Cancer Research UK : Childhood Cancer risk factors

Childhood Cancer risk factors

Very little is known about the causes of most childhood cancers. For many diagnostic groups, the occurrence of the highest incidence at an early age and the cell type of origin strongly suggest that causative factors operate before birth and possibly even before conception.

Chromosome translocations involved in many childhood leukaemias have been shown to originate before birth on the basis of studies of identical twins who both have the same type of leukaemia and by detection in neonatal blood spots.1-2

Putative risk factors can be somewhat arbitrarily divided into environmental and genetic. Some birth characteristics could be markers for environmental or genetic risk, while some predisposing genetic abnormalities may have environmental origins and geneenvironment interactions could well be important in the induction of malignant disease.

Aetiological studies have often been concerned with exposures occurring during the mother's pregnancy, although pre-conception and postnatal factors have also been investigated.

Numerous domestic and other environmental exposures have been linked with childhood cancers. Interpretation is limited by the wide range of cancers studied, variation in the timing of exposure ranging from before conception to during the child's lifetime, the small number of exposed subjects in many studies and lack of information on specific substances.

There is only limited consistency between the numerous studies of most suspected risk factors for childhood cancer. Many studies, particularly those involving rather few cases, have been inconclusive. It is impossible to say for any specific study whether this is because there was no excess risk attributable to the factor in question or because the study was too small to detect it.

This problem has led to an increased emphasis on large national or international studies such as the UK Childhood Cancer Study (UKCCS)3 and the SEARCH collaborative study of childhood brain tumours4 and also to the analysis of pooled data from several pre-existing studies.

Ionising radiation

The increased risk of childhood cancer associated with antenatal obstetric irradiation was discovered over 40 years ago.5 Since then, obstetric x-ray examination in pregnancy has been largely superceded by ultrasound examination. There is no evidence that ultrasound causes childhood cancer.

Environmental ionising radiation could be a cause of childhood cancer, especially leukaemia, although there is little evidence of any increase in leukaemia incidence attributable to fallout from the Chernobyl nuclear power plant accident in 1986,6 and no evidence of a general increase in the incidence of childhood leukaemia around nuclear power stations.7-8

The possibility that paternal preconception exposure to ionising radiation could lead to excesses of leukaemia in the vicinity of certain nuclear installations in Britain was supported by a small case-control study in the area around the Sellafield nuclear reprocessing plant.9

A review of the evidence from two large, overlapping studies of UK radiation workers employed at Sellafield and elsewhere, however, concluded that there was unlikely to be any simple causal relationship.10-12

It has been suggested that inhalation of radon, a natural radioactive gas that is present everywhere but in varying concentrations, may result in irradiation of the bone marrow and thereby increase the risk of leukaemia, but the UKCCS and earlier studies have shown that it accounts for few, if any, cases of childhood leukaemia.13-14

Similarly, the UKCCS found no evidence to link higher levels of natural background gamma radiation with childhood cancer.15

Non-ionising radiation

There has been much public concern about the possible health effects of electromagnetic fields arising from electrical sources such as power lines and domestic wiring.

Analyses of pooled data from case-control studies have shown no evidence for raised risk of childhood leukaemia with exposure to power frequency (50-60Hz) fields at the levels experienced by over 95% of children in western countries.16-17 A doubling of risk has been found at the very highest exposure levels but the reasons for this are unknown and it remains possible that it is partly due to bias or confounding factors.

Excessive exposure to the ultraviolet component of sunlight increases the risk of skin cancer, predominantly in adults, and this might explain the relatively high incidence of childhood melanoma in Australia and New Zealand.18 There is no conclusive evidence that other non-ionising radiation can cause cancer.

Infections

Exposure to infection, especially by viruses, certainly plays a part in the aetiology of some childhood cancers. Worldwide, the most important examples numerically are Burkitt's lymphoma, Hodgkin's disease and nasopharyngeal carcinoma (all associated with Epstein-Barr virus), liver carcinoma (hepatitis B) and Kaposi's sarcoma (HIV and HHV8) but together these associations account for a very small proportion of childhood cancer in western countries.

The early childhood peak of leukaemia incidence in affluent western populations and the persistently lower incidence in socio-economically disadvantaged groups and less developed countries generally has suggested that ALL could be associated with an infectious agent linked to public hygiene conditions.19

Two hypotheses suggest that abnormal response to infection has a key role in the development of leukaemia. Under the 'delayed infection' hypothesis, ALL can result from lack of exposure to infection and consequent failure of immune system modulation during infancy.20

This model is supported by epidemiological studies showing that children with ALL tend to have had relatively few infections in the first months of life, fewer immunisations in infancy and a shorter period of breastfeeding, and are more likely to be first born or only children.21

Under the 'impaired herd immunity' hypothesis, leukaemia is a rare response to a common infection in particularly susceptible children. This is supported by a series of studies in which high levels of population mixing, often but not always as a result of migration, were accompanied by increased incidence of leukaemia.22

Drugs and medication

There have been reports of the possible carcinogenic effects of many different drugs taken by mothers during pregnancy. The only one firmly established as a transplacental carcinogen is diethylstilboestrol (DES), a hormone which in some countries used to be given to pregnant women with threatened abortion.

Exposure to DES in utero caused clear cell adenocarcinoma of the vagina or cervix mostly in young women, though a few cases were observed in girls aged under 1523; however, as its use was discontinued about 30 years ago, and there is no direct evidence for a transgenerational effect, it is unlikely that further childhood cancers attributable to DES will be seen.

