Research improves risk assessment for hereditary breast cancer
Researchers at LUMC have made a breakthrough in understanding PALB2 mutations, an important cause of hereditary breast cancer. By identifying which mutations affect the function of PALB2, doctors can now assess much more accurately which mutations are linked to an increased risk of breast cancer.
Hereditary breast cancer is caused by a genetic mutation that is inherited from a parent. The best‑known breast cancer genes are BRCA1 and BRCA2. Women with a mutation in one of these genes have a much higher risk of developing breast cancer and ovarian cancer. Less well known, but equally important, is the PALB2 gene. Certain mutations in PALB2 can also greatly increase the risk of breast cancer, but until now it was unclear which mutations confer this increased risk.
Publication in Nature Communications
The study was recently published in the scientific journal Nature Communications. This research was funded by the Dutch Cancer Society, project 12754.
Why is PALB2 important?
Every day, thousands of breaks occur in our DNA as part of normal processes in the cell. Fortunately, cells have several repair systems to fix this damage. PALB2 works closely with BRCA1 and BRCA2 to repair DNA breaks accurately. When PALB2 does not function properly because of a mutation, this cooperation is disrupted and DNA damage can no longer be repaired flawlessly. Other repair systems step in, but these are less precise. As a result, errors can build up in the DNA over time and may eventually lead to cancer.
Limited knowledge about PALB2 mutations
Haico van Attikum, Professor Human Genetics, with a focus on chromatin and DNA repair, explains what a mutation is: ‘A mutation is a change in the DNA. A gene is a specific segment of DNA that encodes a protein. A mutation in a gene can prevent a protein from being made, or it can change the protein slightly so that it works less effectively. There are also mutations that have no effect at all. For many PALB2 mutations, their impact on PALB2’s function, and their association with breast cancer risk, remained uncertain.’
Associate professor Maaike Vreeswijk adds: ‘This can cause a lot of uncertainty and anxiety for patients. You know you carry a mutation, but not what it means for your breast cancer risk.’
Creating and testing all possible mutations
To address this knowledge gap, van Attikum and Vreeswijk launched a large‑scale study. Van Attikum explains: ‘In the laboratory, we tested almost all possible mutations in the PALB2 gene to find out which ones affect PALB2’s function. In total, we analysed more than 6,500 PALB2 mutations.’ By testing mutations on this scale, the researchers were able to build a comprehensive library showing exactly how each mutation in the PALB2 gene affects protein function.
Their research shows that 58 percent of mutations have no effect on the production or function of the PALB2 protein, 36 percent result in a protein that works less effectively and 6 percent lead to a defective protein.
From lab to clinical practice
The laboratory data alone were not enough to accurately assess breast cancer risk. Therefore, the researchers compared their laboratory findings with genetic data from large groups of women with and without breast cancer. They had access to DNA data from more than one million women.
Vreeswijk explains: ‘The DNA of these women, including the PALB2 gene, had already been fully sequenced in other studies. We examined which PALB2 mutations occurred in women with and without breast cancer and then linked these mutations to our laboratory results library. This allowed us to show that only mutations that lead to a defective protein increase the risk of breast cancer.’
Van Attikum concludes: ‘PALB2 mutations are very rare. Our study and the library that emerged from it, represent an important step towards better defining the risk associated with a PALB2 mutation. This information will be included in international guidelines, enabling doctors to provide their patients with a clear and reliable assessment of breast cancer risk.’