BRCA1 and tandem duplications in cancer

BRCA tandem dupicator cancer research

Replication of DNA is an essential process in dividing cells, with each daughter cell receiving a complete copy of the genome. Replication errors caused by stalling — where replication pauses at an abnormal DNA structure or other blockage — are a hallmark of some cancers and developmental disorders. Prior research has revealed the cellular mechanisms that help prevent these errors, including important roles for BRCA1 and BRCA2. BRCA mutations are well-known cancer risk factors, but a particular genomic perturbation, called tandem duplications (TDs), is associated with loss of BRCA1 but not BRCA2. TDs involve many extra, repeated segments of DNA inserted in the genome, and they can disrupt expression of important tumor suppressor genes or amplify tumor promoter genes. How TDs form and why they’re specific to BRCA1 cancers, however, was not previously understood.

A team led by Ralph Scully of Beth Israel Deaconess Medical Center/Harvard Medical School and including JAX President and CEO Edison Liu, M.D., and Associate Research Scientist Francesca Menghi, Ph.D., has now uncovered the underlying mechanisms. In a paper published in Nature, the researchers used a protein that pauses replication at specific, known sites, in a method called Tus/Ter. They found that BRCA1 suppresses tandem duplications at these sites in mammalian cells, but it doesn’t suppress defects at double-strand break sites, indicating that its repair role is specific to stalled replication. They were also able to investigate the mechanisms underlying TD formation at the known breakpoints. They determined that it’s based on a process known as “microhomology-mediated break-induced replication” (MMBIR), and the mechanisms involved are found in bacteria and yeast, showing that they are broadly conserved across evolution.

The team hypothesized that TD suppression at stalled replication sites may be a general feature of BRCA1 mutant cancer genomes. To test this idea, they analyzed 71 primary ovarian cancers for which whole genome sequences and transcriptome data were available and found that abundant small TDs indeed correlated strongly with loss of BRCA1. The so-called “small TD” trait may therefore represent a general biomarker for cancers associated with BRCA1 mutations.

Willis et al., Mechanism of tandem duplication formation in BRCA1-mutant cells. Nature (published online November 22, 2017). doi:10.1038/nature24477