Molecular analysis of cancer genomes in children with Lynch syndrome: Exploring causal associations

Lynch syndrome (LS) predisposes to cancer in adulthood and is caused by heterozygous germline variants in a mismatch repair (MMR) gene. Recent studies show an increased prevalence of LS among children with cancer, suggesting a causal relationship. For LS-spectrum (LSS) cancers, including high-grade gliomas and colorectal cancer, causality has been supported by typical MMR-related tumor characteristics, but for non-LSS cancers, causality is unclear. We characterized 20 malignant tumors of 18 children with LS, including 16 non-LSS tumors. We investigated second hits, tumor mutational load, mutational signatures and MMR protein expression. In all LSS tumors and three non-LSS tumors, we detected MMR deficiency caused by second hit somatic alterations. Furthermore, these MMR-deficient tumors carried driver variants that likely originated as a consequence of MMR deficiency. However, in 13 non-LSS tumors (81%), a second hit and MMR deficiency were absent, thus a causal link between LS and cancer development in these children is lacking. These findings demonstrate that causality of LS in children with cancer, which can be determined by molecular tumor characterization, seems to be restricted to specific tumor types. Large molecular and epidemiological studies are needed to further refine the tumor spectrum in children with LS. Lynch syndrome, caused by heterozygous germline variants in a mismatch repair (MMR) gene, predisposes to cancer in adulthood. Recent studies have also shown increased prevalence of Lynch syndrome among children with cancer. However, a large proportion of the cancers in children with Lynch syndrome do not fall within the established Lynch syndrome tumor spectrum. In this systematic analysis of causality based on tumor genomic characteristics, the majority of children with Lynch syndrome and cancers outside the spectrum had no signs of MMR deficiency in those tumors, indicating a lack of causal relationship between tumor development and the underlying syndrome.image