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Multiregion whole-exome sequencing uncovers the genetic evolution and mutational heterogeneity of early-stage metastatic melanoma

Harbst, Katja LU ; Lauss, Martin LU ; Cirenajwis, Helena LU ; Isaksson, Karolin LU ; Rosengren, Frida LU ; Törngren, Therese LU ; Kvist, Anders LU ; Johansson, Maria C. LU ; Vallon-Christersson, Johan LU and Baldetorp, Bo LU , et al. (2016) In Cancer Research 76(16). p.4765-4774
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... (More)

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.

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Cancer Research
volume
76
issue
16
pages
10 pages
publisher
American Association for Cancer Research
external identifiers
  • Scopus:84982179452
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-15-3476
language
English
LU publication?
yes
id
2f179f17-b64e-4999-a5c6-a7b1641fc623
date added to LUP
2016-09-05 16:56:54
date last changed
2016-11-25 14:48:48
@misc{2f179f17-b64e-4999-a5c6-a7b1641fc623,
  abstract     = {<p>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&gt;T transitions differed significantly (P &lt;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.</p>},
  author       = {Harbst, Katja and Lauss, Martin and Cirenajwis, Helena and Isaksson, Karolin and Rosengren, Frida and Törngren, Therese and Kvist, Anders and Johansson, Maria C. and Vallon-Christersson, Johan and Baldetorp, Bo and Borg, Åke and Olsson, Håkan and Ingvar, Christian and Carneiro, Ana and Jönsson, Göran B},
  issn         = {0008-5472},
  language     = {eng},
  month        = {08},
  number       = {16},
  pages        = {4765--4774},
  publisher    = {ARRAY(0x921d180)},
  series       = {Cancer Research},
  title        = {Multiregion whole-exome sequencing uncovers the genetic evolution and mutational heterogeneity of early-stage metastatic melanoma},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-15-3476},
  volume       = {76},
  year         = {2016},
}