Molecular and genetic diversity in the metastatic process of melanoma

Katja Harbst,Göran Jönsson,Christian Ingvar,Johan Staaf,Lotta Lundgren,Sofia K Gruvberger‐Saal,Helena Cirenajwis,Anders Kvist,Eleonor Olsson,Therese Törngren,Jillian Howlin,Håkan Olsson,Karin Jirström,Martin Lauss,Björn Nodin,Jari Häkkinen,Christof Winter,Lao H Saal

doi:10.1002/path.4318

Katja Harbst, Göran Jönsson + Show 16 more

Open Access

https://doi.org/10.1002/path.4318

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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

Highlights

Metastatic melanoma is an aggressive disease, notorious for its resistance to conventional therapy
We analysed the geneexpression profiling of 266 melanoma tumours and identified 28 patients from whom at least two melanoma lesions diagnosed at different time points had been sampled (62 metastases in total; Table 1)
We found that known driver mutations, such as oncogenic BRAF and NRAS mutations, were always somatically preserved, whereas others were somatically acquired during progression

Summary

Introduction

Metastatic melanoma is an aggressive disease, notorious for its resistance to conventional therapy. Treatment resistance could be explained by tumour heterogeneity, i.e. the existence of, or selection for, molecularly distinct subclones with metastatic capability. Supporting this hypothesis, intratumour heterogeneity has been reported in a vemurafenib-resistant subcutaneous melanoma metastasis, which contained a subclone with a de novo NRAS mutation [3]. Colombino et al [4] have reported BRAF mutant metastases presumably seeded by a BRAF wild-type primary tumour and, more intriguingly, BRAF wild-type metastases in the presence of a BRAF mutant primary Together, these findings indicate that some tumours may exhibit profound heterogeneity that contributes to the aggressive clinical course and eventual treatment resistance of melanoma. In contrast to the prevailing theory of metastatic spread originating from the primary tumour at an advanced stage of the disease, recent evidence suggests the parallel development of the primary tumour and metastasis [8], or parallel development of multiple metastases in the same patient [9,10]

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