The “Hopp Children's Cancer Center Heidelberg” (KiTZ) is a joint institution of the German Cancer Research Center (DKFZ), Heidelberg University Hospital (UKHD) and Heidelberg University (Uni HD).
Approximately 5-18% percent of all children with cancer carry disease-causing alterations in known cancer predisposition genes. However, many genetic causes remain undiscovered. Mutations in DNA repair genes, which normally correct errors during cell division in healthy cells, are frequently found in tumors. Whether these genetic alterations are also inherited in some patients was investigated for the first time in the present study by researchers at the Hopp Children’s Cancer Center Heidelberg (KiTZ), the German Cancer Research Center, Heidelberg University Hospital (UKHD), and St. Jude Children’s Research Hospital (Memphis, USA).
The researchers analyzed the genomes of 5,993 children with cancer and compared them with those of 14,477 healthy individuals. A total of 189 genes involved in DNA damage repair were examined for rare, disease-relevant variants. The results were then validated in three independent cohorts comprising an additional 1,497 cases, including two German registries.
The analysis first confirmed known associations between certain DNA repair proteins and tumor types such as adrenocortical carcinomas or brain tumors. In addition, the researchers discovered a previously unknown link between the SMARCAL1 gene and the development of bone cancer. SMARCAL1 is involved in repairing damaged DNA and stabilizing replication forks, the points at which the double-stranded DNA “unzips” so it can be copied. Malfunction of this mechanism leads to increased genetic instability, a key process in cancer development.
About 2.6% of children with osteosarcoma carried mutated variants of this gene. “A highly statistically significant finding,” says Robert Autry, group leader for Clinical Bioinformatics and Translational Genomics Research at KiTZ and DKFZ. As the study showed, tumors not only carried inherited SMARCAL1 mutations, but the “healthy” copies of the gene were deleted in several cases, further underscoring the causal role of SMARCAL1 in tumor development.
“The results may open new avenues for understanding genetic risks in pediatric cancers and for developing targeted early detection or monitoring programs,” says Robert Autry. “In the long term, they could also support the development of new therapies based on DNA repair mechanisms.”
Original publication:
Oak N. et al. Investigation of DNA Damage Response Genes Validates the Role of DNA Repair in Pediatric Cancer Risk and Identifies SMARCAL1 as Novel Osteosarcoma Predisposition Gene. Journal of Clinical Oncology (online pre-publication, October 9, 2025). DOI: 10.1200/JCO.25.01114
