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. 2009 Dec 17:239–255. doi: 10.1007/978-3-7643-8903-1_13

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

Mel Greaves 2
Editor: Graham A W Rook1
PMCID: PMC7123988

Abstract

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.

Keywords: Acute Lymphoblastic Leukaemia, Childhood Leukaemia, Childhood Acute Lymphoblastic Leukemia, Hygiene Hypothesis, Childhood Acute Lymphoblastic Leukaemia

References

  • 1.Greaves M. Cancer. The Evolutionary Legacy. Oxford: Oxford University Press; 2000. [Google Scholar]
  • 2.Greaves M.F., Colman S.M., Beard M.E.J., Bradstock K., Cabrera M.E., Chen P.-M., Jacobs P., Lam-Po-Tang P.R.L., MacDougall L.G., Williams C.K.O., et al. Geographical distribution of acute lymphoblastic leukaemia subtypes: second report of the collaborative group study. Leukemia. 1993;7:27–34. [PubMed] [Google Scholar]
  • 3.Parkin D.M., Stiller C.A., Draper G.J., Bieber C.A., Terracini B., Young J.L., editors. International incidence of childhood cancer. Lyon: IARC Scientific Publications; 1988. [Google Scholar]
  • 4.Feltbower R.G., McKinney P.A., Greaves M.F., Parslow R.C., Bodansky H.J. International parallels in leukaemia and diabetes epidemiology. Arch Dis Child. 2004;89:54–56. doi: 10.1136/adc.2002.022061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Shah A., Coleman M.P. Increasing incidence of childhood leukaemia: a controversy re-examined. Br J Cancer. 2007;97:1009–1012. doi: 10.1038/sj.bjc.6603946. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Poynton F.J., Thursfield H., Paterson D. The severe blood diseases of childhood: a series of observations from the Hospital for Sick Children, Great Ormond Street. Br J Child Dis. 1922;XIX:128–144. [Google Scholar]
  • 7.Preston D.L., Kusumi S., Tomonaga M., Izumi S., Ron E., Kuramoto A., Kamada N., Dohy H., Matsui T., Nonaka H., et al. Cancer incidence in atomic bomb survivors. Part III: Leukemia, lymphoma and multiple myeloma, 1950–1987. Radiat Res. 1994;137(Suppl):S68–S97. doi: 10.2307/3578893. [DOI] [PubMed] [Google Scholar]
  • 8.Greaves M.F. Aetiology of acute leukaemia. Lancet. 1997;349:344–349. doi: 10.1016/S0140-6736(96)09412-3. [DOI] [PubMed] [Google Scholar]
  • 9.Greaves M.F., Maia A.T., Wiemels J.L., Ford A.M. Leukemia, in twins: lessons in natural history. Blood. 2003;102:2321–2333. doi: 10.1182/blood-2002-12-3817. [DOI] [PubMed] [Google Scholar]
  • 10.Greaves M.F., Wiemels J. Origins of chromosome translocations in childhood leukaemia. Nature Rev Cancer. 2003;3:639–649. doi: 10.1038/nrc1164. [DOI] [PubMed] [Google Scholar]
  • 11.Greaves M.F. Speculations on the cause of childhood acute lymphoblastic leukemia. Leukemia. 1988;2:120–125. [PubMed] [Google Scholar]
  • 12.Tsuzuki S., Seto M., Greaves M., Enver T. Modelling first-hit functions of the t(12;21) TEL-AML1 translocation in mice. Proc Natl Acad Sci USA. 2004;101:8443–8448. doi: 10.1073/pnas.0402063101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Hong D., Gupta R., Ancliffe P., Atzberger A., Brown J., Soneji S., Green J., Colman S., Piacibello W., Buckle V., et al. Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia. Science. 2008;319:336–339. doi: 10.1126/science.1150648. [DOI] [PubMed] [Google Scholar]
  • 14.Mori H., Colman S.M., Xiao Z., Ford A.M., Healy L.E., Donaldson C., Hows J.M., Navarrete C., Greaves M. Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc Natl Acad Sci USA. 2002;99:8242–8247. doi: 10.1073/pnas.112218799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Mullighan C.G., Goorha S., Radtke I., Miller C.B., Coustan-Smith E., Dalton J.D., Girtman K., Mathew S., Ma J., Pounds S.B., et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature. 2007;446:758–764. doi: 10.1038/nature05690. [DOI] [PubMed] [Google Scholar]
  • 16.Bateman C.M., Horsley S.W., Chaplin T., Young B.D., Ford A.M., Kearney L., Greaves M. Sequence of genetic events in ETV6-RUNX1 positive B precursor ALL: insights from identical twins with concordant leukaemia: Blood. San Francisco: American Society of Hematology; 2008. [Google Scholar]
