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Nat Commun. 2017 Nov 3;8(1):1315. doi: 10.1038/s41467-017-01358-x.

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

Letouzé E1,2,3,4, Shinde J5,6,7,8, Renault V9, Couchy G5,6,7,8, Blanc JF10,11, Tubacher E9, Bayard Q5,6,7,8, Bacq D12, Meyer V12, Semhoun J9, Bioulac-Sage P10,13, Prévôt S14, Azoulay D15,16, Paradis V17, Imbeaud S5,6,7,8, Deleuze JF12, Zucman-Rossi J18,19,20,21,22.

Author information

1
INSERM, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hématologie, Paris, 75010, France. eric.letouze@inserm.fr.
2
Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, 75006, France. eric.letouze@inserm.fr.
3
Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine, Bobigny, 93000, France. eric.letouze@inserm.fr.
4
Université Paris Diderot, Paris, 75013, France. eric.letouze@inserm.fr.
5
INSERM, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hématologie, Paris, 75010, France.
6
Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, 75006, France.
7
Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine, Bobigny, 93000, France.
8
Université Paris Diderot, Paris, 75013, France.
9
Laboratory for Bioinformatics, Fondation Jean Dausset-CEPH, Paris, 75010, France.
10
Université Bordeaux, Bordeaux Research in Translational Oncology, Bordeaux, 33000, France.
11
Service Hépato-Gastroentérologie et Oncologie Digestive, Centre Medico-Chirurgical Magellan, Hôpital Haut-Lévêque, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, 33000, France.
12
Centre National de Recherche en Génomique Humaine, CEA, Evry, 91000, France.
13
Service de Pathologie, Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, 33000, France.
14
AP-HP, Hôpital Antoine-Béclère, Service d'anatomie pathologique, Clamart, 92140, France.
15
Université Paris Est Créteil, Créteil, 94010, France.
16
AP-HP, Groupe Hospitalier Henri Mondor, Département de Chirurgie Hépato-Biliaire et Transplantation Hépatique, Créteil, 94010, France.
17
Service d'Anatomopathologie, Hôpital Beaujon, Clichy, 92110, France.
18
INSERM, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hématologie, Paris, 75010, France. jessica.zucman-rossi@inserm.fr.
19
Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, 75006, France. jessica.zucman-rossi@inserm.fr.
20
Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine, Bobigny, 93000, France. jessica.zucman-rossi@inserm.fr.
21
Université Paris Diderot, Paris, 75013, France. jessica.zucman-rossi@inserm.fr.
22
Assistance Publique-Hôpitaux de Paris, Hopital Europeen Georges Pompidou, Paris, 75015, France. jessica.zucman-rossi@inserm.fr.

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.

PMID:
29101368
PMCID:
PMC5670220
DOI:
10.1038/s41467-017-01358-x
[Indexed for MEDLINE]
Free PMC Article

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