Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis

Eric Letouzé (), Jayendra Shinde, Victor Renault, Gabrielle Couchy, Jean-Frédéric Blanc, Emmanuel Tubacher, Quentin Bayard, Delphine Bacq, Vincent Meyer, Jérémy Semhoun, Paulette Bioulac-Sage, Sophie Prévôt, Daniel Azoulay, Valérie Paradis, Sandrine Imbeaud, Jean-François Deleuze and Jessica Zucman-Rossi ()
Additional contact information
Eric Letouzé: Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d’Hématologie
Jayendra Shinde: Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d’Hématologie
Victor Renault: Fondation Jean Dausset—CEPH
Gabrielle Couchy: Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d’Hématologie
Jean-Frédéric Blanc: Université Bordeaux, Bordeaux Research in Translational Oncology
Emmanuel Tubacher: Fondation Jean Dausset—CEPH
Quentin Bayard: Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d’Hématologie
Delphine Bacq: Centre National de Recherche en Génomique Humaine, CEA
Vincent Meyer: Centre National de Recherche en Génomique Humaine, CEA
Jérémy Semhoun: Fondation Jean Dausset—CEPH
Paulette Bioulac-Sage: Université Bordeaux, Bordeaux Research in Translational Oncology
Sophie Prévôt: AP-HP, Hôpital Antoine-Béclère, Service d’anatomie pathologique
Daniel Azoulay: Université Paris Est Créteil
Valérie Paradis: Service d’Anatomopathologie, Hôpital Beaujon
Sandrine Imbeaud: Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d’Hématologie
Jean-François Deleuze: Centre National de Recherche en Génomique Humaine, CEA
Jessica Zucman-Rossi: Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d’Hématologie

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Genomic alterations driving tumorigenesis result from the interaction of environmental exposures and endogenous cellular processes. With a diversity of risk factors, liver cancer is an ideal model to study these interactions. Here, we analyze the whole genomes of 44 new and 264 published liver cancers and we identify 10 mutational and 6 structural rearrangement signatures showing distinct relationships with environmental exposures, replication, transcription, and driver genes. The liver cancer-specific signature 16, associated with alcohol, displays a unique feature of transcription-coupled damage and is the main source of CTNNB1 mutations. Flood of insertions/deletions (indels) are identified in very highly expressed hepato-specific genes, likely resulting from replication-transcription collisions. Reconstruction of sub-clonal architecture reveals mutational signature evolution during tumor development exemplified by the vanishing of aflatoxin B1 signature in African migrants. Finally, chromosome duplications occur late and may represent rate-limiting events in tumorigenesis. These findings shed new light on the natural history of liver cancers.

Date: 2017
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DOI: 10.1038/s41467-017-01358-x

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