Revealed: another piece of the breast cancer gene puzzle

Researchers have found that rare mutations in XRCC2 increase the risk of breast cancer. Robert S Donovan

You’ve probably heard of BRCA1 and BRCA2 – the genes that, when mutated, markedly increase the risk of developing breast cancer. We’ve also known for a while that a handful of other genes also increase cancer susceptibility.

But new research, published today in the American Journal of Human Genetics, explains how my colleagues and I have identified another gene – XRCC2 – that, when mutated, is associated with an increased risk of breast cancer. This explains an additional fraction of the underlying genetic risk in heritable breast cancer.

We’ve still got a way to go in identifying all the genes responsible for breast cancer. But my colleagues and I, from the University of Melbourne and a number of international institutions, are currently in the early stages of a large gene sequencing project and hope to soon identify more susceptibility genes.

So how do we do it? Let’s start with some background on gene sequencing technologies.

Sanger sequencing, developed by Frederick Sanger in the 1970s, is a “workhorse” technology that has been used in a range of disciplines including molecular diagnostics, forensics and basic research. Perhaps most notably, it was the sequencing technology behind the Human Genome Project.

Sanger sequencing allows scientists to sequence single stretches of around one thousand nucleotides per channel on today’s instruments.

The development of a new generation of sequencing instruments has allowed us to progress far more quickly with genetic research. The new technology is generally referred to as massively parallel sequencing (MPS), as these instruments can sequence millions of DNA fragments in parallel on a single instrument run.

The capacity of MPS is remarkable – one instrument is capable of sequencing the whole genome of a human in just days, a process which took years by Sanger sequencing using hundreds instruments.

The step from Sanger sequencing to MPS has been something like a laboratory revolution, promising to change the entire diagnostic arena.

The power of incorporating this technology into research has been immediately evident in studies of rare, inherited diseases. Researchers have reported many findings of new genetic explanations for diseases that had until now been unexplained.

But incorporating this new technology into studies of complex human disease has been more challenging. For us, in the context of genetic research into the heritability of breast cancer, success has come via a robust combination of old and new.

The old components of our research are mature, well designed population-based case-control-family studies of breast cancer and studies involving families at high risk of developing breast cancer.

Our studies involve more than 10,000 women and their families, many of whom have been involved with our work for more than two decades, donating their time, information and blood specimens. These families are the foundation of our genetic research.

The new is not just massively parallel sequencing. It’s the entire system that needs to be in place to gain the new information:

  • we’ve developed new ways to prepare DNA for sequencing;
  • we’ve learnt how to use the instruments optimally; and (certainly not least)
  • we’ve had to develop new ways to interpret the enormous data files containing genetic information that are produced by the new instruments.


So what did we find?

Using whole-exome sequencing, we identified XRCC2 mutations in two families with multiple cases of breast cancer. We then undertook a series of parallel studies, in Melbourne and at the International Agency for Research on Cancer (France), and identified many more mutations in XRCC2 in DNA from blood samples of families participating in our research. These results demonstrated the link between XRCC2 mutations and susceptibility to breast cancer.

Our identification of XRCC2 as a breast cancer susceptibility gene shows the power of MPS when incorporated into well-designed studies of complex human disease.

But despite international efforts since the 1980s, the genetic explanation for the majority of breast cancer occurring in multiple-case families remains unknown.

Evidence suggests that no single gene is likely to account for a large proportion of the remaining unexplained genetic susceptibility to breast cancer – so the work must go on!

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