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American, Mexican Research Team Uncovers Potentially Druggable Breast Cancer Mutations

NEW YORK (GenomeWeb News) – Researchers from the US and Mexico have detected recurrent breast cancer mutations and rearrangements affecting genes not previously implicated in the disease. The study appears in the current issue of Nature, alongside several other breast cancer studies published online in the journal over the past few months.

The team, led by Massachusetts researchers and investigators from Mexico's National Institute of Genome Medicine, known as INMEGEN, did whole-exome sequencing on breast cancer samples from more than 100 Mexican and Vietnamese women, combined with whole-genome sequencing on nearly two-dozen matched tumor-normal sample sets.

The search uncovered alterations in both known and previously undetected breast cancer risk genes. Among them: a fusion between the genes MAGI3 and AKT3 found in a fraction of difficult-to-treat triple-negative breast cancers.

Researchers' follow-up experiments suggest that cells containing this fusion respond to compounds targeting certain portions of the AKT3 gene product, hinting that such drugs might eventually prove useful for treating breast cancers that involve the MAGI3-AKT3 fusion.

"The triple-negative subgroup is one [for which] no targeted therapies are currently available," co-first author Shantanu Banerji told GenomeWeb Daily News. "So … ultimately, in those 7 percent [of triple-negative tumors containing the MAGI3-AKT3 fusion], it could be a big deal."

Banerji was a post-doctoral researcher at the Broad Institute and Dana-Farber Cancer Institute when the study was carried out. He is now a medical oncology researcher with CancerCare Manitoba.

He and his colleagues used the Agilent SureSelect system to capture coding sequences from 103 tumor and matched normal samples, obtained from 54 women with breast cancer from Mexico and 49 Vietnamese women with breast cancer.

The Mexican samples were obtained as part of a collaboration between the Broad and INMEGEN that was funded by the Carlos Slim Health Institute, Banerji explained, while the Vietnamese samples came from a commercial sample bank.

Using the Illumina GAIIx or HiSeq 2000 platforms, the team then sequenced each exome to a depth of around 100X and did 30X whole-genome sequencing on 22 tumor-normal pairs, including 17 of those assessed by whole-exome sequencing.

Analyses of the sequences uncovered thousands of candidate point mutations, small insertions, and deletions, with each tumor containing between 14 to more than 300 apparent alterations.

"One of the lessons here is the real diversity of mutations in breast cancer," Broad Institute, Dana-Farber Cancer Institute, and Harvard Medical School researcher Matthew Meyerson, co-senior author on the study, said in a statement.

After doing validation testing on almost 500 potential mutations by complementary methods such as mass spectrometry-based genotyping and/or Roche 454, Pacific Biosciences, Illumina, or Sanger sequencing, the researchers narrowed in on six genes showing the most significant recurrent mutation in the tumors, which included representatives from each of the breast cancer subtypes described in the so-called PAM50 classification scheme.

Five of the six most frequently mutated genes were the known breast cancer risk genes TP53, PIK3CA, GATA3, AKT1, and MAP3K1.

But researchers also saw recurrent rearrangements in the transcription factor-coding gene CBFB, which subsequently led them to deletions in RUNX1, a gene that codes for a protein in the same complex as the CBFB gene product.

While CBFB and RUNX1 are not well known for their role in breast cancer, Banerji explained, the genes have been found to harbor recurrent alterations in blood cancer such as acute myeloid leukemia.

"We know from the leukemic literature that these genes have quite a prominent role in differentiation in leukemias, and perhaps in breast cancers they may have a similar role," Banerji said, though he noted that more research is needed to explore that possibility.

Within other tumor samples, including around 7 percent of so-called triple-negative breast cancers that don't rely on estrogen receptor, progesterone receptor, or HER2 gene activity, meanwhile, they found a recurrent fusion between the MAGI3 and AKT3 genes that appears to spur on cancer cell growth through activation of the PI3-kinase pathway.

Their subsequent cell line studies indicated that cells containing this fusion do not respond to AKT treatments that target part of the resulting protein called the pleckstrin homology domain that is obscured by the fusion.

On the other hand, these cells do seem to be vulnerable to AKT kinase domain inhibitors, the study authors noted, hinting at a potential avenue for treating some of these aggressive triple-negative breast tumors.

"The recurrent genomic fusion involving AKT3 suggests that the use of ATP-competitive AKT inhibitors should be evaluated in clinical trials for the treatment of fusion-positive triple-negative breast cancers," they wrote, "a sub-type where limited therapeutic options exist beyond systemic cytotoxic chemotherapy."

A few samples also contained mutations in ERBB2, a gene that is amplified in some breast cancers. Though the mutations didn't meet the team's statistical threshold for significant recurrence, the presence of these alterations hints that there might be additional ERBB2 mutations that could be targeted with trastuzumab (marketed as Herceptin by Genentech), a drug that is currently used against breast cancers with ERBB2 amplifications.

"All of the laboratory tests that are done are designed to try to identify ERBB2 amplification," Banerji explained. "But the reality is that there are mutations that are present in a small percentage of patients and there's a very good chance that those mutations are doing the same thing that the amplification of the gene does in other cells."

"Therefore, there may be an additional group of patients who benefit from drugs like Herceptin or other ERBB2-targeted drugs who are currently not getting that therapy," he added.

More research is needed to explore that possibility and to explore the functional consequences of the other new mutations identified. Down the road, researchers also hope to get a better understanding of whether any of the newly detected breast cancer mutations are specific to the certain human populations and/or breast cancer sub-types, and how they correspond to breast cancer outcomes.

In addition to follow-up studies focused on alterations detected already, Banerji said there is also interest in teaming up with other groups who have done genome and exome sequencing studies of breast cancer to do a meta-analysis aimed at finding even more new mutations.

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