Much controversy and public concern was generated by a study that found that intramuscular vitamin K given to infants to prevent vitamin K deficiency bleeding was associated with a doubling of the risk of childhood cancer.24

A pooled analysis of six case-control studies, including the one which gave rise to the controversy, found little evidence for raised risk of leukaemia or other cancer among children recorded as having received intramuscular vitamin K, though interpretation was rendered difficult by the poor quality of much of the vitamin K data.25

Parental occupation

Many associations have been reported between parental occupation and childhood cancer. When 48 studies were reviewed, there was rather little consistency between them, though a few biologically plausible associations found in more than one study would merit further investigation.26

The UKCCS was typical of more recent studies in finding no strong evidence to link parental occupational exposures with an increased risk of childhood cancer.27

Smoking

The offspring of mothers who smoke during pregnancy have an increased risk of adverse effects, including low birth weight and perinatal mortality, but the evidence on parental smoking and cancer in children has been somewhat inconclusive.

In a meta-analysis of more than 30 studies there was a 10% increase in risk of all neoplasms with maternal smoking during pregnancy but no evidence for an increased risk of any specific cancer.28 In the UKCCS there was no significant evidence that parental smoking is a risk factor for any of the main types of childhood cancer.29

Parental age

The risk of ALL increases with increasing age of either parent, despite the tendency for risk to be lower with higher birth order.21 This is true even after exclusion of children with Down syndrome, which is more common among the offspring of older mothers and carries an increased risk of childhood leukaemia (see Genetic factors section).

References

Greaves, M.F., et al., Leukemia in twins: lessons in natural history. Blood, 2003. 102(7): p. 2321-33
Greaves, M.F. and J. Wiemels, Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer, 2003. 3(9): p. 639-49
UK Childhood Cancer Study Investigators, Childhood cancer and residential proximity to power lines. Br J Cancer, 2000. 83(11): p. 1573-80
McCredie, M., et al., SEARCH international case-control study of childhood brain tumours: role of index pregnancy and birth, and mother's reproductive history. Paediatr Perinat Epidemiol, 1999. 13(3): p. 325-41
Stewart, A., J. Webb, and D. Hewitt, A survey of childhood malignancies. Br Med J, 1958. 30(5086): p. 1495-508
Parkin, D.M., et al., Childhood leukaemia in Europe after Chernobyl: 5 year follow-up. Br J Cancer, 1996. 73(8): p. 1006-12
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Kaatsch, P., et al., An extended study on childhood malignancies in the vicinity of German nuclear power plants. Cancer Causes Control, 1998. 9(5): p. 529-33
Gardner, M.J., et al., Results of case-control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria. Bmj, 1990. 300(6722): p. 423-9
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Laurier, D., M. Valenty, and M. Tirmarche, Radon exposure and the risk of leukemia: a review of epidemiological studies. Health Phys, 2001. 81(3): p. 272-88
UKCCSI, The United Kingdom Childhood Cancer Study of exposure to domestic sources of ionising radiation: 1: radon gas. Br J Cancer, 2002. 86(11): p. 1721-6.
The United Kingdom Childhood Cancer Study of exposure to domestic sources of ionising radiation: 2: gamma radiation. Br J Cancer, 2002. 86(11): p. 1727-31
Greenland, S., et al., A pooled analysis of magnetic fields, wire codes, and childhood leukemia. Childhood Leukemia-EMF Study Group. Epidemiology, 2000. 11(6): p. 624-34.
Ahlbom, A., et al., A pooled analysis of magnetic fields and childhood leukaemia. Br J Cancer, 2000. 83(5): p. 692-8.
Mackie, Links between exposure to ultraviolet radiation and skin cancer. A report of the Royal College of Physicians. J R Coll Physicians Lond, 1987. 21(2): p. 91-6
Smith, M.A., et al., Evidence that childhood acute lymphoblastic leukemia is associated with an infectious agent linked to hygiene conditions. Cancer Causes Control, 1998. 9(3): p. 285-98
Greaves, M., Childhood leukaemia. Bmj, 2002. 324(7332): p. 283-7
Dockerty, J.D., et al., Case-control study of parental age, parity and socioeconomic level in relation to childhood cancers. Int J Epidemiol, 2001. 30(6): p. 1428-37
Kinlen, L.J., Epidemiological evidence for an infective basis in childhood leukaemia. Br J Cancer, 1995. 71(1): p. 1-5
Giusti, R.M., K. Iwamoto, and E.E. Hatch, Diethylstilbestrol revisited: a review of the long-term health effects. Ann Intern Med, 1995. 122(10): p. 778-88
Golding, J., et al., Childhood cancer, intramuscular vitamin K, and pethidine given during labour. Bmj, 1992. 305(6849): p. 341-6
Roman, E., et al., Vitamin K and childhood cancer: analysis of individual patient data from six case-control studies. Br J Cancer, 2002. 86(1): p. 63-9
Colt, J.S., Blair, A., Parental occupational exposures and risk of childhood cancer. Environ Health Perspect, 1998. 106 Suppl 3: p. 909-25
McKinney, P.A., N.T. Fear, and D. Stockton, Parental occupation at periconception: findings from the United Kingdom Childhood Cancer Study. Occup Environ Med, 2003. 60(12): p. 901-9
Boffetta, P., J. Tredaniel, and A. Greco, Risk of childhood cancer and adult lung cancer after childhood exposure to passive smoke: A meta-analysis. Environ Health Perspect, 2000. 108(1): p. 73-82.
Pang, D., R. McNally, and J.M. Birch, Parental smoking and childhood cancer: results from the United Kingdom Childhood Cancer Study.Br J Cancer, 2003. 88(3): p. 373-81