Inherited-genetic variations up risk of aggressive prostate cancer

Washington, April 10 (ANI): Scientists have discovered two inherited-genetic deletions in the human genome linked to development of aggressive prostate cancer.

The findings by an international research team led by Weill Cornell Medical College investigators indicate a man's risk of developing prostate cancer either triples or quadruples, depending on the genetic variant they inherit.

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 lead co-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 study co-author, Dr. Mark A. Rubin, the Homer T. Hirst Professor of Oncology in Pathology at Weill Cornell Medical College.

Other researchers have linked CNVs to Alzheimer's and Parkinson's disease, mental retardation, autism, schizophrenia and neuroblastoma, a type of brain cancer.

"This study suggests there are other cancers that might be associated with CNVs. It's an exciting new field of research," stated Dr. Rubin.

"The study shows that copy number variations matter in cancer," added co-lead investigator, Dr. Francesca Demichelis, who is now 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.

The two genetic variants identified by the research team are not the only cause of aggressive prostate cancer, Dr. Demichelis noted.

"These variants likely collaborate with other factors early in a man's life leading to development of prostate cancer," she said.

Molecular studies were performed in the U.S. on more than 1900 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 researchers 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 over-expression of genes, Dr. Demichelis said.

She and her colleagues found that one gene that is over-expressed 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 over-expressed in metastatic versus localized prostate cancer," she added.

The role of the other genetic variant, located in the "junk" region of the human genome, is not yet known, but the researchers 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.

The investigators calculated these two newly identified variants occur at a frequency of between 1.5-3 percent of the overall population, but are found at a significantly higher percentage in men diagnosed with aggressive prostate cancer.

Now researchers are looking for other variants they hope to be able to build into a comprehensive DNA test to be used as a diagnostic tool to help clinicians identify men whose prostate cancer will likely progress to advanced stages.

The discovery has been published online in the Proceedings of the National Academy of Sciences (PNAS). (ANI)