, Swift M . Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer Cancer Genet Cytogenet 1996 92: 130–134

    CAS  PubMed  Google Scholar 

  20. Swift M, Reitnauer PJ, Morrell D, Chase CL . Breast and other cancers in families with ataxia-telangiectasia N Engl J Med 1987 316: 1289–1294

    CAS  PubMed  Google Scholar 

  21. Stankovic T, Weber P, Stewart G, Bedenham T, Bryd PJ, Moss PAH, Taylor AMR . Inactivation of ataxia telangectasia mutated gene in B-cell chronic lymphocytic leukemia Lancet 1999 353: 26–29

    CAS  PubMed  Google Scholar 

  22. Schaffner C, Stilgenbauer S, Rappold GA, Dohner H, Lichter P . Somatic ATM mutations indicate a pathogenic role of ATM in B-cell chronic lymphocytic leukemia Blood 1999 94: 748–753

    CAS  PubMed  Google Scholar 

  23. Bullrich F, Rasio D, Kitada S, Starostik P, Kipps T, Keating M, Albitar M, Reed JC, Croce CM . ATM mutations in B cell chronic lymphocytic leukemia Cancer Res 1999 59: 24–27

    CAS  PubMed  Google Scholar 

  24. Starostik P, Manshouri T, O'Brien S, Freireich E, Kantarjian H, Haidar M, Lerner S, Keating M, Albitar M . Deficiency of the ATM protein expression defines an aggressive subgroup of B-cell chronic lymphocytic leukemia Cancer Res 1998 58: 4552–4557

    CAS  PubMed  Google Scholar 

  25. Savitsky K, Sfez S, Tagle DA, Ziv Y, Sartiel A, Collins FS, Shiloh Y, Rotman G . The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species Hum Molec Genet 1995 4: 2025–2032

    CAS  PubMed  Google Scholar 

  26. Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, Tagle DA, Smith S, Uziel T, Sfez S, Ashkenazi M, Pecker I, Frydman M, Harnik R, Patanjali SR, Simmons A, Clines GA, Sartiel A, Gatti RA, Chessa L, Sanal O, Lavin MF, Jaspers NJ, Taylor AR, Arlett CF, Miki T, Weissman SM, Lovett M, Collins FS, Shiloh Y . A single ataxia-telangiectasia gene with a product similar to PI-3 kinase Science 1995 268: 1749–1752

    CAS  PubMed  Google Scholar 

  27. Meyn MS . Ataxia-telangiectasia, cancer and the pathobiology of the ATM gene Clin Genet 1999 55: 289–304

    CAS  PubMed  Google Scholar 

  28. Bevan S, Catovsky D, Marossy A, Popat S, Antonvic P, Bell A, Ben-Bassat I, Berrebi A, Mauro F, Pittion A, Quabeck K, Ribeiro I, Stark P, Sykes H, van Dongen J, Wimperis J, Wright S, Yuille MR, Houlston RS . Linkage analysis for ATM in familial chronic lymphocytic leukemia Leukemia 1999 13: 1497–1500

    CAS  PubMed  Google Scholar 

  29. Klitz W, Aldrich CL, Fildes N, Horning SJ, Begovich AB . Localization of predisposition to Hodgkin disease in the HLA class II region Am J Hum Genet 1994 54: 497–505

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Risch N . Assessing the role of HLA-linked and unlinked determinants of disease Am J Hum Genet 1987 40: 1–14

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Oza AM, Tonks S, Lim J, Fleetwood MA, Lister TA, Bodmer JG . A clinical and epidemiological study of human leukocyte antigen-DPB alleles in Hodgkin's disease Cancer Res 1994 54: 101–105

    Google Scholar 

  32. Taylor GM, Gokhale DA, Crowther D, Woll PJ, Harris M, Ryder D, Ayres M, Radford JA . Further investigation of the role of HLA-DPB1 in adult Hodgkin's disease (HD) suggests an influence on susceptibility to different HD subtypes Br J Cancer 1999 80: 1405–1411

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Hirose S, Hamano Y, Shirai T . Genetic factors predisposing to B-CLL and to autoimmune disease in spontaneous murine model Leukemia 1997 11 (Suppl. 3): 267–270

