The ‘delayed infection’ (aka ‘hygiene’) hypothesis for childhood leukaemia

  • Mel Greaves
Part of the Progress in Inflammation Research book series (PIR)


The common variant of childhood acute lymphoblastic leukaemia (cALL) is the most frequent paediatric cancer subtype. Its incidence rate appears to have increased substantially in Western societies during the mid-20th century and continues to increase at ∼1%/year. Worldwide cALL appears to track with affluence of societies. The ‘delayed infection’ hypothesis, first formulated in 1988, parallels the hygiene hypothesis and has an evolutionary foundation in the concept of a mismatch between prior genetic selection and programming (of the immune system) and contemporary social circumstances. In essence, the hypothesis predicts that ALL is triggered by an abnormal immune response to one or more common microbial infections and that the abnormality arises for two reasons: (i) infectious exposures being delayed beyond the immunologically anticipated period of infancy; (ii) some degree of inherited genetic susceptibility via, for example, allelic variation in genes involved in the MHC and/or immune response network. The hypothesis also has a framework in the underlying cell and molecular biology of ALL and its natural history. Epidemiological studies of social contacts in infancy (as a proxy for common infections) and risk of ALL provide indirect but strong support for the hypothesis. The idea still requires mechanistic and genetic endorsement and the appropriate studies are in progress.


