Genetic factors - Childhood cancer

A small proportion of childhood cancer cases (less than 5%) have an obvious family history.

The most important example of a childhood cancer for which there are familial aggregations of cases is retinoblastoma; about 40% of the cases of this tumour are heritable.

Such aggregations also occur, though to a much smaller extent, for Wilms' tumour. The pattern of inheritance for the heritable form of retinoblastoma is relatively simple and is well understood; that for Wilms' tumour is more complicated.

In addition, certain childhood cancers are associated with rare inherited conditions such as neurofibromatosis, tuberous sclerosis, Fanconi's anaemia, ataxia telangiectasia, and xeroderma pigmentosum, though the actual number of cases of childhood cancer in which these conditions occur is small. In these and other rare conditions more than one child, and also other family members, may have an associated cancer.

Familial aggregations, involving both child and adult cases, also occur in the 'Li-Fraumeni syndrome' which is associated with mutations in the TP53 gene.

There are also associations with various chromosome abnormalities; the most important of these is Down syndrome which occurs in a small percentage of cases of childhood leukaemia: the risk of acute leukaemia among children with Down syndrome is between 10 and 30 times as high as that for other children.1

The striking ethnic distribution of Ewing's sarcoma, which is almost absent from black populations both in Africa and the USA, suggests that genetic influences are important in the aetiology of this tumour.

It is clear from these and other observations that the causes of some childhood cancers are partly genetic. For a detailed discussion of genetic factors in the epidemiology of childhood cancers.2

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Retinoblastoma
There are about 45 cases of retinoblastoma in Great Britain each year, and about 20 of these are of the type that can be inherited. The pattern of inheritance is that of an autosomal dominant condition with a high degree of penetrance, though the disease is actually the result of mutation in the tumour suppressor gene RB1.

Retinoblastoma may be either bilateral, that is, affecting both eyes, or unilateral. All bilateral cases are heritable; a few unilateral cases are known to be heritable because a related family member also has retinoblastoma. Nearly half the children of a parent with heritable retinoblastoma will themselves be affected.

For children of cases not known to be heritable the estimated risk is very low, around 1%. Likewise if there is no previous family history the risks for siblings of unilateral and bilateral cases are respectively about 1% and 2%.3

Using modern molecular genetics and pre-natal screening more definite advice about the risk can often be obtained.

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Risk to siblings
When a child is diagnosed with cancer it is likely that questions will be raised concerning the risks to the siblings of the affected child. Sometimes a second sibling will be affected by cancer purely as a result of chance; in other cases such an occurrence may reflect an increased risk in particular families.

In the general population the chance of a child developing cancer is about 1 in 500. In the absence of a relevant clinically observed genetic condition in the child, or a family history of such a disease, or a 'cancer syndrome', and excluding twins, the risks for siblings of affected children are about double what would be expected by chance, giving a risk of 1 in 250; this is the risk that such siblings will develop cancer between birth and age 15.4

It should be emphasised that the risk is less than 1 in 250 for siblings who are already part way through childhood when the affected child is diagnosed, and have therefore passed part of the period when they would be at risk.

The risks are considerably higher if the affected child is a member of a family affected by one of the genetic conditions referred to above. The existence of such a condition may actually be recognised as a result of a second sibling being affected. In fact, many familial aggregations of childhood cancer can, sometimes retrospectively, be recognised as forming part of a known genetic condition or syndrome.5

But, for genetic counselling, risk estimates sometimes have to be made before such knowledge becomes available for a particular family, and in this situation the estimated doubling of the population risk for the siblings of affected cases is appropriate.

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Risk to twins
For a child with cancer who has a twin the situation is different. For dizygotic (nonidentical) twins of affected children, although there is little direct evidence, it can be assumed that the risks are the same as they would be for other siblings in the same family.

For monozygous (identical) twins there is a high risk for the co-twins of children with leukaemia, especially those diagnosed in the first year of life.6 In this case the risk for co-twins appears to be usually, if not always, attributable to the transfer of leukaemic cells from one twin to the other during pregnancy.

An identical twin of a child with retinoblastoma also has a high risk of developing retinoblastoma, though the actual level of risk will vary a great deal, depending on whether or not there is a family history and whether the tumour is bilateral or unilateral.

For other childhood cancers there is insufficient information to make any estimate of risk, but it seems likely that identical co-twins of affected children will have a high risk of developing the same disease.

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Risk for offspring of children with cancer in the absence of known genetic disease in the family
Now that large numbers of children survive their cancer and go on to have children of their own, there is inevitably concern about whether their offspring will have an increased risk of cancer.

In general, after the exclusion of hereditary cancer syndromes, there is no evidence of a significantly raised risk of cancer among the offspring of survivors.7