Children who develop cancer produce an unusually high number of antibodies that attack DNA repair machinery, new research suggests. The findings, published in Frontiers in Immunology, could help lead to early screening that prevents cancer from developing later on, during adolescence.
The pathogenic, penetrating autoantibodies, which can cross over into cells, predominantly targeted six proteins involved in DNA repair. They may represent a previously unrecognized mechanism through which people are predisposed to cancer at a young age.
Researcher Ola Myklebost, PhD, from the University of Bergen, speculated there could be several reasons behind their production. “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,” he hypothesized.
Pediatric cancers, such as leukemia, myeloma, neuroblastoma, and osteosarcoma, differ fundamentally from adult cancers. Children have less time than adults to accumulate DNA damage, so pediatric cancers therefore tend to carry less mutations than those in adults and arise from less mature cells.
To investigate these characteristics further, researchers conducted proteome analysis on tumor and blood samples from 175 adults and children with sarcoma or acute lymphoblastic leukemia that were collected in Norway between 2014 and 2017. The team, led by Anastassia Serguienko, PhD, also from the University of Bergen, then compared these samples with those from healthy donors, also in Norway.
Results showed that children between two and 19 years of age with pediatric cancer had far higher numbers of circulating immunoglobulin (Ig)G antibodies against DNA repair proteins than young adults and older individuals. The autoantibodies mainly targeted the autoantigens RAD52, NUMA1, ALKBH7, APBB1, UNG, and MGMT, which are involved in DNA repair.
Extending the study, the researchers then looked at samples from 59 British children, half of whom went on to develop cancer on average six years later, before the age of 30 years. They found that those who went on to have cancer were around eight times more likely than others to have antibodies to at least one core antigen involved in DNA repair.
Experimental studies revealed that serum IgG can enter cells, particularly during times of growth or division, and move to the TIGER membraneless organelle, which is involved in translation of messenger RNA into certain proteins.
“We propose that a preexisting subclinical autoimmune condition characterized by penetrating autoantibodies may compromise genome integrity or other vital cellular functions in critical periods of accelerated tissue growth or differentiation and therefore can predispose to cancer,” the authors concluded. “This model certainly requires final proof but may also lead to new opportunities for cancer prevention.”