    Google Scholar 

  34. Okada T, Takiura F, Tokushige K, Nozawa S, Kiyosawa T, Nakauchi H, Hirose S, Shirai T . Major histocompatibility complex controls clonal proliferation of CD5+ B cells in H-2-congenic New Zealand mice: a model for B cell chronic lymphocytic leukemia and autoimmune disease Eur J Immunol 1991 21: 2743–2748

    CAS  PubMed  Google Scholar 

  35. Bevan S, Catovsky D, Matutes E, Antonovic P, Auger MJ, Ben-Bassat I, Bell A, Berrebi A, Gaminara EJ, Mauro FR, Quabeck K, Rassam S, Reid C, Ribeiro I, Stark P, van Dongen J, Wimperis J, Wright S, Marossy A, Yuille MR, Houlston RS . Linkage analysis for MHC related genetic susceptibility in familial chronic lymphocytic leukemia Blood 2000 96: 3982–3984

    CAS  PubMed  Google Scholar 

  36. Payelle-Brogard B, Magnac C, Mauro FR, Mandelli F, Dighiero G . Analysis of the B-cell receptor B29 (CD79b) gene in familial chronic lymphocytic leukemia Blood 1999 94: 3516–3522

    CAS  PubMed  Google Scholar 

  37. Horwitz M, Wiernik PH . Pseudoautosomal linkage of Hodgkin disease Am J Hum Genet 1999 65: 1413–1422

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Yuille MR, Catovsky D, Houlston RS . Pseudoautosomal linkage in chronic lymphocytic leukemia Br J Haematol 2000 109: 899–900

    PubMed  Google Scholar 

  39. Ashley CT, Warren ST . Trinucleotide repeat expansion and human disease Ann Rev Genet 1995 29: 703–728

    CAS  PubMed  Google Scholar 

  40. Koob MD, Benzow KA, Bird TD, Day JW, Moseley ML, Ranum LP . Rapid cloning of expanded trinucleotide repeat sequences from genomic DNA Nat Genet 1998 18: 72–75

    CAS  PubMed  Google Scholar 

  41. Oscier DG, Thompsett A, Zhu D, Stevenson FK . Differential rates of somatic hypermutation in V(H) genes among subsets of chronic lymphocytic leukemia defined by chromosomal abnormalities Blood 1997 89: 4153–4160

    CAS  PubMed  Google Scholar 

  42. Fais F, Ghiotto F, Hashimoto S, Sellars B, Valetto A, Allen SL, Schulman P, Vinciguerra VP, Rai K, Rassenti LZ, Kipps TJ, Dighiero G, Schroeder HW Jr, Ferrarini M, Chiorazzi N . Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors J Clin Invest 1998 102: 1515–1524

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Pritsch O, Troussard X, Magnac C, Mauro FR, Davi F, Payelle-Brogard B, Dumas G, Pulik M, Clerget F, Mandelli F, Chiorazzi N, Schroeder HW Jr, Leporrier M, Dighiero G . VH gene usage by family members affected with chronic lymphocytic leukaemia Br J Haematol 1999 107: 616–624

    CAS  PubMed  Google Scholar 

  44. Sakai A, Marti GE, Caporaso N, Pittaluga S, Touchman JW, Fend F, Raffeld M . Analysis of expressed immunoglobulin heavy chain genes in familial B-CLL Blood 2000 95: 1413–1419

    CAS  PubMed  Google Scholar 

  45. Capello D, Fais F, Vivenza D, Migliaretti G, Chiorazzi N, Gaidano G, Ferrarini M . Identification of three subgroups of B cell chronic lymphocytic leukemia based upon mutations of BCL-6 and IgV genes Leukemia 2000 14: 811–815

    CAS  PubMed  Google Scholar 

  46. Cartwright RA, Bernard SM, Bird CC, Darwin CM, O'Brien C, Richards ID, Roberts B, McKinney PA . Chronic lymphocytic leukemia: case–control epidemiological study in Yorkshire Br J Cancer 1987 56: 79–82

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Linet MS, Van Natta ML, Brookmeyer R, Khoury MJ, McCaffrey LD, Humphrey RL, Szklo M . Familial cancer history and chronic lymphocytic leukemia. A case–control study Am J Epidemiol 1989 130: 655–664

