Advanced

Molecular and genetic diversity in the metastatic process of melanoma.

Harbst, Katja LU ; Lauss, Martin LU ; Cirenajwis, Helena LU ; Winter, Christof LU ; Howlin, Jillian LU ; Törngren, Therese LU ; Kvist, Anders LU ; Nodin, Björn LU ; Olsson, Eleonor LU and Häkkinen, Jari LU , et al. (2014) In Journal of Pathology 233(1). p.39-50
Abstract
Diversity between metastatic melanoma tumours in individual patients is known; however, the molecular and genetic differences remain unclear. To examine the molecular and genetic differences between metastatic tumours, we performed gene-expression profiling of 63 melanoma tumours obtained from 28 patients (two or three tumours/patient), followed by analysis of their mutational landscape, using targeted deep sequencing of 1697 cancer genes and DNA copy number analysis. Gene-expression signatures revealed discordant phenotypes between tumour lesions within a patient in 50% of the cases. In 18 of 22 patients (where matched normal tissue was available), we found that the multiple lesions within a patient were genetically divergent, with one or... (More)
Diversity between metastatic melanoma tumours in individual patients is known; however, the molecular and genetic differences remain unclear. To examine the molecular and genetic differences between metastatic tumours, we performed gene-expression profiling of 63 melanoma tumours obtained from 28 patients (two or three tumours/patient), followed by analysis of their mutational landscape, using targeted deep sequencing of 1697 cancer genes and DNA copy number analysis. Gene-expression signatures revealed discordant phenotypes between tumour lesions within a patient in 50% of the cases. In 18 of 22 patients (where matched normal tissue was available), we found that the multiple lesions within a patient were genetically divergent, with one or more melanoma tumours harbouring 'private' somatic mutations. In one case, the distant subcutaneous metastasis of one patient occurring 3 months after an earlier regional lymph node metastasis had acquired 37 new coding sequence mutations, including mutations in PTEN and CDH1. However, BRAF and NRAS mutations, when present in the first metastasis, were always preserved in subsequent metastases. The patterns of nucleotide substitutions found in this study indicate an influence of UV radiation but possibly also DNA alkylating agents. Our results clearly demonstrate that metastatic melanoma is a molecularly highly heterogeneous disease that continues to progress throughout its clinical course. The private aberrations observed on a background of shared aberrations within a patient provide evidence of continued evolution of individual tumours following divergence from a common parental clone, and might have implications for personalized medicine strategies in melanoma treatment. Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk. (Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Pathology
volume
233
issue
1
pages
39 - 50
publisher
John Wiley & Sons
external identifiers
  • pmid:24399611
  • wos:000334376500006
  • scopus:84898597696
ISSN
0022-3417
DOI
10.1002/path.4318
language
English
LU publication?
yes
id
740b05d2-5cf3-401d-91df-28d3cc76c6a5 (old id 4291924)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24399611?dopt=Abstract
date added to LUP
2014-02-06 21:47:07
date last changed
2017-09-10 03:03:22
@article{740b05d2-5cf3-401d-91df-28d3cc76c6a5,
  abstract     = {Diversity between metastatic melanoma tumours in individual patients is known; however, the molecular and genetic differences remain unclear. To examine the molecular and genetic differences between metastatic tumours, we performed gene-expression profiling of 63 melanoma tumours obtained from 28 patients (two or three tumours/patient), followed by analysis of their mutational landscape, using targeted deep sequencing of 1697 cancer genes and DNA copy number analysis. Gene-expression signatures revealed discordant phenotypes between tumour lesions within a patient in 50% of the cases. In 18 of 22 patients (where matched normal tissue was available), we found that the multiple lesions within a patient were genetically divergent, with one or more melanoma tumours harbouring 'private' somatic mutations. In one case, the distant subcutaneous metastasis of one patient occurring 3 months after an earlier regional lymph node metastasis had acquired 37 new coding sequence mutations, including mutations in PTEN and CDH1. However, BRAF and NRAS mutations, when present in the first metastasis, were always preserved in subsequent metastases. The patterns of nucleotide substitutions found in this study indicate an influence of UV radiation but possibly also DNA alkylating agents. Our results clearly demonstrate that metastatic melanoma is a molecularly highly heterogeneous disease that continues to progress throughout its clinical course. The private aberrations observed on a background of shared aberrations within a patient provide evidence of continued evolution of individual tumours following divergence from a common parental clone, and might have implications for personalized medicine strategies in melanoma treatment. Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk.},
  author       = {Harbst, Katja and Lauss, Martin and Cirenajwis, Helena and Winter, Christof and Howlin, Jillian and Törngren, Therese and Kvist, Anders and Nodin, Björn and Olsson, Eleonor and Häkkinen, Jari and Jirström, Karin and Staaf, Johan and Lundgren, Lotta and Olsson, Håkan and Ingvar, Christian and Gruvberger, Sofia and Saal, Lao and Jönsson, Göran B},
  issn         = {0022-3417},
  language     = {eng},
  number       = {1},
  pages        = {39--50},
  publisher    = {John Wiley & Sons},
  series       = {Journal of Pathology},
  title        = {Molecular and genetic diversity in the metastatic process of melanoma.},
  url          = {http://dx.doi.org/10.1002/path.4318},
  volume       = {233},
  year         = {2014},
}