PUBLISHED ON: 30 April 2015

This blog is the sixth in a series exploring the achievements of Breast Cancer Campaign and Breakthrough Breast Cancer as both charities work towards launching as one brand new charity.  The last post looked at the work we have done to change the policy on genetic tests for breast cancer. This blog looks at the research we contributed to the discovery of PALB2 as a breast cancer gene.

If asked to name a gene associated with breast cancer, most people would probably say either BRCA1 or BRCA2. And understandably so, as BRCA genes have become synonymous with the genetics of breast cancer due to celebrities such as Angelina Jolie, Michelle Heaton and Kelly Osbourne.  And there was even a storyline in BBC One’s EastEnders about them.

However, research into breast cancer genetics extends way beyond BRCA, and scientists are learning more and more about how different genes influence a person’s risk of breast cancer.  What’s more, research is uncovering new breast cancer genes, one of which forms the foundation of this blog: PALB2.

We’ll talk a little more about PALB2 soon, but first, here’s a brief history of the search for genes that increase risk of breast cancer; so-called breast cancer genes. 

The hunt for breast cancer genes

Doctors and researchers have known for a long time that some families had many members who have been diagnosed with breast cancer. Because a person’s genes are inherited from their mother and father, they guessed there were probably genetic faults being passed down the generations which were increasing the risk of breast cancer in these families. The task at hand for scientists was to pinpoint what these faults were.

The discovery of BRCA1 in 1994, and then BRCA2 in 1995, were major milestones in our understanding of how breast cancer develops.  Specific faults that occur in these genes were subsequently shown to increase a person’s risk of breast cancer.  During the search for the BRCA genes it became apparent that there were not just one or two breast cancer genes, but many different genetic faults and variations, all affecting risk by different amounts.

PALB2 is another breast cancer gene and scientists funded by Breast Cancer Campaign helped link it to breast cancer risk.

The new kid on the block

A research team led by Professor Nazneen Rahman, and partly funded by Breast Cancer Campaign, studied the genes of 923 individuals with breast cancer who had a family history of the disease, and more than 1,000 people without breast cancer. In 2006, the team announced to the world that they had found faults in a gene called PALB2, which seemed to double a person’s risk of breast cancer.  In short, PALB2 could also be added to the list of breast cancer susceptibility genes, alongside BRCA1, BRCA2 and others.

But as is so often the case in research, that was not the end of the PALB2 story. In 2014, researchers from the University of Cambridge published results of their own study into PALB2 and the genetics of familial breast cancer. They showed that the risk associated with PALB2 faults was much higher than previously thought – in fact, it was found that the chances of a woman with a PALB2 mutation getting breast cancer by the age of 80 are about 44%, or nearly one in two, on average. For women with no family history of breast cancer this figure was slightly lower at 41%, whereas for women with a mother and sister who’ve both had breast cancer by the age of 50, their own lifetime risk was shown to be around 67%, or two in three.

At the moment, people who have a significant family history of breast or other cancers in their family can be tested for faults in BRCA1, BRCA2 or another gene called TP53. The researchers involved in this most recent study now believe these people should also be tested  for mutations in PALB2, given the significant contribution these faults can make to a person’s risk of breast cancer.

Another breast cancer gene – so what?

Gathering information about how faults in PALB2 and other genes increase breast cancer risk is more than just genetic ‘stamp collecting’ – this knowledge is vital for at least three other reasons too.

The first and most direct benefit of this kind of information is to help people understand their personal risk of breast cancer. Previously, people with a family history of the disease might have only a vague idea of their own chances of developing breast cancer. But now, geneticists are able to give a person a more precise assessment of their risk, which could help guide decisions they might make to reduce their chances of developing the disease – such as extra screening, lifestyle changes, risk-reducing drugs, or even surgery.

One major programme of work which is already making great contributions in this area is the Generations Study, which aims to find new genetic markers that influence risk, and understand how these and non-genetic factors (such as lifestyle factors or age) combine to give an overall risk of breast cancer for one individual. 

Secondly, if a person with a genetic fault happens to develop breast cancer, their genetic information could help their doctors pick the most appropriate treatment.  For example, a new class of drugs called PARP inhibitors are particularly effective against tumours which carry faults in either of the BRCA genes and it’s possible that breast tumours in people with PALB2 mutations could also be more susceptible to these drugs.  

Thirdly, by identifying which faulty genes affect risk of breast cancer, researchers can then start to answer exactly why these mutations increase risk, i.e. what is happening in the cells of someone who has a genetic variation that doesn’t happen in someone who doesn’t? This knowledge of breast cancer biology could lead to new ways to reduce a person’s risk, or new treatments for people with breast cancer. For example, Dr Rachael Natrajan, one of our Scientific Fellows and group lead at the London Research Centre, is trying to find new genetic faults in breast tumours and understand how these weaknesses could be used to develop new treatments.

The future

Genetics might seem a dry subject to some but it’s at the core of breast cancer research. In the future, genetics will help accurately predict a person’s chances of developing breast cancer, guide treatment decisions and help develop the next generation of breast cancer treatments. Our scientists have already made great contributions to the field, such as helping to identify new breast cancer susceptibility genes like PALB2, and we will continue to build upon this work to ultimately save lives.