According to a study published online in Proceedings of the National Academy of Sciences (PNAS), researchers have identified two inherited-genetic deletions in the human genome associated to the development of prostate cancer.
The study, led by Weill Cornell Medical College researchers in collaboration with the Brigham and Women's Hospital and Innsbruck University Hospital, reveals that men are three or four times more likely to develop the disease depending on the genetic variant they inherit.
The researchers found that one genetic deletion affects the functioning of a known gene, and the other genetic deletion, identified in a non-coding region of the genome previously believed to be "junk DNA", appears to control a cascade of genes.
The study shows that copy number variations (CNVs), in either protein coding or non-coding areas of the human genome, specifically plays a considerable role in the development of aggressive prostate cancer, and cancer in general.
Dr. Mark A. Rubin, the Home T. Hirst Professor of Oncology in Pathology at Weill Cornell Medical College, and co-author of the study, explained:
"We used to think that only genes that made proteins were responsible for disease, but this study shows us that there is inherited information in the non-coding areas of the genome that appear to play a strong role in development of cancer."
CNVs have been linked to:
- Parkinson's disease
- Alzheimer's disease
- Mental retardation
- Neuroblastoma (a type of brain cancer)
"This study suggests there are other cancers that might be associated with CNVs."
Co-lead researcher, Dr. Francesca Demichelis, who is currently an Assistant Professor at the Center of Integrative Biology at the University of Trento in Italy and an Adjunct Assistant Professor in the Institute for Computational Biomedicine at Weill Cornell Medical College, explained:
"The study shows that copy number variations matter in cancer."
According to Dr. Demichelis, the two genetic variants discovered in the study are not the only cause of aggressive prostate cancer. "These variants likely collaborate with other factors early in a man's life leading to development of prostate cancer."
1 in 6 men will be affected by prostate cancer at some stage during their life, and family history is the strongest risk factor for the disease. Due to the inheritable nature of prostate cancer, the researchers set out to find DNA that is either significantly duplicated or deleted in the genome of prostate cancer patients, in order to compare it to healthy men.
The team analyzed blood samples from a population of men from the Tyrol Early Prostate Cancer Detection Program in Austria. The program is designed to detect prostate cancer as early as possible and has been screening men aged between 45 to 75 years, who live in the Tyrol region, with prostate specific antigen (PSA) since 1993.
The researchers examined men who developed the disease and men with elevated PSA whose biopsy results showed no prostate cancer. Furthermore, they examined the germline variation in these men in order to determine whether there is a risk factor as why some men with elevated PSA have the disease, while others do not.
Molecular studies were conducted in the United States on blood samples from 867 men from Tyrol with unrelated cancer and 1,036 controls.
The team identified two CNVs that were considerably different between those with aggressive prostate cancer and men without cancer. This finding was reproduced in another group involving 800 patients in the United States. After examining the effect of the two variants in laboratory cells, the team found that they increase the ability of cancer cells to grow and to invade.
According to Dr. Demichelis, both variants are small deletions in DNA that cause over-expression of genes. The team found that one gene that is over-expressed as a result of the variant deletion is MGAT4C, which leads to the ability of cells to grow and spread. Dr. Demichelis, explained:
"A man with the variant is four times more likely to develop prostate cancer if he inherited this variant than if he did not. Interestingly, MGAT4C was found to be significantly over-expressed in metastatic versus localized prostate cancer."
Although researchers do not know the role of the other genetic variant, they believe it triggers a cascade of other genes. According to their calculations, if this variant is inherited, a man is three times more likely to develop prostate cancer.
Furthermore, calculations reveals that these two variants occur at a frequency of between 1.5 to 3% of the overall population, although they are more prevalent in men diagnosed with aggressive prostate cancer.
Dr. Demichelis, said:
"For the gene coding variant, MGAT4C, we were able to analyze metastatic human samples where we observed the high-risk gene is abundantly present."
The team is currently seeking other variants in order to develop a comprehensive DNA test to be used as a diagnostic tool to help clinicians identify which prostate cancer patients will likely progress to advanced stages.
Dr. Demichelis, explained:
"We could also potentially use such a DNA test for chemoprevention if risk of developing aggressive prostate cancer is deemed to be high. This is the start of a new strategy. It would not replace PSA, but would identify other risk factors."
According to Dr. Rubin:
"In this new area of research, we are starting to appreciate that the differences in inherited genomic variants account not only for why we look different or respond in various ways to medication, but also for why we develop disease.
This is the first study to suggest these variants may account for susceptibility to cancer. This new line of research will also allow us to study the biology around prostate cancer initiation."
The study was partially funded by the Starr Cancer Consortium, the Early Detection Research Network from the National Cancer Institute, the Clinical and Translational Science Center, the Department of Defense and the National Human Genome Research Institute.