title: Intra-Tumor Genetic Heterogeneity in Wilms Tumor: Clonal Evolution and Clinical Implications.
abstract: The evolution of pediatric solid tumors is poorly understood. There is conflicting evidence of intra-tumor genetic homogeneity vs. heterogeneity (ITGH) in a small number of studies in pediatric solid tumors. A number of copy number aberrations (CNA) are proposed as prognostic biomarkers to stratify patients, for example 1q+ in Wilms tumor (WT); current clinical trials use only one sample per tumor to profile this genetic biomarker. We multisampled 20 WT cases and assessed genome-wide allele-specific CNA and loss of heterozygosity, and inferred tumor evolution, using Illumina CytoSNP12v2.1 arrays, a custom analysis pipeline, and the MEDICC algorithm. We found remarkable diversity of ITGH and evolutionary trajectories in WT. 1q+ is heterogeneous in the majority of tumors with this change, with variable evolutionary timing. We estimate that at least three samples per tumor are needed to detect >95% of cases with 1q+. In contrast, somatic 11p15 LOH is uniformly an early event in WT development. We find evidence of two separate tumor origins in unilateral disease with divergent histology, and in bilateral WT. We also show subclonal changes related to differential response to chemotherapy. Rational trial design to include biomarkers in risk stratification requires tumor multisampling and reliable delineation of ITGH and tumor evolution.
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: George D
authors.initials: GD
authors.lastname: Cresswell
authors.affiliation: UCL Institute of Child Health, London, United Kingdom; Department of Paediatric Haematology and Oncology, Great Ormond Street Hospital, London, United Kingdom.
authors.forename: John R
authors.initials: JR
authors.lastname: Apps
authors.affiliation: UCL Institute of Child Health, London, United Kingdom.
authors.forename: Tasnim
authors.initials: T
authors.lastname: Chagtai
authors.affiliation: The Francis Crick Institute, London, United Kingdom.
authors.forename: Borbala
authors.initials: B
authors.lastname: Mifsud
authors.affiliation: The Francis Crick Institute, London, United Kingdom; UCL Genetics Institute, Department of Genetics, Evolution & Environment, University College London, United Kingdom.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Bentley
authors.affiliation: UCL Institute of Child Health, London, United Kingdom.
authors.forename: Mariana
authors.initials: M
authors.lastname: Maschietto
authors.affiliation: Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London, United Kingdom.
authors.forename: Sergey D
authors.initials: SD
authors.lastname: Popov
authors.affiliation: UCL Institute of Child Health, London, United Kingdom.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Weeks
authors.affiliation: Department of Radiology, Great Ormond Street Hospital, London, United Kingdom.
authors.forename: Øystein E
authors.initials: ØE
authors.lastname: Olsen
authors.affiliation: UCL Institute of Child Health, London, United Kingdom; Department of Histopathology, Great Ormond Street Hospital, London, United Kingdom.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Sebire
authors.affiliation: UCL Institute of Child Health, London, United Kingdom; Department of Paediatric Haematology and Oncology, Great Ormond Street Hospital, London, United Kingdom.
authors.forename: Kathy
authors.initials: K
authors.lastname: Pritchard-Jones
authors.affiliation: The Francis Crick Institute, London, United Kingdom; UCL Genetics Institute, Department of Genetics, Evolution & Environment, University College London, United Kingdom; Okinawa Institute of Science & Technology, Okinawa, Japan.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Luscombe
authors.affiliation: UCL Institute of Child Health, London, United Kingdom.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Williams
authors.affiliation: UCL Institute of Child Health, London, United Kingdom; Department of Histopathology, Great Ormond Street Hospital, London, United Kingdom. Electronic address: w.mifsud@ucl.ac.uk.
authors.forename: William
authors.initials: W
authors.lastname: Mifsud
mesh_terms: D000483:Alleles; D014408:Biomarkers, Tumor / Q000235:genetics; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11; D060965:Clonal Evolution; D005260:Female; D018628:Gene Dosage; D016678:Genome; D006801:Humans; D007223:Infant; D007680:Kidney Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D019656:Loss of Heterozygosity / Q000502:physiology*; D008279:Magnetic Resonance Imaging; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D009396:Wilms Tumor / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor
keywords: Copy number aberrations; Intra-tumor genetic heterogeneity; Molecular biomarkers; Pediatric solid tumors; Tumor evolution; Tumor multisampling; Wilms tumor