A team of scientists in Norway has found evidence for a new, previously unknown 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 which identify and correct damage or errors in the genome. This important discovery could open the door to the early screening of small children, in the hope of ultimately preventing them from developing such pediatric cancers years in their teenage years.
"We showed that many children with various types of cancer have antibodies against some of their own DNA repair proteins. We also demonstrated that such 'auto-antibodies' can enter live cells and bind to – and probably inhibit – the activity of these essential proteins," said corresponding author Dr Ola Myklebost, an emeritus professor of molecular oncology at the University of Bergen. The authors published their findings in Frontiers in Immunology .
Why pediatric cancers are different
Pediatric 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. Pediatric cancers thus tend to carry fewer mutations than adult ones and arise from less mature cells, for example stem or progenitor cells.
Serguienko, Myklebost, and colleagues characterized the 'proteome' – the ensemble of expressed proteins – in tumor and blood samples from 175 adults and children with sarcoma or acute lymphoblastic leukemia, collected between 2014 and 2017 through the NoSarC Norwegian Sarcoma Study, the Norwegian Childhood Cancer Biobank, and the Oslo University Hospital Cancer Research Biobank. They compared these with samples from healthy anonymized people such as blood donors and children participating in the Bergen Growth Study or visiting a clinic in Bergen.
The results showed that compared to young adults and older people, children between two and 19 years of age with pediatric cancer had much greater numbers antibodies of the IgG class against DNA repair proteins circulating in their blood. These auto-antibodies 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 auto-antibodies 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.
"Although this cohort is small, it was the best we could find internationally," said Myklebost. "Even so, we 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."
Likely role in development of cancer
The authors hypothesized that the targeting of DNA repair proteins by these auto-antibodies could provide a phenotype resembling what we see for related proteins with defective hereditary variants that cause a predisposition to cancer. When they enter a cell or its nucleus, they could bind to and immobilize or inhibit directly the targeted proteins and thus hinder the normal DNA repair. Such weakened repair might in turn cause pediatric cancer.
Crucially, in follow-up experiments the scientists were able to show that these auto-antibodies can enter cells, especially during the phase when cells end their growth and prepare to divide. Inside the cell, they seem to zone 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.
But what might trigger the production of antibodies against normal DNA repair proteins?
"They could be triggered by infections, by crossreacting to some microbial proteins or overstimulation of the immune response, or by some imbalance in immune tolerance," hypothesized Myklebost.
The results immediately 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 its early detection.
"At present we are investigating the effect of patient antibodies on the repair of induced mutations in cultured cells. Ultimately, we hope to clone white blood cells that secrete such auto-antibodies, and test for any cancer-causing effects in mice to definitively prove our hypothesis," said Myklebost.
