NEW YORK (GenomeWeb News) – Rearrangements involving genes from two gene families turn up in a significant fraction of breast cancers, according to a study published online in Nature Medicine yesterday.
An international group led by investigators at the University of Michigan found gene fusions in breast cancer when they used transcriptome sequencing to screen dozens of breast cancer cell lines and tissue samples. Though the combinations of genes varied, they found that the fusions found often included genes from the microtubule-associated serine-threonine, or MAST, kinase family or Notch family. From findings so far, they estimate that these sorts of recurrent rearrangements occur in some 5 to 7 percent of breast tumors.
Given the frequency of these fusions — and the fact that they seem capable of driving breast tumor formation — the study authors suggest that it might be possible to design treatments that correspond to the gene families involved in the rearrangements.
"[T]hese gene fusions and rearrangements can give us targets for potential therapies," co-corresponding author Arul Chinnaiyan, a pathology researcher at the University of Michigan and director of the Michigan Center for Translational Pathology, said in a statement.
Genetic rearrangements and chromosome translocations have a long-documented role in blood cancers, and studies over the past few years have uncovered rearrangements in some solid cancers as well. In 2005, for instance, Chinnaiyan and his colleagues described a recurrent fusion between the genes TMPRSS2 and ERG in prostate cancer. They have since detected even more rearrangements in prostate, lung, and other cancers.
Some rearrangements have been found for a type of breast cancer known as secretory breast cancer, the researchers explained, but driver rearrangements have not yet been detected for most forms of breast cancer.
In an effort to track down new rearrangements, including possible drivers, the team used the Illumina GAII or HiSeq 2000 to do paired-end transcriptome sequencing on 89 breast cancer cell lines or tumor tissue samples collected at the University of Michigan or the Institute of Cancer Research Breakthrough Breast Cancer Research Centre in London.
The samples included estrogen receptor-positive breast cancers, ERBB2-positive forms of the disease, and so-called "triple negative" breast cancers, which had low expression of the estrogen receptor, ERBB2, and progesterone receptor.
After analyzing the sequence data using a discovery pipeline they had used in their previous rearrangement detection studies, researchers found 384 gene fusions expressed in the breast cancers tested. On average, the cell lines harbored a slightly higher proportion of these fusions than primary tumor samples, they noted.
Two-dozen genes participated in more than one of these fusions, though only one recurrent fusion contained the same two genes, SEC16A and NOTCH1.
While the combinations varied from one breast cancer to the next, though, the team did see recurrence in the types of genes involved. Genes from the MAST kinase family and Notch family were particularly common, turning up in five and eight of the fusions, respectively.
The researchers uncovered even more fusions involved in Mast family genes when they screened pooled transcripts from 74 more breast carcinoma samples.
In their subsequent cell line and mouse xenograft experiments, the team found clues that Mast or Notch family gene fusions may drive tumor formation, while inhibiting these fusions slowed cell proliferation.
Despite the recurrence of rearrangements from each gene family, the investigators did not see breast cancer samples containing fusions involving genes from both the Mast and Notch families, hinting that they may occur in different subsets of the disease. Moreover, fusions between NOTCH1 or NOTCH2 and other genes were only detected in estrogen receptor-negative tumors.
"The MAST and Notch aberrations in breast cancer are new classes of rare but functionally recurrent gene fusions with therapeutic implications," they argued, noting that these "mutually exclusive aberrations" are likely found in as many as 5 to 7 percent of breast cancers.