Abstract SY31-02: Liver specific platinum mutagenesis in children

Abstract BACKGROUND: Some cytotoxic chemotherapeutics are directly mutagenic which may link chemotherapy exposure to late adverse effects, for example, to secondary cancer. The platinum agents, cisplatin and carboplatin, are important examples of mutagenic agents as they are widely used in paediatric practice. The mutational damage that platinum agents can cause in normal tissues has been extensively documented in studies of adults, principally focusing on blood. The picture is less clear in children with large scale studies in survivors showing no, or only small effects. A likely reason for this discrepancy are technical limitations of conventional sequencing and mutation calling which relies on the presence of clonal expansions, which are common in adults but rare in children. Here, we utilised single molecule sequencing, which enables mutation survey of polyclonal normal tissue, to study platinum mutagenesis in normal tissues of children. APPROACH: We assembled a cohort of paediatric liver (hepatoblastoma tumour and adjacent normal liver), blood and other tissues, obtained from surgical resections and at post-mortem (n=202 platinum-treated samples and n=61 platinum naïve). We deployed a duplex sequencing method (NanoSeq), which enables mutation calling from single DNA molecules with an error rate lower than five errors per billion base pairs. We deployed NanoSeq at whole genome scale, to obtain mutational spectra, as well as studying selection of mutations at the level of individual genes. We validated our findings in external cohorts and through in vitro studies. FINDINGS: NanoSeq revealed that platinum signatures pervaded all tissues extensively, elevating mutation burdens of paediatric tissues to levels seen in adults (e.g. average of 2200 mutations per normal liver sample). We show that as little as one cycle of platinum-based treatment generates a substantial increase in mutations. Apart from known platinum signatures, we found a tissue-specific mutational signature in the liver of children exposed to platinum chemotherapy. This novel signature was absent in blood from the same children. We were able to further corroborate this finding through in vitro cell line experiments, and re-examination of published cancer mutation catalogues from <1650 donors across at least 60 cancer types. In addition, examined the functional potential of the platinum-induced mutations by gene focused NanoSeq. It revealed that platinum agents cause a vast repertoire of cancer-causing variants across normal tissues, such as leukaemogenic mutations in blood. CONCLUSION: Our findings reveal extensive and differential platinum mutagenesis in normal tissues of children. Platinum agents elevated the mutation burden of paediatric tissues to that seen in adults and caused a vast repertoire of functional variants. Furthermore, we made the unprecedented finding of differential mutagenesis: The same exposure caused a distinctive signature in liver tissues that was absent from other tissues. Overall our observations rewrite our understanding of platinum agent mutagenesis in children and may provide a plausible link between chemotherapy exposure in childhood and late adverse effects. Citation Format: Sam Behjati. Liver specific platinum mutagenesis in children [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr SY31-02.