  • 17.Greaves M. Infection, immune responses and the aetiology of childhood leukaemia. Nat Rev Cancer. 2006;6:193–203. doi: 10.1038/nrc1816. [DOI] [PubMed] [Google Scholar]
  • 18.Gluckman P., Hanson M. Mismatch. Why our world no longer fits our bodies. Oxford: Oxford University Press; 2006. [Google Scholar]
  • 19.Greaves M. Darwinian medicine: a case for cancer. Nat Rev Cancer. 2007;7:213–221. doi: 10.1038/nrc2071. [DOI] [PubMed] [Google Scholar]
  • 20.Strachan D.P. Family size, infection and atopy: the first decade of the “hygiene hypothesis”. Thorax. 2000;55:S2–S10. doi: 10.1136/thorax.55.suppl_1.S2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Zur Hausen H. Infections causing human cancer. Weinheim: Wiley-VCH; 2006. [Google Scholar]
  • 22.UK Childhood Cancer Study Investigators The United Kingdom Childhood Cancer Study: objectives, materials and methods. Br J Cancer. 2000;82:1073–1102. doi: 10.1054/bjoc.1999.1045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.UK Childhood Cancer Study Investigators Childhood cancer and residential proximity to power lines. Br J Cancer. 2000;83:1573–1580. doi: 10.1054/bjoc.2000.1550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.UK Childhood Cancer Study Investigators The United Kingdom Childhood Cancer Study of exposure to domestic sources of ionising radiation: 2: gamma radiation. Br J Cancer. 2002;86:1727–1731. doi: 10.1038/sj.bjc.6600277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Gilham C., Peto J., Simpson J., Roman E., Eden T.O.B., Greaves M.F., Alexander F. f., the UKCCS Investigators Day care in infancy and risk of childhood acute lymphoblastic leukaemia: findings from a UK case-control study. Br Med J. 2005;330:1294–1297. doi: 10.1136/bmj.38428.521042.8F. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Ma X., Buffler P.A., Wiemels J.L., Selvin S., Metayer C., Loh M., Does M.B., Wiencke J.K. Ethnic difference in daycare attendance, early infections, and risk of childhood acute lymphoblastic leukemia. Cancer Epidemiol Biomarkers Prev. 2005;14:1928–1934. doi: 10.1158/1055-9965.EPI-05-0115. [DOI] [PubMed] [Google Scholar]
  • 27.Kamper-Jørgensen M., Woodward A., Wohlfahrt J., Benn C.S., Simonsen J., Hjalgrim H., Schmiegelow K. Childcare in the first 2 years of life reduces the risk of childhood acute lymphoblastic leukemia. Leukemia. 2007;22:189–193. doi: 10.1038/sj.leu.2404884. [DOI] [PubMed] [Google Scholar]
  • 28.Louhiala P.J., Jaakkola N., Ruotsalainen R., Jaakkola J.J. Form of day care and respiratory infections among Finnish children. Am J Public Health. 1995;85:1109–1112. doi: 10.2105/AJPH.85.8_Pt_1.1109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.McNally R.J.Q., Eden T.O.B. An infectious aetiology for childhood acute leukaemia: a review of the evidence. Br J Haematol. 2004;127:243–263. doi: 10.1111/j.1365-2141.2004.05166.x. [DOI] [PubMed] [Google Scholar]
  • 30.Roman E., Simpson J., Ansell P., Kinsey S., Mitchell C.D., McKinney P.A., Birch J.M., Greaves M., Eden T. Childhood acute lymphoblastic leukemia and infections in the first year of life: a report from the United Kingdom Childhood Cancer Study. Am J Epidemiol. 2007;165:496–504. doi: 10.1093/aje/kwk039. [DOI] [PubMed] [Google Scholar]
  • 31.Cardwell C.R., McKinney P.A., Patterson C.C., Murray L.J. Infections in early life and childhood leukaemia risk: a UK case-control study of general practitioner records. Br J Cancer. 2008;99:1529–1533. doi: 10.1038/sj.bjc.6604696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Greaves M., Buffler P.A. Infections in early life and risk of childhood ALL. Br J Cancer. 2009;100:863. doi: 10.1038/sj.bjc.6604950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Taylor G.M., Dearden S., Ravetto P., Ayres M., Watson P., Hussain A., Greaves M., Alexander F., Eden O.B., UKCCS Investigators Genetic susceptibility to childhood common acute lymphoblastic leukaemia is associated with polymorphic peptide-binding pocket profiles in HLA-DPB1*0201. Hum Mol Genet. 2002;11:1585–1597. doi: 10.1093/hmg/11.14.1585. [DOI] [PubMed] [Google Scholar]
