Researchers at Leiden University Medical Center (LUMC) have made a breakthrough in understanding PALB2 gene mutations, a critical but lesser-known contributor to hereditary breast cancer. By pinpointing which mutations impair PALB2 function, doctors can now more accurately determine which genetic changes increase a woman’s risk of developing breast cancer.
While BRCA1 and BRCA2 mutations are widely recognized for their strong link to breast and ovarian cancer, PALB2 mutations have remained less understood. Certain alterations in PALB2 can similarly elevate breast cancer risk, but until now, it was unclear which specific mutations were dangerous. The findings were published in Nature Communications.
The Role of PALB2 in DNA Repair
Every day, thousands of breaks occur in human DNA as part of normal cellular processes. PALB2 plays a key role in repairing these breaks by working closely with BRCA1 and BRCA2 to ensure DNA is accurately restored. When PALB2 is compromised by a mutation, this repair process falters, allowing errors to accumulate in DNA over time and increasing the likelihood of cancer development.
“Mutations in a gene can either prevent a protein from being produced, alter its function, or have no effect at all,” explained Professor Haico van Attikum, a human genetics expert at LUMC. “For many PALB2 mutations, their effect on protein function and associated breast cancer risk was previously unknown.”
Associate Professor Maaike Vreeswijk added, “Patients carrying PALB2 mutations often face uncertainty. You know there’s a mutation, but you don’t know what it means for your breast cancer risk.”
Testing Thousands of Mutations
To fill this knowledge gap, the LUMC team conducted an unprecedented study, analyzing more than 6,500 potential PALB2 mutations in the laboratory. Their goal: to determine which mutations disrupt PALB2 function.
The results revealed that 58% of mutations had no effect, 36% produced proteins with reduced functionality, and 6% resulted in defective proteins. This large-scale analysis allowed researchers to create a comprehensive library mapping the functional impact of nearly all possible PALB2 mutations.
Translating Laboratory Findings into Clinical Insight
Laboratory data alone were insufficient to assess cancer risk. Researchers compared their findings with genetic data from more than one million women, examining which PALB2 mutations appeared in patients with and without breast cancer. By linking these clinical data to their mutation library, the team demonstrated that only mutations producing defective PALB2 proteins significantly increase breast cancer risk.
“PALB2 mutations are rare, but understanding which ones are harmful is a major step forward,” said van Attikum. “Our findings will be incorporated into international guidelines, helping doctors provide patients with precise and reliable risk assessments.”
This landmark study promises to reduce uncertainty for women carrying PALB2 mutations and offers a crucial tool for personalized breast cancer prevention and care.
