Aggressive prostate cancer may be linked to genetic deletions

An international research team led by investigators from Weill Cornell Medical College, New York has discovered two inherited-genetic deletions in the human genome linked to the development of aggressive prostate cancer.

The findings, published online in the Proceedings of the National Academy of Sciences (April 10, 2012), indicate a man’s risk of developing prostate cancer either triples or quadruples, depending on the genetic variant he inherits.

In the study, one genetic deletion is shown to affect the functioning of a known gene, while the other, found in a non-coding area of the genome once considered to be "junk DNA," seems to be regulating a cascade of genes. According to the authors, the study is potentially groundbreaking because it demonstrates that so-called copy number variations (CNVs) in either protein coding or non-coding areas of the human genome play a significant role in the development of cancer in general, and in aggressive prostate cancer specifically.

"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," said senior author Mark A. Rubin, MD, of Weill Cornell Medical College.

In the study, researchers from Weill Cornell; Brigham and Women’s Hospital, Boston; and Innsbruck University Hospital, Innsbruck, Austria examined blood samples from a population of men from the Tyrol Early Prostate Cancer Detection Program in Austria. Since 1993, this program has been aggressively screening PSA in men aged 45 to 75 years who live in the Tyrol region to detect prostate cancer as early as possible. The population includes men who developed prostate cancer as well as men with elevated PSA who have no prostate cancer based on a biopsy.

Molecular studies were performed in the U.S. on more than 1,900 blood samples from Tyrolean men (867 unrelated cancer patients and 1,036 controls). Researchers discovered two CNVs that were significantly different between Tyrolean individuals with aggressive prostate cancer and those without cancer, and then reproduced that finding in another group of 800 U.S. patients. The authors then tested the effect of the two variants in laboratory cells and discovered they increase the ability of cancer cells to grow and to invade.

Both of these variants are small deletions in DNA that lead to overexpression of genes, said first author Francesca Demichelis, MD, of the University of Trento in Italy and Weill Cornell Medical College. She and her colleagues found that one gene that is overexpressed due to the variant deletion is MGAT4C, which leads to the ability of cells to grow and migrate.

"A man with the variant is four times more likely to develop prostate cancer if he inherited this variant than if he did not," Dr. Demichelis said. "Interestingly, MGAT4C was found to be significantly overexpressed in metastatic versus localized prostate cancer."

The role of the other genetic variant, located in the "junk" region of the human genome, is not yet known, but the authors believe it activates a cascade of other genes. They calculated a man is three times more likely to develop prostate cancer if he has inherited this variant.

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