Acute Lymphoblastic Leukaemia Childhood Leukaemia Childhood Acute Lymphoblastic Leukemia Hygiene Hypothesis Childhood Acute Lymphoblastic Leukaemia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Greaves M (2000) Cancer. The Evolutionary Legacy. Oxford University Press, OxfordGoogle Scholar
  2. 2.
    Greaves MF, Colman SM, Beard MEJ, Bradstock K, Cabrera ME, Chen P-M, Jacobs P, Lam-Po-Tang PRL, MacDougall LG, Williams CKO et al (1993) Geographical distribution of acute lymphoblastic leukaemia subtypes: second report of the collaborative group study. Leukemia 7: 27–34PubMedGoogle Scholar
  3. 3.
    Parkin DM, Stiller CA, Draper GJ, Bieber CA, Terracini B, Young JL (eds) (1988) International incidence of childhood cancer. IARC Scientific Publications, LyonGoogle Scholar
  4. 4.
    Feltbower RG, McKinney PA, Greaves MF, Parslow RC, Bodansky HJ (2004) International parallels in leukaemia and diabetes epidemiology. Arch Dis Child 89: 54–56CrossRefPubMedGoogle Scholar
  5. 5.
    Shah A, Coleman MP (2007) Increasing incidence of childhood leukaemia: a controversy re-examined. Br J Cancer 97: 1009–1012PubMedGoogle Scholar
  6. 6.
    Poynton FJ, Thursfield H, Paterson D (1922) The severe blood diseases of childhood: a series of observations from the Hospital for Sick Children, Great Ormond Street. Br J Child Dis XIX: 128–144Google Scholar
  7. 7.
    Preston DL, Kusumi S, Tomonaga M, Izumi S, Ron E, Kuramoto A, Kamada N, Dohy H, Matsui T, Nonaka H et al (1994) Cancer incidence in atomic bomb survivors. Part III: Leukemia, lymphoma and multiple myeloma, 1950–1987. Radiat Res 137 (Suppl): S68–S97CrossRefPubMedGoogle Scholar
  8. 8.
    Greaves MF (1997) Aetiology of acute leukaemia. Lancet 349: 344–349CrossRefPubMedGoogle Scholar
  9. 9.
    Greaves MF, Maia AT, Wiemels JL, Ford AM (2003) Leukemia, in twins: lessons in natural history. Blood 102: 2321–2333CrossRefPubMedGoogle Scholar
  10. 10.
    Greaves MF, Wiemels J (2003) Origins of chromosome translocations in childhood leukaemia. Nature Rev Cancer 3: 639–649CrossRefGoogle Scholar
  11. 11.
    Greaves MF (1988) Speculations on the cause of childhood acute lymphoblastic leukemia. Leukemia 2: 120–125PubMedGoogle Scholar
  12. 12.
    Tsuzuki S, Seto M, Greaves M, Enver T (2004) Modelling first-hit functions of the t(12;21) TEL-AML1 translocation in mice. Proc Natl Acad Sci USA 101: 8443–8448CrossRefPubMedGoogle Scholar
  13. 13.
    Hong D, Gupta R, Ancliffe P, Atzberger A, Brown J, Soneji S, Green J, Colman S, Piacibello W, Buckle V et al (2008) Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia. Science 319: 336–339CrossRefPubMedGoogle Scholar
  14. 14.
    Mori H, Colman SM, Xiao Z, Ford AM, Healy LE, Donaldson C, Hows JM, Navarrete C, Greaves M (2002) Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc Natl Acad Sci USA 99: 8242–8247CrossRefPubMedGoogle Scholar
  15. 15.
    Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD, Girtman K, Mathew S, Ma J, Pounds SB et al (2007) Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446: 758–764CrossRefPubMedGoogle Scholar
  16. 16.
    Bateman CM, Horsley SW, Chaplin T, Young BD, Ford AM, Kearney L, Greaves M (2008) Sequence of genetic events in ETV6-RUNX1 positive B precursor ALL: insights from identical twins with concordant leukaemia: Blood. American Society of Hematology, San FranciscoGoogle Scholar
  17. 17.
    Greaves M (2006) Infection, immune responses and the aetiology of childhood leukaemia. Nat Rev Cancer 6: 193–203CrossRefPubMedGoogle Scholar
  18. 18.
    Gluckman P, Hanson M (2006) Mismatch. Why our world no longer fits our bodies. Oxford University Press, OxfordGoogle Scholar
  19. 19.
    Greaves M (2007) Darwinian medicine: a case for cancer. Nat Rev Cancer 7: 213–221CrossRefPubMedGoogle Scholar
  20. 20.
    Strachan DP (2000) Family size, infection and atopy: the first decade of the “hygiene hypothesis”. Thorax 55: S2–S10CrossRefPubMedGoogle Scholar
  21. 21.
    Zur Hausen H (2006) Infections causing human cancer. Wiley-VCH, WeinheimCrossRefGoogle Scholar
  22. 22.
    UK Childhood Cancer Study Investigators (2000) The United Kingdom Childhood Cancer Study: objectives, materials and methods. Br J Cancer 82: 1073–1102CrossRefGoogle Scholar
  23. 23.
    UK Childhood Cancer Study Investigators (2000) Childhood cancer and residential proximity to power lines. Br J Cancer 83: 1573–1580CrossRefGoogle Scholar
  24. 24.
    UK Childhood Cancer Study Investigators (2002) The United Kingdom Childhood Cancer Study of exposure to domestic sources of ionising radiation: 2: gamma radiation. Br J Cancer 86: 1727–1731CrossRefGoogle Scholar
  25. 25.
    Gilham C, Peto J, Simpson J, Roman E, Eden TOB, Greaves MF, Alexander FE, for the UKCCS Investigators (2005) Day care in infancy and risk of childhood acute lymphoblastic leukaemia: findings from a UK case-control study. Br Med J 330: 1294–1297CrossRefGoogle Scholar
  26. 26.
    Ma X, Buffler PA, Wiemels JL, Selvin S, Metayer C, Loh M, Does MB, Wiencke JK (2005) Ethnic difference in daycare attendance, early infections, and risk of childhood acute lymphoblastic leukemia. Cancer Epidemiol Biomarkers Prev 14: 1928–1934CrossRefPubMedGoogle Scholar
  27. 27.