    CAS  PubMed  Google Scholar 

  48. Pottern LM, Linet M, Blair A, Dick F, Burmeister LF, Gibson R, Schuman LM, Fraumeni JF Jr . Familial cancers associated with subtypes of leukamia and non-Hodgkin's lymphoma Leukemia Res 1991 15: 305–314

    CAS  Google Scholar 

  49. Radovanovic Z, Markovic-Denic L, Jakovic S . Cancer mortality of family mambers of patients with chronic lymphocytic leukemia Eur J Epidemiol 1994 10: 211–213

    CAS  PubMed  Google Scholar 

  50. Guasch J . Heredite des leucemies Sang 1954 25: 384–419

    CAS  PubMed  Google Scholar 

  51. Brem TH, Morton ME . Defective serum gamma globulin formation Ann Intern Med 1955 43: 465–479

    CAS  PubMed  Google Scholar 

  52. Videbaek A . Familial leukemia Acta Pathol Microbiol Scand 1958 44: 372–374

    Google Scholar 

  53. Hudson RP, Wilson SJ . Hypogammaglobulinemia and chronic lymphatic leukemia Cancer 1960 13: 200–204

    CAS  PubMed  Google Scholar 

  54. Gunz FW, Fitzgerald PH, Adams A . An abnormal chromosome in chronic lymphocytic leukemia Br Med J 1962 2: 1097

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Fitzgerald PH, Hamer JW . Third case of chronic lymphocytic leukemia in a carrier of the inherited Ch1 chromosome Br Med J 1969 3: 752–754

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Furbetta D, Solinas P . Hereditary chronic lymphatic leukemia Proc Sec Intern Congr Hum Genet 1961 2: 1078–1079

    Google Scholar 

  57. Wisniewski D, Weinreich J . Lymphatische leukamie bie Vater und Sohn Blut 1966 12: 241–244

    CAS  PubMed  Google Scholar 

  58. Rigby PG, Rosenlof RC, Pratt PI, Lemon HM . Leukemia and lymphoma JAMA 1966 197: 95–100

    Google Scholar 

  59. Ardizzone G, Rossi-Ferrini PL, Montali E, Matassi L . Anomalia chromosomica Ch1 in una famiglia con due casi di leukemia linfatica cronica Rev Crit Clin Med 1968 68: 1102–1103

    Google Scholar 

  60. Magaraggia L, Vettori G . Leucemia linfatica cronica familiare associata ad epitelioma cutaneo Il Fracastoro 1968 61: 269–271

    CAS  PubMed  Google Scholar 

  61. McPhedran P, Heath CW, Lee J . Patterns of familial leukemia: 10 cases of leukemia in two inter-related families Cancer 1969 24: 403–407

    CAS  PubMed  Google Scholar 

  62. Fraumeni JF, Vogel CL, DeVita VT . Familial chronic lymphocytic leukemia Ann Intern Med 1969 71: 279–284

    PubMed  Google Scholar 

  63. Blattner WA, Dean JH, Fraumeni JF . Familial lymphoproliferative malignancy: clinical and laboratory follow-up Ann Intern Med 1979 90: 943–944

    CAS  PubMed  Google Scholar 

  64. Gunz FW, Veale AMO . Leukemia in close relatives – accident or predisposition? J Natl Cancer Inst 1969 42: 517–524

    CAS  PubMed  Google Scholar 

  65. Undritz E, Schnyder F . Vier Geschwister mit chronischer lymphatischer leukamie im Wallis Schweiz Med Wochenschr 1971 101: 1779–1780

    CAS  PubMed  Google Scholar 

  66. Potolosky AI, Heath CW, Buckley CE, Rowlands DT . Lymphoreticular malignancies and immunologic abnormalities in a sibship Am J Med 1971 50: 42–48

    Google Scholar 

  67. Schweitzer M, Melief CMJ, Ploem JE . Chronic lymphocytic leukemia in five siblings Scand J Haematol 1973 11: 97–105

    CAS  PubMed  Google Scholar 

  68. Blattner WA, Strober W, Muchmore AV, Blaese R, Broder S, Fraumeni J . Familial chronic lymphocytic leukemia. Immunologic and cellular charcaterisation Ann Int Med 1976 84: 554–557

    CAS  PubMed  Google Scholar 

  69. Neuland CY, Blattner WA, Mann DL, Faser MC, Tsai S, Strong DM . Familial chronic lymphocytic leukemia JNCI 1983 71: 1143–1150

