Genes

All cancers arise when a cell is genetically altered and unable to control its own growth and proliferation. Over the last decade there have been significant advances made in understanding the molecular genetics of several childhood cancers (Pritchard‐Jones, 1996). There are three known major classes of cancer genes: (1) Oncogenes – mutated forms of normal cellular genes that have become cancer causing. They increase the speed of cell division (proliferation), block differentiation and act in a dominant manner, i.e., mutation in only one of the pair of genes is sufficient for pathogenicity; (2) Tumour suppressor genes – whose function is to inhibit cell division, survival and associated properties of cancer cells (e.g., p53, see next section); (3) Deoxyribonucleic acid (DNA) processing genes – whose normal function is to regulate DNA replication and when mutated, allow rapid accumulation of mutations in other cancer‐causing genes. Chronological mutation of all three of these cancer genes may be involved in the development and progression of a single cancer.

p53

The most important tumour suppressor gene in human cells is p53, which expresses a protein that controls cell division and survival. The protein is mutated or inactivated in about 60% of cancer cases; it is found in increased amounts in a wide variety of transformed cells.

Genetic predisposition

Inherited variants in p53 cause a familial cancer syndrome called Li‐Fraumeni syndrome; in these families, the affected relatives develop a diverse set of malignancies including leukaemia, breast carcinomas, sarcomas (bone tumours), and brain tumours at unusually early ages.

There are other known genetic predispositions for some cancers, for example, children with Down syndrome are known to have a higher risk of developing leukaemia (Siegel, Naishadham & Jemal, 2013). However, some solid tumours occur less frequently than expected in Down syndrome, specifically there is a complete absence of neuroblastoma and Wilms tumour (nephroblastoma) (Satgé, Sasco & Lacour, 2003). It is therefore likely that there are genes on chromosome 21 that increase the risk of some cancers while others have an opposite effect. Furthermore, children who have hereditary retinoblastoma (RBS) (a rare tumour of the eye) have an increased risk of developing osteosarcoma. This is a classic example of a cancer resulting from an inherited genetic abnormality. It is not unusual for families to contain more than one affected member and in more than one generation. In most familial cases, both eyes are affected, indeed heritable RBS is usually defined as any case with bilateral tumours or a family history (Stiller, 2004a).

The familial aggregation of childhood cancer is widely studied. Often a familial link for childhood cancer will only come to light following the diagnosis of a second sibling. Table 3.1 lists examples of congenital factors associated with childhood cancer, which give rise to an increased risk of childhood cancer.

Environmental factors

Despite numerous literature reviews of environmental or exogenous exposures, there is little evidence of these being firmly established as risk factors for childhood cancer (Stiller, 2004b). They include: neonatal administration of vitamin K, parental use of medications and drugs, proximity to electromagnetic fields, parental employment and exposure to potential mutagens (Vora, 2016).

Ionising radiation (IR)

IR has been implicated in the induction of leukaemia (Vora, 2016). Research also shows that cells can detect and respond epigenetically, altering gene expression after low doses of IR (Jones et al., 2010). More than 67 years ago, a correlation between antenatal obstetric diagnostic X‐rays and cancer in the offspring were discovered (Stewart et al., 1958). At that time it was thought that 5% of all childhood cancers were as a result of in utero irradiation. However, this number has reduced and is attributable to significantly lower numbers of women being exposed to irradiation in pregnancy.

Viruses

There is an association with Epstein–Barr virus (EBV) and both paediatric Hodgkin and Burkitt lymphomas (Paola & Preciado, 2013). International variations in the incidence of childhood lymphoma are therefore apparent (Stiller, 2004a).

Hormones

The hormone diethylstilboestrol (DES) is the only established trans‐placental carcinogen; it was administered to pregnant women threatening abortion >40 years ago (Giusti et al., 1995). This drug is no longer used and thus DES‐related clear‐cell adenocarcinoma of the vagina or cervix in young women should cease.