LUMC research helps better determine risk in hereditary breast cancer

LUMC researchers achieved a breakthrough in understanding PALB2 mutations, a major cause of hereditary breast cancer. By testing which mutations affect PALB2 protein function, doctors can now better assess which mutations increase breast cancer risk.

Hereditary breast cancer is caused by genetic defects passed from parent to child. The best-known genes are BRCA1 and BRCA2. Women with mutations in these genes have significantly increased risk of breast and ovarian cancer. Less known but equally important is the PALB2 gene, though it was unclear which PALB2 mutations increase cancer risk.

The importance of PALB2
Thousands of DNA breaks occur daily through normal cell processes. Fortunately, cells have repair mechanisms. PALB2 works with BRCA1 and BRCA2 to repair DNA breaks accurately. When PALB2 doesn’t work properly due to mutation, DNA breaks cannot be repaired accurately. Less precise repair mechanisms take over, allowing DNA errors to accumulate and potentially cause cancer.

Limited knowledge about PALB2 mutations
Professor Haico van Attikum explains: “A mutation is a DNA change. Mutations in genes can either stop proteins from being made or change their structure so they don’t function properly. Some mutations have no effect. For many PALB2 mutations, we didn’t know their effect or what they mean for breast cancer risk.” Associate Professor Maaike Vreeswijk adds: “This creates uncertainty for patients. You know you have a mutation but not what it means for your future.”

Creating and testing all possible mutations
To address this, Van Attikum and Vreeswijk launched a large-scale study. “We tested nearly all possible PALB2 gene mutations in the lab to determine which affect PALB2 function. We tested over 6,500 mutations,” Van Attikum explains. This testing created a comprehensive library showing exactly what each PALB2 mutation does. Their research shows: 58% of mutations don’t affect PALB2 protein production or function, 36% produce a suboptimal protein, and 6% produce a defective protein.

From lab to practice
Lab information alone wasn’t sufficient for accurate breast cancer risk assessment. Researchers compared their results with genetic data from large groups of women with and without breast cancer. LUMC had access to DNA data from over one million women. “These women’s DNA, including the PALB2 gene, was fully mapped in other studies,” Vreeswijk explains. “We identified which PALB2 mutations occurred in women with and without breast cancer, then linked those to our lab results. This confirmed that only mutations producing defective proteins increase breast cancer risk.” “PALB2 mutations are very rare,” Van Attikum concludes. “Our research and resulting library are important steps toward better determining PALB2 mutation risk. This information will be incorporated into international guidelines so doctors can give patients clear, reliable breast cancer risk assessments.”