    CAS  PubMed  Google Scholar 

  70. Shen A, Humphries C, Tucker P, Blattner F . Human heavy-chain variable region gene family nonrandomly rearranged in familial chronic lymphocytic leukemia Proc Natl Acad Sci USA 1987 84: 8563–8567

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Caporaso NE, Whitehouse J, Bertin P, Amos C, Papadopoulos N, Muller J, WhangPent J, Tucker MA, Fleisher TA, Marti GE . A 20-year clinical and laboratory study of familial B-chronic lymphocytic leukemia in a single kindred Leuk Lymphoma 1991 3: 331–342

    CAS  PubMed  Google Scholar 

  72. Gunz FW, Gunz JP, Veal AMO, Chapman CJ, Houston IB . Familial leukemia: a study of 909 families Scand J Haematol 1975 15: 117–131

    CAS  PubMed  Google Scholar 

  73. Petzholdt R, Hartwich G, Demmler K . Familiar-gehauftes Auftreten der Chronischen Lymphatischen Leukamie Med Klin 1976 71: 2123–2126

    Google Scholar 

  74. Fazekas VT, Bach K, Toth S, Bodor F . Familiares vorkommen von Chronischer Lympatischer Leukamie. HLA-antigen und Zytogenetische Unterschungen Wien Med Wochenschr 1978 9: 262–264

    Google Scholar 

  75. Branda RF, Ackerman SK, Handwerger BS, Howe RB, Douglas SD . Lymphocyte studies in familial chronic lymphatic leukemia Am J Med 1978 64: 508–514

    CAS  PubMed  Google Scholar 

  76. Conley CL, Misiti J, Laster AJ . Genetic factors predisposing to chronic lymphocytic leukemia and to autoimmune disease Medicine 1980 5: 323–334

    Google Scholar 

  77. Alfinito F, Formisano S, Rotoli B . Familial leukemia: uncommon type of chronic lymphocytic leukemia in two sisters Haematologica 1982 67: 406–410

    CAS  PubMed  Google Scholar 

  78. Vanni M, Deambrogio P . Riscontro in due membri della stressa di leucemia linfatica chronica Min Med 1983 74: 443–446

    CAS  Google Scholar 

  79. Brok-Simoni F, Rechavi G, Katzir N, Ben-Bassat I . Chronic lymphocytic leukemia in twin sisters: monozygous but not identical Lancet 1987 1: 329–330

    CAS  PubMed  Google Scholar 

  80. Hakim I, Amariglio N, Brok-Simoni F, Berkowitz M, Rosner E, Kneller A, Hulu N, Ramot B, Ben-Bassat I, Silverman GJ et al. Preferred usage of specific immunogloblin gene segments in chronic lymphocytic leukaemia cells of three HLA-identicalsisters Br J Haematol 1995 91: 915–917

    CAS  PubMed  Google Scholar 

  81. Eriksson M, Bergstrom I . Familial malignant blood disease in the country of Jamtland, Sweden Eur J Haematol 1987 38: 241–245

    CAS  PubMed  Google Scholar 

  82. Shah AR, Maeda K, Deegan MJ, Roth MS, Schnitzer B . A clinicopathologic study of familial chronic lymphocytic leukemia Am J Clin Path 1992 97: 184–188

    CAS  PubMed  Google Scholar 

  83. Cuttner J . Increased incidence of hematological malignancies in first-degree relatives of patients with chronic lymphocytic leukemia Cancer Invest 1992 10: 103–109

    CAS  PubMed  Google Scholar 

  84. Fernhout F, Dinkelaar RB, Hagemeijer A, Groeneveld K, van Kammen E, van Dongen JJ . Four aged siblings with B cell chronic lymphocytic leukemia Leukemia 1997 11: 2060–2065

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors’ work is supported by the Leukaemia Research Fund. We thank all the families and their clinicians that have contributed to our research.

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  1. Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK

    RS Houlston

  2. Academic Department of Haematology and Cytogenetics, Institute of Cancer Research, Sutton, UK

    D Catovsky & MR Yuille

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  1. RS Houlston
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Houlston, R., Catovsky, D. & Yuille, M. Genetic susceptibility to chronic lymphocytic leukemia. Leukemia 16, 1008–1014 (2002). https://doi.org/10.1038/sj.leu.2402538

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