title: Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer.
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.
authors.affiliation: Department of Clinical Genetics, Lund University, Biomedical Center C13, SE22184 Lund, Sweden.
authors.forename: Linda Holmquist
authors.initials: LH
authors.lastname: Mengelbier
authors.affiliation: Department of Clinical Genetics, Lund University, Biomedical Center C13, SE22184 Lund, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Karlsson
authors.affiliation: Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village 404-406, SE22363 Lund, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Lindgren
authors.affiliation: Department of Clinical Genetics, Lund University, Biomedical Center C13, SE22184 Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Valind
authors.affiliation: Department of Clinical Genetics, Lund University, Biomedical Center C13, SE22184 Lund, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Lilljebjörn
authors.affiliation: Department of Clinical Genetics, Lund University, Biomedical Center C13, SE22184 Lund, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Jansson
authors.affiliation: Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village 404-406, SE22363 Lund, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bexell
authors.affiliation: Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village 404-406, SE22363 Lund, Sweden.
authors.forename: Noémie
authors.initials: N
authors.lastname: Braekeveldt
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE75003 Uppsala, Sweden.
authors.forename: Adam
authors.initials: A
authors.lastname: Ameur
authors.affiliation: Department of Clinical Genetics, Lund University, Biomedical Center C13, SE22184 Lund, Sweden.
authors.forename: Tord
authors.initials: T
authors.lastname: Jonson
authors.affiliation: Array and Analysis Facility, Department of Medical Sciences, Uppsala University, SE75003 Uppsala, Sweden.
authors.forename: Hanna Göransson
authors.initials: HG
authors.lastname: Kultima
authors.affiliation: Array and Analysis Facility, Department of Medical Sciences, Uppsala University, SE75003 Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Isaksson
authors.affiliation: Department of Pathology, Karolinska University Hospital, SE17176 Solna, Sweden.
authors.forename: Jurate
authors.initials: J
authors.lastname: Asmundsson
authors.affiliation: Department of Human Genetics, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Rogier
authors.initials: R
authors.lastname: Versteeg
authors.affiliation: Department of Clinical Genetics, Lund University, Biomedical Center C13, SE22184 Lund, Sweden.
authors.forename: Marianne
authors.initials: M
authors.lastname: Rissler
authors.affiliation: Department of Clinical Genetics, Lund University, Biomedical Center C13, SE22184 Lund, Sweden.
authors.forename: Thoas
authors.initials: T
authors.lastname: Fioretos
authors.affiliation: Division of Pediatric Oncology, Department of Women's and Children's Health, Karolinska Institute, SE17165 Solna, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Sandstedt
authors.affiliation: Department of Pediatrics, Lund University, University Hospital, SE22185 Lund, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Börjesson
authors.affiliation: Department of Pediatrics, Lund University, University Hospital, SE22185 Lund, Sweden.
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Backman
authors.affiliation: Astrid Lindgren Children's Hospital, Karolinska University Hospital, SE17176 Solna, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Pal
authors.affiliation: Department of Pediatrics, Lund University, University Hospital, SE22185 Lund, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Øra
authors.affiliation: Array and Analysis Facility, Department of Medical Sciences, Uppsala University, SE75003 Uppsala, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Mayrhofer
authors.affiliation: 1] Department of Clinical Genetics, Lund University, Biomedical Center C13, SE22184 Lund, Sweden [2] Department of Pathology, Skåne Regional and University Laboratories, SE22185 Lund, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Gisselsson
mesh_terms: D000483:Alleles; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D019143:Evolution, Molecular; D018740:Genetic Heterogeneity; D015894:Genome, Human; D042822:Genomic Instability; D006801:Humans; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D011379:Prognosis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents