Ovarian cancer oncogene found in 'junk DNA'
A research team mined junk DNA sequences to identify a non-protein-coding RNA whose expression is linked to ovarian cancer.
Most genetic studies have focused on the portion of the human genome that encodes protein, which is a fraction that accounts for just 2% of human DNA overall. Yet the vast majority of genomic alterations associated with cancer lie outside protein-coding genes, in what traditionally has been derided as junk DNA. Researchers today know that junk DNA is anything but junk, as much of it is transcribed into RNA, for example, but finding meaning in those sequences remains a challenge.
Supported by the Basser Research Center for BRCA at the Abramson Cancer Center at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, a research team led by Lin Zhang, PhD, built a DNA copy number profile for nearly 14,000 long noncoding RNAs, or lncRNAs. They did this across 12 cancer types, including ovarian and breast cancers that include the two major BRCA-related cancers. They found that the number of copies of lncRNA genes on a chromosome consistently changes in 12 different cancer types. Also, lncRNA genes are widely expressed in cancer cells.
Using clinical, genetic, and gene expression data as filters to distinguish genes whose copy number alteration causes cancer from those for whom copy number changes are incidental, the team whittled down their list from 14,000 to a more manageable number, each of which they systematically tested using genetic experiments in animals. Their study was published in Cancer Cell (2014; doi:10.1016/j.ccr.2014.07.009).
Of the 37 lncRNAs the team fully tested, one known as focally amplified lncRNA on chromosome 1 (FAL1) had all the makings of an RNA oncogene. FAL1 is one of only a handful of lncRNAs to be linked to cancer to date. This knowledge is being applied for clinical applications.
For example, FAL1 expression may be a biomarker of BRCA-related cancer prognosis and the basis of new anticancer therapeutics. As proof-of-principle of the potential efficacy, Zhang's team grew human ovarian tumors in immunocompromised mice, then injected short-interfering RNAs to block the tumors' growth using RNA interference against FAL1. The tumors in treated animals shrank over the course of the experiment, while tumors in control animals continued to grow.
FAL1 is overexpressed in ovarian and breast cancer samples. Blocking the activity of the gene via RNA interference reduces cancer cells' growth, while overexpressing it in normal cells increases their growth. High FAL1 expression in human ovarian cancer samples tended to correlate with poor clinical prognosis.
"This is the first genome-wide study to use bioinformatics and clinical information to systematically identify one lncRNA, which we found to be oncogenic," Zhang said.
FAL1 expression may be able to serve as a biomarker of BRCA-related cancer prognosis, assuming these findings can be validated in other populations. But there also is the potential for new anticancer therapeutics, Zhang said, whether those are therapeutics specifically targeting FAL1 RNA or small molecules that block the interaction between FAL1 and BMI1.