Cancer cells often rearrange and exchange pieces of their genome to form new DNA sequences. These DNA sequences in turn express proteins that could initiate tumor development. Edison Liu at the A*STAR Genome Institute of Singapore and an international team of researchers1 have now used the latest DNA sequencing technology to examine how the genome is reorganized in breast cancer cell lines and tumor samples obtained from breast cancer patients. They identified genomic rearrangements that may lead to proteins for causing breast cancer.
When two parts of the genome that are usually not connected come into contact with each other, different gene segments may come together to form 'fusion’ genes. By analyzing the messenger RNA (mRNA) from cancer cells, Liu and co-workers were able to determine which of the fusion genes were transcribed in the cells. They found that fusions of two full genes were more likely to be transcribed by the cells than fusion events that brought together two gene fragments, which instead were more likely to silence the expression of the genes. The gene families whose expression was most likely to be affected by fusions in the breast cancer cells included those that play a role in cell adhesion, cell signaling and embryonic development.
The researchers also determined which of the fusion mRNA transcripts could be translated into proteins by assessing whether the fusion transcripts were found in ribosomes — cellular organelles that are responsible for forming proteins. Surprisingly, they observed 44% of fusion mRNA transcripts from the breast cancer cells were bound up in ribosomes. Many of these transcripts were translated into new proteins that may wreak havoc on a normal cell, leading to the induction of cancer.
Liu and co-workers focused on one particular genome rearrangement on chromosome 17 that is known to be present in many breast cancer cells, and can bring about the formation of a fusion mRNA transcript. The researchers found that the presence of the fusion transcript in breast cancer samples was linked to a poorer outcome in patients.
The findings demonstrate an association between genomic rearrangements and cancer formation, which is expected to have serious implications in cancer diagnostics and treatment. The researchers plan to apply the same approach to studying the effects of fusion transcripts in other cancers. "In the next stage of our research, we will be exploring the functional consequences of the entire constellation of fusion transcripts present in any one cancer," says Liu.
The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore