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  • Opinion
  • Published:

Tissue-specific tumorigenesis: context matters

Abstract

How can we treat cancer more effectively? Traditionally, tumours from the same anatomical site are treated as one tumour entity. This concept has been challenged by recent breakthroughs in cancer genomics and translational research that have enabled molecular tumour profiling. The identification and validation of cancer drivers that are shared between different tumour types, spurred the new paradigm to target driver pathways across anatomical sites by off-label drug use, or within so-called basket or umbrella trials which are designed to test whether molecular alterations in one tumour entity can be extrapolated to all others. However, recent clinical and preclinical studies suggest that there are tissue- and cell type-specific differences in tumorigenesis and the organization of oncogenic signalling pathways. In this Opinion article, we focus on the molecular, cellular, systemic and environmental determinants of organ-specific tumorigenesis and the mechanisms of context-specific oncogenic signalling outputs. Investigation, recognition and in-depth biological understanding of these differences will be vital for the design of next-generation clinical trials and the implementation of molecularly guided cancer therapies in the future.

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Figure 1: Hereditary cancer predisposition syndromes and tissue- specific tumorigenesis.
Figure 2: Somatic mutation frequencies in common cancers from the Catalogue of Somatic Mutations in Cancer (COSMIC).
Figure 3: Models of context-specific carcinogenesis and intertumour heterogeneity based on the cell of origin and its differentiation status.
Figure 4: Determinants of context-specific oncogenic signalling networks.
Figure 5: Approaches to identification, analysis and validation of cancer drivers in context.

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Acknowledgements

The authors apologize to all colleagues whose work could not be included owing to space constraints. G.S. is supported by grants from the Deutsche Krebshilfe (grant 110908), the German Research Foundation (DFG; grant SFB824/C9), the Wilhelm Sander Foundation (grant 2016.004.1) and a joint funding project of the German Cancer Consortium (DKTK). R.R. is supported by grants from the DKTK and the Helmholtz- Alliance Preclinical Comprehensive Cancer Center (PCCC). D.S. is supported by grants from the European Research Council (grant 648521), the DKTK, the DFG (grants SA 1374/4-2 and SFB824/C9) and the Helmholtz Alliance PCCC.

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Glossary

Chromoanasynthesis

Local gene rearrangements that lead to multiple copy number alterations (including deletions, duplications and triplications) as well as extensive translocations and inversions. These rearrangements result from template switching during locally defective DNA replication.

Chromoplexy

Complex chained DNA rearrangements that affect multiple chromosomes and result from several broken DNA strands.

Chromothripsis

The massive catastrophic shattering and reassembly of one or a few chromosomes, resulting in the simultaneous acquisition of multiple genetic alterations in a cell.

Desmoplasia

A dense fibrous connective tissue reaction, usually to malignant epithelial tumours in the stroma of a carcinoma, caused by the proliferation of fibroblasts and increased deposition of extracellular matrix components.

Mosaicism

The presence of two or more genetically distinct cell populations.

Steatosis

The abnormal retention and accumulation of lipid droplets within cells, resulting in fatty changes in or degeneration of a solid organ.

Super-enhancers

Genomic regulatory regions containing multiple enhancers with a very strong enrichment for transcriptional co-activator binding; these regions therefore drive gene transcription.

Transdifferentiation

A cell fate switch (metaplasia) such that a differentiated adult somatic cell transforms into another mature somatic cell type.

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Schneider, G., Schmidt-Supprian, M., Rad, R. et al. Tissue-specific tumorigenesis: context matters. Nat Rev Cancer 17, 239–253 (2017). https://doi.org/10.1038/nrc.2017.5

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