title: Multiregion Whole-Exome Sequencing Uncovers the Genetic Evolution and Mutational Heterogeneity of Early-Stage Metastatic Melanoma.
abstract: Cancer genome sequencing has shed light on the underlying genetic aberrations that drive tumorigenesis. However, current sequencing-based strategies, which focus on a single tumor biopsy, fail to take into account intratumoral heterogeneity. To address this challenge and elucidate the evolutionary history of melanoma, we performed whole-exome and transcriptome sequencing of 41 multiple melanoma biopsies from eight individual tumors. This approach revealed heterogeneous somatic mutations in the range of 3%-38% in individual tumors. Known mutations in melanoma drivers BRAF and NRAS were always ubiquitous events. Using RNA sequencing, we found that the majority of mutations were not expressed or were expressed at very low levels, and preferential expression of a particular mutated allele did not occur frequently. In addition, we found that the proportion of ultraviolet B (UVB) radiation-induced C>T transitions differed significantly (P < 0.001) between early and late mutation acquisition, suggesting that different mutational processes operate during the evolution of metastatic melanoma. Finally, clinical history reports revealed that patients harboring a high degree of mutational heterogeneity were associated with more aggressive disease progression. In conclusion, our multiregion tumor-sequencing approach highlights the genetic evolution and non-UVB mutational signatures associated with melanoma development and progression, and may provide a more comprehensive perspective of patient outcome. Cancer Res; 76(16); 4765-74. ©2016 AACR.
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Katja
authors.initials: K
authors.lastname: Harbst
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Lauss
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Cirenajwis
authors.affiliation: Department of Surgery, Skåne University Hospital, Lund, Sweden.
authors.forename: Karolin
authors.initials: K
authors.lastname: Isaksson
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Frida
authors.initials: F
authors.lastname: Rosengren
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Therese
authors.initials: T
authors.lastname: Törngren
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Kvist
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Johansson
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Vallon-Christersson
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Baldetorp
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Borg
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. Department of Oncology, Skåne University Hospital, Lund, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Olsson
authors.affiliation: Department of Surgery, Skåne University Hospital, Lund, Sweden. Division of Surgery, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Ingvar
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. Department of Oncology, Skåne University Hospital, Lund, Sweden.
authors.forename: Ana
authors.initials: A
authors.lastname: Carneiro
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. goran_b.jonsson@med.lu.se.
authors.forename: Göran
authors.initials: G
authors.lastname: Jönsson
mesh_terms: D004252:DNA Mutational Analysis / Q000379:methods*; D019143:Evolution, Molecular; D059472:Exome; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D009154:Mutation; D059467:Transcriptome