Researchers at Sweden’s Karolinska Institutet and the University of Oulu in Finland have elucidated gene regulatory mechanisms that can explain how 100 known gene variants influence prostate cancer risk. The findings, published in the journal Nature Genetics, reveal widespread deregulation of androgen receptor function, a key player in prostate cancer.
The vast majority of the three billion base-pairs in the human genome are identical across individuals. Nevertheless, genome sequence variation that does occur in the population has a profound effect on an individual's predisposition for developing various diseases. In the case of prostate cancer, 100 regions of genetic variation have been identified through comparative genetic studies. Each has a small but significant influence on prostate cancer risk. Previous studies have demonstrated an association of these genomic regions with disease, but the molecular processes accounting for the disease association have not yet been uncovered for most of these 100 regions.
Using computational and statistical analysis, Thomas Whitington and colleagues at Karolinska Institutet devised a method for analysing the molecular processes at these genomic regions. The researchers identified mechanisms that can explain many of the known associations between genetic variation and prostate cancer risk. These discoveries were validated using molecular techniques by a research team led by Gong-Hong Wei at University of Oulu.
"In particular, we discovered that binding of physical complexes involving the androgen receptor, a key transcription factor in prostate cancer, is often disrupted by DNA sequence variation associated with the disease", says Thomas Whitington at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet, one of the researchers behind the study.
“Landmark analysis using combined experimental and clinical data reveals that these DNA sequence variations cooperate with the transcription factor complexes to regulate many important genes for prostate cancer cell growth and tumor progression”, said by Gong-Hong Wei, a senior author of the work.
Transcription factors are key molecular components of the cell that bind to DNA and affect the activity of nearby genes. The androgen receptor is a transcription factor that promotes proliferation and survival of prostate cancer cells. In the current study, the investigators found that binding of androgen receptor at these locations of genetic variation was frequently tumor-specific, and not present in normal prostate tissue.
"This work refines our understanding of how this molecular machinery is involved in disease processes", says Thomas Whitington. "An improved understanding of androgen receptor binding may in particular prove useful, as its activity becomes pivotal during the treatment of late stage aggressive prostate cancer."
“The findings may have impact on public health, and be repurposed to predict the risk of prostate cancer in men at early stage, and facilitate the development of prostate cancer therapeutic approaches”, says Gong-Hong Wei.
The research was conducted by scientists based at Karolinska Institutet, University of Oulu, and University of Cambridge. The work was co-supervised by Fredrik Wiklund, Johan Lindberg, and Gong-Hong Wei. Thomas Whitington and Ping Gao were co-first authors. It was funded by, among others, the Swedish Cancer Society, Linneaus grant from the Swedish Research Council, and The Academy of Finland.
Gene regulatory mechanisms underpinning prostate cancer susceptibility, Thomas Whitington, Ping Gao, Wei Song, Helen Ross-Adams, Alastair Lamb, Yuehong Yang, Ilaria Svezia, Daniel Klevebring, Ian Mills, Robert Karlsson, Silvia Halim, Mark Dunning, Lars Egevad, Anne Warren, David Neal, Henrik Grönberg, Johan Lindberg, Gong-Hong Wei, Fredrik Wiklund, Nature Genetics, doi: 10.1038/ng.3523
Last updated: 8.3.2016