Childhood cancer - molecular biology and genetics

Up to 5% of childhood cancers have an obvious family history,1-2 and many of these cases are associated with rare familial cancer syndromes (Table 7.1). 

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Research is continuing to provide new insights into the treatment and management of childhood cancers, with some genes being identified as targets for new drugs, or having potential to be used as biomarkers to aid early diagnosis of the diseases. The recognition of familial cancer syndromes also helps the earlier detection of cancers through genetic counselling and screening. Some examples of genetic anomalies associated with childhood cancers are described below.

Retinoblastoma is the most notable example of a childhood cancer that clusters in families, with around 40% of cases being inherited and the remainder occurring sporadically.3-4 The inherited forms of retinoblastoma are more likely to be bilateral and tend to have an earlier age of onset than the non-hereditary forms, an observation that led Knudson to develop the groundbreaking two-hit hypothesis in the early 1970s.5 Knudson’s work led indirectly to the cloning of the first tumour suppressor gene, RB1, marking the start of a new era in cancer genetics.6-7

Less than 2% of Wilms tumour cases are hereditary, with the incidence in siblings being fourteen times higher than in the general population.8-9 Genes implicated in familial Wilms tumour development include WT1, FWT1 and FWT2.10-13 Wilms tumour is associated with a broad range of syndromes, congenital abnormalities and chromosomal disorders, and up to 1 in 6 children diagnosed with Wilms tumour also have a malformation syndrome, such as WAGR syndrome, Denys–Drash syndrome or Beckwith-Weidemann syndrome - the highest proportion recorded for any childhood malignancy.14-15

Approximately 1-2% of neuroblastoma cases have a family history, with the incidence in siblings being almost ten times higher than in the general population.9 Most hereditary cases are caused by germline mutations (changes to a gene before birth) in the ALK gene.16 Mutations in the PH0X2B gene have been shown to confer an increased risk of neuroblastoma in families with genetic conditions such as Hirschsprung disease and congenital central hypoventilation syndrome.17-18 A gene linked to more agressive forms of neuroblastoma has also been mapped.19

In children, rhabdomyosarcomas can be broadly divided into two histological subgroups: alveolar and embryonal. The more aggressive alveolar subtype of this disease is frequently characterised by chromosome translocations (the switching of one part of a chromosome with another) between the PAX3 or PAX7 genes and the FKHR gene.20-21  Less is known about the genetic basis of embryonal rhabdomyosarcoma, but it is often associated with the disruption of a specific gene cluster on chromosome 11 (also seen in Wilms tumour and hepatoblastoma cases).20

Familial leukaemia is rare. For cases diagnosed in the first year of life, the chances of a co-twin developing the disease is particularly high because precursor leukaemia cells can transfer from one twin to the other during pregnancy.22 Children with Down’s syndrome are at greater risk of developing leukaemia, with most studies reporting an increased risk of between 10- and 20-fold.23-24 Leukaemia is also associated with rare genetic syndromes characterised by chromosomal breakage, such as ataxia telangiectasia and Bloom syndrome.25 More than 200 genes have been implicated in the development of leukaemia; the TEL-AML1 gene is one of the most common, occurring in 20% of all ALL cases.26

The genetic alterations underlying Hodgkin lymphoma and non-Hodgkin lymphoma are not well understood. A small proportion of Hodgkin lymphoma cases are hereditary. Incidence rates in identical twins of people with Hodgkin lymphoma are around 99 times higher than the general population, whereas non-identical twins have no increase in risk.27 Familial clusters of NHL are known to occur, though the relative contribution of genetic and environmental factors is undefined.28