A rare but serious hereditary syndrome, CMMRD, leads to a very high risk of developing childhood cancer. This syndrome occurs in 1 in a million children. Children with CMMRD have inherited a fault in a DNA repair gene from both parents. All cells of these children have a very high risk of DNA damage, which can cause cancer.
Children with CMMRD develop cancer at a young age and often several times in their lives. At first diagnosis, it is not always clear that they have this hereditary predisposition. Better ways to recognize the syndrome are urgently needed.
In search of patterns
Researchers in the Kuiper group at the Princess Máxima Center, in collaboration with the Radboudumc, studied 41 tumors from 17 children who were known to have CMMRD syndrome, including three brother-sister pairs. The scientists read the entire DNA of the tumors, looking for patterns. Their research was published in Nature Communications last week, and was funded by KWF and KiKa.
The research showed that the type of cancer a child had – a brain tumor, leukemia or lymphoma, or bowel cancer – determined the pattern of DNA errors in the tumor. They also found specific ‘genetic footprints’ for the various underlying genes that cause CMMRD syndrome.
Dilys Weijers is a PhD candidate in the Kuiper group who worked on the new study. She says: ‘Many children with CMMRD are recognized when they develop a brain tumor. Thanks to our research, we can now pick out the syndrome much better in children who are first diagnosed with leukemia or lymphoma. We were also able to see that specific treatments can increase the risk of developing a new tumor.’
Temozolomide
Some chemotherapies are effective because they cause so much damage to tumor cells that the DNA repair mechanism is blocked, and the tumor cell dies. The drug temozolomide, part of the treatment for some brain tumors, works in this way, for example. But because the DNA repair mechanism does not work in CMMRD, this treatment is not at all effective in these children.
In children with CMMRD, temozolomide not only affects the tumor, but also the healthy cells. Prof. Roland Kuiper, research group leader at the Máxima who led the study: ‘We found DNA damage in second tumors that is caused by treatment with temozolomide. This emphasizes how important it is to recognize that a child has CMMRD at the time of diagnosis. It shows that in children with a brain tumor, you first have to rule out that they have CMMRD before they are given temozolomide.’
Better treatment
The research increases knowledge about CMMRD and contributes to better diagnosis and treatment. Kuiper: ‘These genetic footprints give us more insight into how cancer develops in children with CMMRD. That knowledge will help lead to better treatment for children with this type of hereditary cancer predisposition.’