The collaboration, called the international PALB2 Interest Group, have been investigating the impact of a faulty PALB2 gene on breast cancer risk. Their study, published in the New England Journal of Medicine, showed that women who carried rare mutations to the PALB2 gene were found to be more at risk of breast cancer than the general population. Importantly, the level of risk associated with these mutations was influenced by a woman’s family history of breast cancer.

What is PALB2 and what are rare mutations?

PALB2 is a gene which produces a protein involved in the repair of damaged DNA. Mutations to this gene can cause the repair mechanism to be disrupted and lead to ‘genomic instability’. Ultimately, this means that DNA is more likely to pick up cancer-causing mutations. 

This is the same principle which causes women with a faulty BRCA gene to be more at risk of developing breast cancer. Mutations to PALB2 are rare and studies usually show that they’re found in only 0.4-3.4% of breast cancer cases. However, as this and other studies have shown, these rare mutations are associated with a hefty increase in breast cancer risk.

What did this study find?

Analysis of breast cancer rates amongst women carrying a faulty PALB2 gene revealed that their risk of breast cancer increased to an average of 35% (risk in the general population is about 12%). Importantly, women were more likely to develop breast cancer at a younger age if they carried a faulty PALB2 gene.

One extremely interesting finding from this study was the gene’s relationship with a person’s family history of breast cancer. Breast cancer risk for mutation carriers with no family history of breast cancer was approximately 33%, while for carriers who had a sister and a mother diagnosed with breast cancer by age 50, the risk increased to 58%.

What does it all mean?

The authors of the paper state that the increased risk of breast cancer caused by the faulty PALB2 gene, even in the absence of a family history of breast cancer, may be enough to justify adding PALB2 to genetic testing for BRCA1 and BRCA2.  Genetic screening for a faulty PALB2 gene could be useful to help identify at-risk women, who could then be offered preventative interventions such as increased screening or risk-reducing drugs.

The arm of the research group based at Cambridge have developed a clinical test for PALB2 which they say will become part of the NHS service at Addenbrookes Hospital. We don’t yet know whether this test will be made available at other hospitals, but it’s clear that the more we know about the causes of breast cancer, the more accurately we can predict risk.

A touch of deja vu?

The interesting thing about the PALB2 gene mutation is that it all sounds so familiar to what we know about BRCA. It’s related to family history, it’s a rare mutation with a big effect and the gene’s normal function is to repair damage to DNA. The latter has led to experiments to test the effect of PARP inhibitors on breast cancer cells carrying a faulty PALB2 gene, with positive results. We will watch closely as this story unfolds…

Dr Matthew Lam is Breakthrough Breast Cancer’s Senior Research Officer