The publication1,2 of the human genome sequence in 2001 was accompanied by optimism that a rise in the availability of genomic data might improve clinical treatments. It was hoped that such data might one day enable an approach termed ‘precision medicine’, in which therapies are tailored to target the abnormalities specific to a particular cancer. Since then, technological advances in DNA-sequencing techniques, combined with substantially lower costs, have led to a boom in the sequencing of cancer samples. Given this progress, one might assume that the key genetic alterations that drive common cancers are already well known. However, writing in Cell, Takeda et al.3, Viswanathan et al.4 and Quigley et al.5 detail a previously unidentified type of genetic alteration that frequently occurs in late-stage human prostate cancer.
The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) have undertaken some of the largest-scale projects reported so far to sequence the DNA of human cancers. These efforts have identified many DNA alterations that drive cancer growth, including mutations and genomic rearrangements. TCGA has sequenced the protein-coding regions of approximately 11,000 individual genomes and 33 types of cancer (https://portal.gdc.cancer.gov), whereas the ICGC has sequenced the protein-coding regions from more than 20,000 individual genomes and 22 kinds of cancer (https://dcc.icgc.org). Both projects have focused mainly on sequencing the protein-coding regions of genes, which represent less than 2% of the entire genome. In the Pan Cancer Analysis of Whole Genomes (PCAWG) project, the ICGC and TCGA systematically analysed whole-genome sequencing data from many types of cancer. These data allowed scientists to investigate alterations in DNA regions that regulate gene expression, and in untranslated parts of gene sequences. This revealed that, in cancer cells, alterations in these non-protein-coding regions of DNA occur at a similar frequency to those in the protein-coding regions6.
Many of the sequencing studies reported by TCGA and the ICGC focused predominantly on tumour samples taken from patients before cancer treatment. The work of Takeda, Viswanathan, Quigley and their respective colleagues provides some information about genetic alterations present in prostate cancers that are resistant to clinical treatment.
Prostate-cancer growth is usually driven by signalling pathways that act through the androgen receptor (AR), and a standard clinical treatment for advanced prostate cancer is to reduce the level of androgen hormones that activate ARs. Although this limits cancer growth for a while, tumours eventually become resistant to this therapy, and a highly malignant form of the cancer arises that is usually lethal. Such a tumour can migrate to other sites in the body through a process known as metastasis, and this sort of late-stage, treatment-resistant tumour is called a metastatic, castration-resistant prostate cancer.
When treatment resistance occurs, an altered version of the gene that encodes AR is commonly found in the tumour. Mutations of the AR gene or amplifications of DNA that increase the copies of sequence encoding AR might enable tumour cells to enhance AR-pathway signalling even when androgen levels are low7,8. Analyses of protein-coding-sequence changes linked to prostate cancer have found alterations in AR, as well as in other known cancer-promoting genes9. Although a wealth of DNA sequencing data of protein-coding regions are available for prostate-cancer samples, there are comparatively few whole-genome sequences (only approximately 200 have been reported by the PCAWG project, for example; https://dcc.icgc.org/pcawg), and still fewer whole-genome sequencing data are available for metastatic, castration-resistant prostate cancer.
Takeda et al. re-evaluated previously published data10 from clinical samples of castration-resistant prostate cancer and identified repeated DNA sequences that caused abnormal amplification of the region upstream of AR (Fig. 1). The authors describe this region as a type of gene-regulatory element called an enhancer, which is a sequence that can help to promote gene expression. When Takeda and colleagues used a genome-editing technique to target and suppress this region in human prostate-cancer cells grown in vitro, both cell proliferation and AR expression were reduced. The authors also engineered prostate-cancer cells grown in vitro to contain a duplication of the enhancer, and found that such cells showed increased AR expression and decreased sensitivity to an AR-targeting drug called enzalutamide that is used to treat metastatic, castration-resistant prostate cancer.
