The PALB2 gene and its links to breast cancer

20 Aug 2021

When it comes to discussing a hereditary predisposition for breast cancer, usually the genes BRCA1 and BRACA2 are the ones that take centre stage. And for good reason. Research suggests that women carrying a mutation in either gene have a 7 in 10 chance of developing breast cancer by age 80. But there is another gene that scientists are studying for its relation to breast cancer predisposition: the PALB2 gene.

Genes and proteins
Discovered relatively recently (in scientific terms) to have an association with breast cancer, the PALB2 gene was already known to the scientific community when a study linked it to breast cancer risk.

“The PALB2 breast cancer link was discovered in a study that was looking at so-called ‘candidate genes’ for breast cancer risk,” explains Professor Melissa Southey, Chair of Precision Medicine, School of Clinical Sciences at Monash Health. “And it was considered a candidate because it operated in the same biological pathway as BRCA1 and BRCA2.”

Indeed, PALB2 means 'Partner and Localizer of the BRCA2 gene'.

The PALB2 gene makes a protein that actually binds to the BRCA1 and BRCA2 proteins. These proteins interact with each other in a process that repairs damaged DNA. If there is a DNA error made in a cell, they are in the machinery that tries to fix it. If you have a fault in one of those genes, and therefore a fault in one of these proteins, your body won’t be as good at repairing DNA errors. This, she says, puts you at risk of cancer development.

Risk assessment
However, up until recently, there hadn’t been enough data to fully understand what cancer risks were associated with carrying a mutation in the PALB2 gene. But over the past decade, Professor Southey has been a key member of a ground-breaking, international study called the PALB2 Interest Group, which has been looking into the effects of the PALB2 gene mutations on the people who carry them and their families.

The study, which launched in 2009, began with five families who shared their data with the research team. Since then, and with the help of over 600 families and more research, the group has been able to increase the precision around estimates of risk across age groups to help inform women about their risk and make decisions about risk management that are based on evidence.

This research has also been used to create standardised risk management strategies for PALB2 mutation carriers in Australia and overseas.

“We've worked really hard to collect the data to be able to publish guidelines for the management of PALB2 mutation carriers,” Professor Southey says. “Now families around this nation are given the same advice based on real information about what their risks are and what the best risk management strategies are.”

A rare mutation
However, Professor Southey points out that mutations in the PALB2 gene are much rarer than mutations in either the BRCA1 or BRCA2 genes.

“There are less people in our communities that carry mutations in the PALB2 gene,” she explains. “It's about 1% of people that have a really strong family history of breast cancer, and most women who already know they carry a BRCA1 or BRCA2 gene mutation don't carry a PALB2 mutation as well.”

So, what are the risks? Well, the data collected by the PALB2 Interest Group shows that women carrying a PALB2 gene mutation have about a 17% chance of developing breast cancer and about a 1% chance of developing ovarian cancer before age 50, and a 53% and 5% chance by age 80.

To put that data into perspective, around 12% of women in the general population develop breast cancer over their lives and 2% develop ovarian cancer.

Risk management
But Professor Southey says if you do carry a PALB2 mutation, try to seek out expert advice and not focus too much on the terminology and numbers.

“The best thing you can do if you are a PALB2 mutation carrier is to access current up-to-date information and speak to a professional about risk management,” she says. “We're actually really fortunate in this country that we have access to both of those things at no cost.”

And, she adds, if you would like to be part of online studies and initiatives, including the PALB2 interest group, to speak to your doctor or visit their website.

“We are really interested in following women with PALB2 mutations and their families, and understanding their personal and their medical experiences,” she explains, “because we will only know this information with certainty if women and their families are generous enough to give us their time and share their information. Each participant in our research studies is important to helping us understand the true consequences of carrying a PALB2 gene mutation.”

And while PALB2 gene research might only be relevant to a small percentage of the population, Professor Southey points out this new information about PALB2 is important for all women who have a significant family history of breast cancer, who have not yet been able to identify a genetic reason for it. These women now have another gene to look at that perhaps could explain their breast cancer susceptibility.