Speaker

Thomas G Hofmann

Biography :

Dysfunction of the DNA damage response is a driving force for genome instability and cancer. In childhood cancers, inherited mutations in cancer predisposition genes substantially contribute to cancer development and was linked to specific cancer-predisposing syndromes (CPS). Numerous CPS including Li-Fraumeni syndrome (LFS), Li-Fraumeni like syndrome (LFLS) and Fanconi anemia (FA)/Breast Cancer Associated (BRCA) have been described. In general, LFS and LFLS patients harbor germline mutations in genes regulating the tumor suppressor p53 pathway, while FA/BRCA patients harbor mutations in genes required for DNA double-strand break (DSB) repair. Interestingly, a substantial part of FA, LFS and LFLS patients do not harbor the known homozygous mutations in the genes linked to the respective CPS. Consequently, the mechanisms driving the CPS in those patients remain unclear. In this collaborative project, we used whole-exome sequencing (WES) of parents-children trios to identify germline mutations in children with cancer. Our bioinformatic analysis revealed a set of novel combined heterozygous mutations in the FA/BRCA and the LFS/LFLS pathway as well as in genes coding for the DNA damage signaling kinases ATM, ATR and HIPK2 in the germline of children with cancer.