Analysis of Genetic Alterations in Cutaneous Malignant Melanomas Unveils Unique Loco-Regional Variations and Novel Predictors of Metastatic Potential

ABSTRACTCancer cells rely on dysregulated gene expression programs to maintain their malignant phenotype. A cell’s transcriptional state is controlled by a small set of interconnected transcription factors that form its core-regulatory circuit (CRC). Previous work in pediatric cancers has shown, that disruption of the CRC by genetic alterations causes tumor cells to become highly dependent on its components creating new opportunities for therapeutic intervention. However, the role of CRCs and the mechanisms by which they are controlled remain largely unknown for most tumor types. Here, we developed a method that infers lineage dependency scores to systematically predict functional CRCs and associated biological processes from context-dependent essentiality data sets. Analysis of genome-scale CRISPR-Cas9 screens in 558 cancer cell lines showed that most tumor types specifically depend on a small number of transcription factors for proliferation. We found that these transcription factors compose the CRCs in these tumor types. Moreover, they are frequently altered in patient tumor samples indicating their oncogenic potential. Finally, we show that biological processes associated with each CRC are revealed by analyzing codependency between lineage-specific essential genes. Our results demonstrate that genetic addiction to lineage-specific core transcriptional mechanisms occurs across a broad range of tumor types. We exploit this phenomenon to systematically infer CRCs from lineage specific gene essentiality. Furthermore, our findings shed light on the selective genetic vulnerabilities that arise as the consequence of transcriptional dysregulation in different tumor types and show how the plasticity of regulatory circuits might influence drug resistance and metastatic potential.

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MP78-06 GENETIC ALTERATIONS IN SPECIFIC CHROMOSOMAL REGIONS INDICATE METASTATIC POTENTIAL IN CCRCC PATIENTS

The Journal of Urology ◽

10.1016/j.juro.2016.02.1962 ◽

2016 ◽

Vol 195 (4S) ◽

Author(s):

Julia Grimm ◽

Martin Janssen ◽

Arndt Hartmann ◽

Christine Stöhr ◽

Frank Kunath ◽

...

Keyword(s):

Metastatic Potential ◽

Genetic Alterations

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Do we have Markers for the Metastatic Potential of Malignant Melanomas?

Dermatology ◽

10.1159/000248564 ◽

1988 ◽

Vol 177 (4) ◽

pp. 197-199 ◽

Cited By ~ 1

Author(s):

G.E. Piérard

Keyword(s):

Metastatic Potential ◽

Malignant Melanomas

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Sequential detection of mRNA for the chemokine IL-8 and macrophages (F4/80) in human melanoma

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010014141x ◽

1995 ◽

Vol 53 ◽

pp. 1008-1009

Author(s):

C.D. Bucana ◽

R. Sanchez ◽

R. Singh ◽

I.J. Fidler

Keyword(s):

Tumor Cells ◽

Nude Mice ◽

Constitutive Expression ◽

Metastatic Potential ◽

Melanoma Cells ◽

Human Melanoma ◽

Angiogenic Factor ◽

Infiltrating Cells ◽

Immunoperoxidase Assay ◽

Multifunctional Cytokine

The purpose of this study was to demonstrate by ISH the presence of IL-8 mRNA, and by immunohistochemistry (IHC) the presence of the chemokine IL-8 and the distribution of infiltrating macrophages in subcutaneous melanomas in the same tumor. IL-8 is a multifunctional cytokine produced by melanoma cells, activated macrophages and monocytes and it has been shown to be a growth and angiogenic factor for tumor cells. More recently it was shown that constitutive expression of IL-8 correlated directly with metastatic potential of human melanoma cells in nude mice. IL-8 content of a solid tumor as determined by Western blot analysis does not take into account the contribution of macrophages. Previous studies showed that murine tumors contain many infiltrating cells interspersed among tumor cells whereas human tumors growing in nude mice exhibit macrophages at the periphery or between tumor islands. In this study we demonstrate the expression of IL-8 and the distribution of macrophages by immunoperoxidase assay and IL-8 mRNA by ISH.

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High performance Nanogold™-in situ hybridzation and its use in the detection of hybridized and PCR-amplified microscopical preparations

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100166944 ◽

1996 ◽

Vol 54 ◽

pp. 896-897

Author(s):

G. W. Hacker ◽

I. Zehbe ◽

J. Hainfeld ◽

A.-H. Graf ◽

C. Hauser-Kronberger ◽

...

Keyword(s):

Polymerase Chain Reaction ◽

Messenger Rna ◽

High Performance ◽

Detection System ◽

Direct Methods ◽

Genetic Alterations ◽

Chain Reaction ◽

Protein Encoding ◽

Polymerase Chain

In situ hybridization (ISH) with biotin-labeled probes is increasingly used in histology, histopathology and molecular biology, to detect genetic nucleic acid sequences of interest, such as viruses, genetic alterations and peptide-/protein-encoding messenger RNA (mRNA). In situ polymerase chain reaction (PCR) (PCR in situ hybridization = PISH) and the new in situ self-sustained sequence replication-based amplification (3SR) method even allow the detection of single copies of DNA or RNA in cytological and histological material. However, there is a number of considerable problems with the in situ PCR methods available today: False positives due to mis-priming of DNA breakdown products contained in several types of cells causing non-specific incorporation of label in direct methods, and re-diffusion artefacts of amplicons into previously negative cells have been observed. To avoid these problems, super-sensitive ISH procedures can be used, and it is well known that the sensitivity and outcome of these methods partially depend on the detection system used.

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