Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer

Linda Holmquist Mengelbier, Jenny Karlsson, David Lindgren, Anders Valind, Henrik Lilljebjörn, Caroline Jansson, Daniel Bexell, Noémie Braekeveldt, Adam Ameur, Tord Jonson, Hanna Göransson Kultima, Anders Isaksson, Jurate Asmundsson, Rogier Versteeg, Marianne Rissler, Thoas Fioretos, Bengt Sandstedt, Anna Börjesson, Torbjörn Backman, Niklas Pal, Ingrid Øra, Markus Mayrhofer and David Gisselsson ()
Additional contact information
Linda Holmquist Mengelbier: Lund University
Jenny Karlsson: Lund University
David Lindgren: Translational Cancer Research, Lund University
Anders Valind: Lund University
Henrik Lilljebjörn: Lund University
Caroline Jansson: Lund University
Daniel Bexell: Translational Cancer Research, Lund University
Noémie Braekeveldt: Translational Cancer Research, Lund University
Adam Ameur: Genetics and Pathology, Science for Life Laboratory, Uppsala University
Tord Jonson: Lund University
Hanna Göransson Kultima: Array and Analysis Facility, Uppsala University
Anders Isaksson: Array and Analysis Facility, Uppsala University
Jurate Asmundsson: Karolinska University Hospital
Rogier Versteeg: Academic Medical Center
Marianne Rissler: Lund University
Thoas Fioretos: Lund University
Bengt Sandstedt: Karolinska Institute
Anna Börjesson: Lund University, University Hospital
Torbjörn Backman: Lund University, University Hospital
Niklas Pal: Astrid Lindgren Children’s Hospital, Karolinska University Hospital
Ingrid Øra: Lund University, University Hospital
Markus Mayrhofer: Array and Analysis Facility, Uppsala University
David Gisselsson: Lund University

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: Abstract Genetic differences among neoplastic cells within the same tumour have been proposed to drive cancer progression and treatment failure. Whether data on intratumoral diversity can be used to predict clinical outcome remains unclear. We here address this issue by quantifying genetic intratumoral diversity in a set of chemotherapy-treated childhood tumours. By analysis of multiple tumour samples from seven patients we demonstrate intratumoral diversity in all patients analysed after chemotherapy, typically presenting as multiple clones within a single millimetre-sized tumour sample (microdiversity). We show that microdiversity often acts as the foundation for further genome evolution in metastases. In addition, we find that microdiversity predicts poor cancer-specific survival (60%; P=0.009), independent of other risk factors, in a cohort of 44 patients with chemotherapy-treated childhood kidney cancer. Survival was 100% for patients lacking microdiversity. Thus, intratumoral genetic diversity is common in childhood cancers after chemotherapy and may be an important factor behind treatment failure.

Date: 2015
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DOI: 10.1038/ncomms7125

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