Navigating the highly variable features behind the epigenomic basis of cancer is no easy task: What’s up is down, what’s down is up! Thankfully, to aid our quest, the lab of Manel Esteller at the Bellvitge Biomedical Research Institute (IDIBELL) in Spain has brought forth a map as massive as the DNA methylation changes behind cancer itself.
First, the talented cartographers applied whole-genome bisulfite sequencing (WGBS) to interrogate 22 diverse samples from brain, blood, breast, prostate, liver, lung, colon, and placenta. These samples included 8 normal tissues as well as 13 samples from primary tumors, their metastases, and cancer cell lines.
Here are the features the team’s maps led them to:
- Cancer cells exhibited both a global loss of DNA methylation and specific gains of methylation
- Global DNA methylation progressively decreased from normal tissue to primary tumor to metastases
- However, the decrease in methylation was heterogeneous, as shown by the loss of association between methylation levels of neighboring CpG sites
- The team then focused on hypomethylated regions (HMRs) in normal tissues, which cover 2% of the genome
- In general, HMRs shared across cells (c-HMRs) belonged to promoters of cell maintenance genes while the tissue-specific HMRs (t-HMRs) belonged to enhancers of tissue-specific genes
To apply their WGBS findings, the team took their sample size to the next level and used the 450K array to examine 1112 primary samples of 12 different tumor types. They focused in on c-HMRs hypermethylated in cancer cells and demonstrated that these c-HMRs cluster cancer samples according to their tissue of origin and thus have potential as type-specific cancer markers. Finally, the authors went after the function of c-HMRs commonly hypermethylated in cancer, finding that they belong to genes involved in development and differentiation as well as tumor suppressor genes.
Esteller shares, “Our analysis has allowed us to get a first unbiased look at all the tumor cell methylomes in solid tumors. We have not only found that many anti-cancer genes specifically slow down their activity in the cancer-affected organs, but we have also shown that there are other alterations in distant chromosomal regions that affect these organs, since in the three-dimensional world of the cells these sequences are in very close relative positions.”
Check out all the massive and specific changes over at Oncogene, June 2017