Search for Driver Mutations Highlights the Genetic Diversity of Breast Cancer

A recent paper underscored the genetic diversity of breast tumors by adding nine new genes to the list of over 40 genes that have been linked to the development of this disease.

Investigators at the Wellcome Trust Sanger Institute (Hinxton, United Kingdom) in cooperation with the Oslo Breast Cancer Consortium (OSBREAC) examined the genomes of 100 tumors for somatic copy number changes and mutations in the coding exons of protein-coding genes. In particular, they were looking for “driver mutations,” which confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis.

They reported in the May 16, 2012, online edition of the journal Nature that the number of somatic mutations varied markedly between individual tumors. They found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about 10% of tumors characterized by numerous cytosine mutations in certain dinucleotides.

Driver mutations were identified in nine new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1, and TBX3. Overall, among the 100 tumors studied, driver mutations were found in at least 40 cancer genes and 73 different combinations of mutated cancer genes.

“In 28 cases we found only a single driver, but the maximum number of driver mutations in an individual cancer was six,” said contributing author Dr. Mike Stratton, director of the Wellcome Trust Sanger Institute. “We found that breast cancer can be caused by more than 70 different combinations of mutations. If we consider three breast cancers, each with four driver mutations: they might share none of those driver mutations – so each is a different genetic “animal.” They are different cancers driven by different genes. We need to classify them as carefully as we can. This study is a step towards that goal.”

“The picture is certainly more complicated than we would have wanted, but as with many other things knowledge is our strongest weapon. These comprehensive insights reveal the faulty wiring of the cellular circuit board that causes cells to behave as cancers. Understanding our enemy at this level of detail will allow us to take more rational approaches to therapy, to understand why some cancers respond to drugs and others do not, and direct us to new vulnerabilities to be exploited in new treatments,” said Dr. Stratton.

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Wellcome Trust Sanger Institute