    Kamper-Jørgensen M, Woodward A, Wohlfahrt J, Benn CS, Simonsen J, Hjalgrim H, Schmiegelow K (2007) Childcare in the first 2 years of life reduces the risk of childhood acute lymphoblastic leukemia. Leukemia 22: 189–193CrossRefPubMedGoogle Scholar
  28. 28.
    Louhiala PJ, Jaakkola N, Ruotsalainen R, Jaakkola JJ (1995) Form of day care and respiratory infections among Finnish children. Am J Public Health 85: 1109–1112CrossRefPubMedGoogle Scholar
  29. 29.
    McNally RJQ, Eden TOB (2004) An infectious aetiology for childhood acute leukaemia: a review of the evidence. Br J Haematol 127: 243–263CrossRefPubMedGoogle Scholar
  30. 30.
    Roman E, Simpson J, Ansell P, Kinsey S, Mitchell CD, McKinney PA, Birch JM, Greaves M, Eden T (2007) Childhood acute lymphoblastic leukemia and infections in the first year of life: a report from the United Kingdom Childhood Cancer Study. Am J Epidemiol 165: 496–504CrossRefPubMedGoogle Scholar
  31. 31.
    Cardwell CR, McKinney PA, Patterson CC, Murray LJ (2008) Infections in early life and childhood leukaemia risk: a UK case-control study of general practitioner records. Br J Cancer 99: 1529–1533CrossRefPubMedGoogle Scholar
  32. 32.
    Greaves M, Buffler PA (2009) Infections in early life and risk of childhood ALL. Br J Cancer 100: 863CrossRefPubMedGoogle Scholar
  33. 33.
    Taylor GM, Dearden S, Ravetto P, Ayres M, Watson P, Hussain A, Greaves M, Alexander F, Eden OB, UKCCS Investigators, (2002) Genetic susceptibility to childhood common acute lymphoblastic leukaemia is associated with polymorphic peptide-binding pocket profiles in HLA-DPB1 *0201. Hum Mol Genet 11: 1585–1597CrossRefPubMedGoogle Scholar
  34. 34.
    Josephs ZM, Gonzalez De Castro D, Johnson DC, Novosel A, Borkhardt A, Pritchard-Jones K, Greaves MF (2005) The impact of Tht/Th2 response variations on risk of developing childhood leukaemia: a pilot study. Blood 106: Abstract 849Google Scholar
  35. 35.
    Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, Struewing JP, Morrison J, Field H, Luben R et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447: 1087–1093CrossRefPubMedGoogle Scholar
  36. 36.
    Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, Dong Q, Zhang Q, Gu X, Vijayakrishnan J et al (2008) Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 40: 616–622CrossRefPubMedGoogle Scholar
  37. 37.
    Ford A, Palmi C, Bueno C, Hong D, Cardus P, Knight D, Cazzaniga G, Enver T, Greaves M (2009) The TEL-AML1 leukaemia fusion gene dysregulates the TGFß pathway in early B lineage progenitor cells. J Clin Invest 119: 826–836PubMedGoogle Scholar
  38. 38.
    Pasqualucci L, Bhagat G, Jankovic M, Compagno M, Smith P, Muramatsu M, Honjo T, Morse III HC, Nussenzweig MC, Dalla-Favera R (2008) AID is required for germinal center-derived lymphomagenesis. Nat Genet 40: 108–112CrossRefPubMedGoogle Scholar
  39. 39.
    Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J, White D, Hughes TP, Le Beau MM, Pui C-H et al (2008) BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 453: 110–114CrossRefPubMedGoogle Scholar
  40. 40.
    Spix C, Eletr D, lettner M, Kaatsch P (2008) Temporal trends in the incidence rate of childhood cancer in Germany 1987–2004. Int J Cancer 122: 1859–1867CrossRefPubMedGoogle Scholar
  41. 41.
    Li CK, Zee B, Lee J, Chik KW, Ha SY, Lee V (2007) Impact of SARS on development of childhood acute lymphoblastic leukaemia. Leukemia 21: 1353–1356CrossRefPubMedGoogle Scholar
  42. 42.
    Kinlen LJ (1995) Epidemiological evidence for an infective basis in childhood leukaemia. Br J Cancer 71: 1–5PubMedGoogle Scholar
  43. 43.
    Alexander FE, Chan LC, Lam TH, Yuen P, Leung NK, Ha SY, Yuen HL, Li CK, Li CK, Lau YL et al (1997) Clustering of childhood leukaemia in Hong Kong: association with the childhood peak and common acute lymphoblastic leukaemia and with population mixing. Br J Cancer 75: 457–463PubMedGoogle Scholar
  44. 44.
    Heath Jr CW, Hasterlik RJ (1963) Leukemia among children in a suburban community. Am J Med 34: 796–812CrossRefGoogle Scholar
  45. 45.
    Steinmaus C, Lu M, Todd RL, Smith AH (2004) Probability estimates for the unique childhood leukemia cluster in Fallon, Nevada, and risks near other U.S. military aviation facilities. Environ Health Perspect 112: 766–771PubMedCrossRefGoogle Scholar
  46. 46.
    Goedert JJ (ed) (2000) Infectious Causes of Cancer. Humana Press, New JerseyGoogle Scholar
  47. 47.
    Balkwill F (2004) Cancer and the chemokine network. Nat Rev Cancer 4: 540–550CrossRefPubMedGoogle Scholar
  48. 48.
    Isaacson PG, Du M-Q (2004) MALT lymphoma: from morphology to molecules. Nat Rev Cancer 4: 644–653CrossRefPubMedGoogle Scholar
  49. 49.
    Gutensohn N, Cole P (1980) Epidemiology of Hodgkin’s disease. Sem Oncol 7: 92–102Google Scholar
  50. 50.
    Backett EM (1957) Social patterns of antibody to poliovirus. Lancet i: 778–783CrossRefGoogle Scholar
  51. 51.
    Stearns SC, Koella JC (eds) (2008) Evolution in health and disease. Oxford University Press, New YorkGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2009

Authors and Affiliations

  • Mel Greaves
    • 1
  1. 1.Section of Haemato-OncologyThe Institute of Cancer ResearchSutton, SurreyUK

Personalised recommendations