HERITABILITY OF CHILDHOOD CANCERS: INTRIGUING QUESTIONS

HERITABILITY  OF CHILDHOOD  CANCERS:  INTRIGUING  QUESTIONS

Cancers in children are relatively uncommon. They represent less than 1% of all new cases of cancer diagnosed in the US each year. Certain tumours of developing organs and tissues, such as retinoblastomas in the eye and osteosarcomas in bone, are more common in children.

The causative mechanisms of childhood cancers are largely unknown. Up to 10% of all cancers in children are caused by a heritable mutation, says NCI. Inheritance of a mutation in a gene called RB1 from parents has been identified as a reason for about 45% of children with retinoblastoma, a cancer of the eye. Mutations associated with Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, Fanconi anaemia syndrome, Noonan syndrome and von Hippel-Lindau syndrome are also found to increase the risk of childhood cancer.

Children having an extra copy of chromosome 21 (Down’s), are 10 to 20 times more likely to develop leukaemia theoretically. However, only a very small proportion of childhood leukaemia is linked to the syndrome.

Based on this, the American Association for Cancer Research published its first recommendations for screening and clinical care.

Recently, it has been discovered that a mutation in the gene for the histone protein H3.3 prevents a specific modification of the protein present in most diffuse intrinsic pontine glioma (DIPG), a type of paediatric brain tumour associated with aggressive disease and shorter survival.

 

Fusion oncoproteins, polymorphism

Fusion oncoproteins are also found driving certain childhood cancers. These abnormal proteins, formed due to the accidental joining of two genes within a cell, have been implicated in certain aggressive forms of leukaemia and other paediatric malignancies.

The Paediatric Cancer Genome Project found 8.5% of children with cancer had germline mutations in cancer predisposition genes, which their family histories failed to predict. The most commonly affected genes were TP53, APC, BRCA2, NF1, PMS2, RB1, and RUNX1.

In addition to predisposition syndromes, studies have identified new associations of germline mutations of TP53, PMS2 and RET mutations with Ewing sarcoma; APC and SDHB mutations with neuroblastoma, and a diverse range of mutations in APC, VHL, CDH1, PTCH1, and SDHA with leukaemia.

Testing for TMPT status for dose adjustments for mercaptopurine is a standard practice in ALL today.

Sensitive, next-generation sequencing–based minimal residual disease (MRD) monitoring is being tested prospectively in several paediatric oncology consortia.

Also, several genome-wide association studies have identified polymorphisms in genes that predict susceptibility to common chemotherapy-related complications. A range of trials using precision medicine in paediatric oncology is currently underway. Efforts to use cell-free DNA assays for detecting gene variants and the sharing of resulting clinical and genomic data elements for secondary analyses will lead to a greater understanding of the paediatric cancer genome.

 

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