Extensive and differential platinum chemotherapy mutagenesis in children
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Anna Wenger Henry Lee-Six Manas Dave Mehdi Layeghifard Andrew RJ Lawson Federico Abascal Pantelis A Nicola Taryn D Treger Toochi Ogbonnah Conor Parks Thomas RW Oliver Jonathan Kennedy Angus Hodder Nathaniel D Anderson Felipe Luz Torres Silva Mi K Trinh Thomas Dowe Marwo Habarwaa James Sun Sergio Assia-Zamora Miriam Cortes-Cerisuelo Wayel Jassem Charlotte Town Anil Dhawan Vandana Jain Karin Straathof Maesha Deheragoda Iñigo Martincorena Liina Palm J Ciaran Hutchinson Tim HH Coorens Claire Trayers Nigel Heaton Adam Shlien Yoh Zen Foad Rouhani Sam Behjati
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Abstract
Childhood cancer survivors often develop long-term adverse effects, which may be caused by direct mutagenesis of cytotoxic agents. Some of these agents generate distinctive DNA imprints (mutational signatures), as exemplified by platinum chemotherapeutics. Here, we examined chemotherapy mutagenesis in paediatric tissues by deploying a duplex sequencing method (NanoSeq), which enables mutation calling from single DNA molecules. We surveyed whole genomes of paediatric liver, blood and other tissues, obtained from surgical resections and at post-mortem. Platinum signatures pervaded all tissues extensively, elevating mutation burdens of paediatric tissues to levels seen in adults. Remarkably, we found a tissue-specific mutational signature in the liver. We examined the functional potential of mutations by gene focused NanoSeq, which revealed that platinum agents cause a vast repertoire of cancer causing variants across normal tissues, such as leukaemogenic mutations in blood. This finding may conceivably link cancer treatment in childhood to mutation-driven long term sequelae.
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