Why do children get cancer?

Q: Why do children get cancer?

Krishna: Earlier researchers and doctors used to give this answer:

Childhood cancer is primarily caused by random, spontaneous genetic mutations that happen during rapid cell growth and development, rather than lifestyle choices or environmental habits. [1]

The first observation that comes out of the medical literature on paediatric cancers is that they have fewer mutations than adult tumours. In adults there is an accumulation of mutations in many genes, and that phenomenon both creates the cancer and helps it progress. In children, fewer mutations are needed to initiate cancer.

While all cancers feature mutations in important genes, the cancer-causing mutations that happen in children tend to be seen in genes that control progression through the cell cycle. The RB1 gene is a perfect example. When absent, the cell cycle keeps going without regulation, with cells dividing and dividing and turning into tumours.

We also see more fusion genes in paediatric cancers versus adult cancers. A fusion gene is when one half of a gene gets combined with one half of another gene, creating a new protein that did not exist before. It may not seem like much, but when the first gene has a very important role to play intermittently and the second gene acts as a license to do it all the time, we end up with an overactive gene that favours the uncontrolled division of cells. It’s like installing a rocket engine at the back of a car and snipping the brake line during the fitting. The part-car, part-rocket vehicle will cause havoc on the highway.

Finally, childhood cancers differ from adult cancers not just genetically but also epigenetically. Genes make proteins but genes do not make proteins continually. Just like the cell cycle is tightly regulated, so is the production of proteins through gene expression. That process is known as epigenetic regulation, where “epigenetic” means “on top of the gene.” There are ways in which the genes are rendered inaccessible or silent, and it involves things like methylation and histones, and the genes coding for those very things are often mutated in childhood cancers. It means that gene expression is not as restrained as it should normally be, which leads to tumours forming faster.

Childhood cancers are also different from adult cancers in these ways:

Not lifestyle-linked: Adult cancers are often tied to long-term habits like smoking, alcohol, or decades of exposure to carcinogens. Children have not lived long enough for these factors to play a role. 

Cell replication errors: As a child's body grows quickly, cells divide rapidly. Random mistakes or "bad luck" can happen in the DNA during this cell division, turning normal genes into cancer-driving genes (oncogenes) or shutting down protective genes (tumour suppressor genes). 

Early development: Many of these genetic changes occur very early in life, sometimes even before birth while the baby is still in the womb. 

Abnormal antibodies that disrupt DNA repair could explain childhood cancer

Paediatric cancers, such as leukemia, myeloma, neuroblastoma and osteosarcoma, differ from adult cancers in their causes, location and type, and response to therapy.

Compared to adults, children have had less time to accumulate cancerous DNA damage through exposure to environmental stressors, lifestyle factors and aging. Paediatric cancers thus tend to carry fewer mutations than adult ones and arise from less mature cells, for example, stem or progenitor cells.

A team of scientists has now found evidence for a new mechanism for the development of cancer in children: They seem to produce an unusual amount of aberrant antibodies against the building blocks that make up the DNA repair machinery, a diverse set of hundreds of proteins that identify and correct damage or errors in the genome.
This discovery could open the door to the early screening of small children, in the hope of ultimately preventing them from developing such paediatric cancers in their teenage years.
The researchers showed that many children with various types of cancer have antibodies against some of their own DNA repair proteins. They also demonstrated that such 'autoantibodies' can enter live cells and bind to—and probably inhibit—the activity of these essential proteins.

The results showed that compared to young adults and older people, children between 2 and 19 years of age with pediatric cancer had much greater numbers of antibodies of the IgG class against DNA repair proteins circulating in their blood. These autoantibodies mainly targeted RAD52, NUMA1, ALKBH7, APBB1, UNG and MGMT, all key genes closely involved in DNA repair but not significantly mutated in these cancers.

Could these autoantibodies explain why these children had developed cancer? To find out, the scientists looked at selected samples from 59 school-age children who had taken part in the British "Avon Longitudinal Study of Parents and Children" and "Born in Bradford" long-term cohort studies. Half of these children had developed cancer years later (but before the age of 30 years), while the other half had not.
They were able to show that indeed, children who later got cancer (on average six years after blood sampling) were about eight times more likely than their healthy peers to have antibodies to at least one core antigen involved in DNA repair.

The authors hypothesized that the targeting of DNA repair proteins by these autoantibodies could provide a phenotype resembling what we see for related proteins with defective hereditary variants that cause a predisposition to cancer.

When the autoantibodies enter a cell or its nucleus, they could bind to and immobilize or directly inhibit the targeted proteins and thus hinder normal DNA repair. Such weakened repair might in turn cause paediatric cancer.

In follow-up experiments, the scientists were able to show that these autoantibodies can enter cells, especially during the phase when cells end their growth and prepare to divide. Inside the cell, they seem to home in on the TIGER organelle, a site where transcription factors and other short-lived but essential proteins are produced and modified.

"[These results] together provide a plausible mechanism for increased cellular damage that could lead to cancer development," concluded the authors in their research paper.
But what might trigger the production of antibodies against normal DNA repair proteins?

They could be triggered by infections, by cross-reacting to some microbial proteins or overstimulation of the immune response, or by some imbalance in immune tolerance.
The results point to the possibility of screening children to detect any autoimmune predisposition to cancer early, with the hope of preventing their later progression to the disease or detecting it early.

Research Paper: Pathogenic autoantibodies targeting DNA repair proteins are shared by cancer patients and healthy children later diagnosed with cancer, Frontiers in Immunology (2026). DOI: 10.3389/fimmu.2026.1911932

Footnotes:

1. https://www.mcgill.ca/oss/article/medical-general-science/why-do-ki...

2. https://www.cancerresearchuk.org/about-cancer/childrens-cancer/risk...