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Tumour evolution

Epigenetic and genetic heterogeneity in metastasis

Nature Reviews Cancer volume 17, page 141 (2017)Cite this article

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Makohon-Moore, Zhang, Reiter et al. carried out whole-genome sequencing (WGS) of 39 samples from four patients with stage IV (metastatic) PDAC to generate a picture of the genetic driver alterations in primary tumours and metastases from various organs. They identified 614 PDAC-associated mutations, which they used to estimate the heterogeneity between primary tumours and metastases. They found there was less heterogeneity than expected and that primary tumours and metastases were highly similar. Targeted sequencing of 59 spatially distinct samples of the four primary tumours revealed the phylogeny of the tumour and metastatic subclones. They found that no single subclone gave rise to all or most metastases in a patient and all driver genes in metastases were found in all sequenced regions of the primary tumours. This suggests that driver mutations in these PDACs are not highly heterogeneous and metastasis-specific driver mutations could not be identified.

McDonald, Li et al. investigated the impact of epigenetic heterogeneity on the progression of PDAC using a panel of matched primary and metastatic PDAC samples from five patients. Immunostaining revealed differences in global epigenetic reprogramming in primary tumour subclones that seed regional (peritoneal) and distant (liver and lung) metastases. Investigating further, they produced 160 data sets of histone modifications, gene expression changes and whole-genome DNA methylation changes from a subset of the primary tumour, regional metastasis and distant metastasis samples. In peritoneal metastasis, histone 3 lysine 9 dimethylation (H3K9me2) was enriched in large organized chromatin H3K9-modified (LOCK) heterochromatin, but these same regions had reduced H3K9me2 in lung metastasis and primary tumour samples. Correspondingly, the LOCKs had differential gene expression and reductions in DNA methylation in distant metastasis compared with peritoneal metastasis. Next, they looked at gene-rich euchromatin domains (ECDs), defined by enrichment for acetylated H3K27 (H3K27ac) and H3K36 trimethylation (H3K36me3) and depletion of modifications associated with heterochromatin. Mapping gene expression data and ECDs revealed local reprogramming such that upregulated genes in ECDs had increased levels of H3K36me3 and H3K27ac. Thus, they found that substantial epigenetic reprogramming occurs at sites of heterochromatin and euchromatin and that this differs between regional and distant metastasis.

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References

  1. Makohon-Moore, A. P. et al. Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. Nat. Genet. http://dx.doi.org/10.1038/ng.3764 (2017)

  2. McDonald, O. G. et al. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat. Genet. http://dx.doi.org/10.1038/ng.3753 (2017)

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Authors
  1. Gemma K. Alderton
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Alderton, G. Epigenetic and genetic heterogeneity in metastasis. Nat Rev Cancer 17, 141 (2017). https://doi.org/10.1038/nrc.2017.11

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