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Molecular and genetic diversity in the metastatic process of melanoma
Author(s) -
Harbst Katja,
Lauss Martin,
Cirenajwis Helena,
Winter Christof,
Howlin Jillian,
Törngren Therese,
Kvist Anders,
Nodin Björn,
Olsson Eleonor,
Häkkinen Jari,
Jirström Karin,
Staaf Johan,
Lundgren Lotta,
Olsson Håkan,
Ingvar Christian,
GruvbergerSaal Sofia K,
Saal Lao H,
Jönsson Göran
Publication year - 2014
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4318
Subject(s) - neuroblastoma ras viral oncogene homolog , melanoma , tumour heterogeneity , genetic heterogeneity , pten , biology , metastasis , cancer research , germline mutation , gene , cancer , mutation , phenotype , genetics , kras , apoptosis , pi3k/akt/mtor pathway
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