Conservation of Genetic Alterations in Recurrent Melanoma Supports the Melanoma Stem Cell Hypothesis

Marianna Sabatino,Yingdong Zhao,Brian J Nickoloff,Laszlo Karai,Paul Robbins,Alessandro Monaco,Sonia Voiculescu,Michele Maio,Francesco M Marincola,Ena Wang,Silvia Selleri

doi:10.1158/0008-5472.can-07-1939

Abstract

It is generally accepted that human cancers derive from a mutated single cell. However, the genetic steps characterizing various stages of progression remain unclear. Studying a unique case of metastatic melanoma, we observed that cell lines derived from metachronous metastases arising over a decade retained a central core of genetic stability in spite of divergent phenotypes. In the present study, we expanded our previous observations comparing these autologous cell lines of clonal derivation with allogeneic ones and correlated array comparative genomic hybridization (aCGH) with gene expression profiling to determine their relative contribution to the dynamics of disease progression. aCGH and gene expression profiling were performed on autologous cell lines and allogeneic melanoma cell lines originating from other patients. A striking correlation existed between total extent of genetic imbalances, global transcriptional patterns, and cellular phenotypes. They did not follow a strict temporal progression but stemmed independently at various time points from a central core of genetic stability best explained according to the cancer stem cell hypothesis. Although their contribution was intertwined, genomic imbalances detectable by aCGH contributed only 25% of the transcriptional traits determining autologous tumor distinctiveness. Our study provides important insights about the dynamics of cancer progression and supports the development of targeted anticancer therapies aimed against stable genetic factors that are maintained throughout the end stage of disease.

Highlights

It is generally recognized that cancers originate from the clonal expansion of a single mutated founder cell [1]
It was of interest to note that, in spite of the genetic entropy displayed by cells cultured from subsequent metastases, a conserved core of genetic alterations was maintained throughout the natural history of the disease that could have been inherited from the progenitor stem cell or resulted from a process of convergent evolution dictated by the structural organization of the genome
The natural history of cancer is likely determined by the accumulation in time of genetic alterations within a cell lineage

Summary

Introduction

It is generally recognized that cancers originate from the clonal expansion of a single mutated founder cell [1]. The veracity of this statement is critical because clonal derivation may affect the effectiveness of cancer therapies targeting genetic elements passed on to each generation by parental cells throughout the natural history of the disease. Mutational analysis of b-catenin gene, methylation of the human androgen receptor, karyotyping, and chromosomal comparative genomic hybridization (cCGH) documented a clonal origin of each cell line from a single ancestor. All cell lines originated from the same founder, each did not likely derive from the most recent previous metastasis because aberrations in each recurrence were sufficiently different to exclude a purely sequential process. Most observations were performed at a single time point relevant to either primary or metastatic lesions, no longitudinal long-term studies have been reported due to the rarity in which

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Results

Conclusion