  • 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 849
  • 35.Easton D.F., Pooley K.A., Dunning A.M., Pharoah P.D., Thompson D., Ballinger D.G., Struewing J.P., Morrison J., Field H., Luben R., et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature. 2007;447:1087–1093. doi: 10.1038/nature05887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Amos C.I., Wu X., Broderick P., Gorlov I.P., Gu J., Eisen T., Dong Q., Zhang Q., Gu X., Vijayakrishnan J., et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet. 2008;40:616–622. doi: 10.1038/ng.109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Ford A., Palmi C., Bueno C., Hong D., Cardus P., Knight D., Cazzaniga G., Enver T., Greaves M. The TEL-AML1 leukaemia fusion gene dysregulates the TGFß pathway in early B lineage progenitor cells. J Clin Invest. 2009;119:826–836. doi: 10.1172/JCI36428. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Pasqualucci L., Bhagat G., Jankovic M., Compagno M., Smith P., Muramatsu M., Honjo T., Morse H.C., III, Nussenzweig M.C., Dalla-Favera R. AID is required for germinal center-derived lymphomagenesis. Nat Genet. 2008;40:108–112. doi: 10.1038/ng.2007.35. [DOI] [PubMed] [Google Scholar]
  • 39.Mullighan C.G., Miller C.B., Radtke I., Phillips L.A., Dalton J., Ma J., White D., Hughes T.P., Le Beau M.M., Pui C.-H., et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008;453:110–114. doi: 10.1038/nature06866. [DOI] [PubMed] [Google Scholar]
  • 40.Spix C., Eletr D., Lettner M., Kaatsch P. Temporal trends in the incidence rate of childhood cancer in Germany 1987–2004. Int J Cancer. 2008;122:1859–1867. doi: 10.1002/ijc.23281. [DOI] [PubMed] [Google Scholar]
  • 41.Li C.K., Zee B., Lee J., Chik K.W., Ha S.Y., Lee V. Impact of SARS on development of childhood acute lymphoblastic leukaemia. Leukemia. 2007;21:1353–1356. doi: 10.1038/sj.leu.2404729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Kinlen L.J. Epidemiological evidence for an infective basis in childhood leukaemia. Br J Cancer. 1995;71:1–5. doi: 10.1038/bjc.1995.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Alexander F.E., Chan L.C., Lam T.H., Yuen P., Leung N.K., Ha S.Y., Yuen H.L., Li C.K., Li C.K., Lau Y.L., et al. Clustering of childhood leukaemia in Hong Kong: association with the childhood peak and common acute lymphoblastic leukaemia and with population mixing. Br J Cancer. 1997;75:457–463. doi: 10.1038/bjc.1997.77. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Heath C.W., Jr, Hasterlik R.J. Leukemia among children in a suburban community. Am J Med. 1963;34:796–812. doi: 10.1016/0002-9343(63)90088-3. [DOI] [PubMed] [Google Scholar]
  • 45.Steinmaus C., Lu M., Todd R.L., Smith A.H. Probability estimates for the unique childhood leukemia cluster in Fallon, Nevada, and risks near other U.S. military aviation facilities. Environ Health Perspect. 2004;112:766–771. doi: 10.1289/ehp.6592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Goedert J.J., editor. Infectious Causes of Cancer. New Jersey: Humana Press; 2000. [Google Scholar]
  • 47.Balkwill F. Cancer and the chemokine network. Nat Rev Cancer. 2004;4:540–550. doi: 10.1038/nrc1388. [DOI] [PubMed] [Google Scholar]
  • 48.Isaacson P.G., Du M.-Q. MALT lymphoma: from morphology to molecules. Nat Rev Cancer. 2004;4:644–653. doi: 10.1038/nrc1409. [DOI] [PubMed] [Google Scholar]
  • 49.Gutensohn N., Cole P. Epidemiology of Hodgkin’s disease. Sem Oncol. 1980;7:92–102. [PubMed] [Google Scholar]
  • 50.Backett E.M. Social patterns of antibody to poliovirus. Lancet. 1957;i:778–783. doi: 10.1016/S0140-6736(57)91042-5. [DOI] [PubMed] [Google Scholar]
  • 51.Stearns S.C., Koella J.C., editors. Evolution in health and disease. New York: Oxford University Press; 2008. [Google Scholar]

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