Women harboring a loss-of-function mutation in the PALB2 gene demonstrated an increased risk of developing breast cancer that was similar to the predisposition seen with mutations in BRCA.
Marc Tischkowitz, MD, PhD
Women harboring a loss-of-function mutation in thePALB2gene demonstrated an increased risk of developing breast cancer that was similar to the predisposition seen with mutations inBRCA, according to a study published inThe New England Journal of Medicine (NEJM).
The estimated cumulative risk of breast cancer for femalePALB2mutation carriers was 14% by age 50 and 35% by 70, representing a significant increase over the general population. The relative risk associated withPALB2mutations was 8 to 9 in individuals below age 40, 6 to 8 for those between 40 and 60, and approximately 5 for those 60 and older. In general, the risk of developing breast cancer by age 70 for women with a mutation inBRCA1orBRCA2is approximately 60% and 45%, according to the National Cancer Institute.
"Since theBRCA1andBRCA2mutations were discovered in the mid-90s, no other genes of similar importance have been found.PALB2is a potential candidate to beBRCA3," lead study author Marc Tischkowitz, MD, PhD, a researcher in the department of medical genetics at the University of Cambridge, said in a statement. “Now that we have identified this gene, we are in a position to provide genetic counseling and advice. If a woman is found to carry this mutation, we would recommend additional surveillance, such as MRI breast screening.”
ThePALB2gene codes the PALB2 protein that interacts with BRCA2 allowing it to connect with BRCA1, forming the BRCA complex. MonoallelicPALB2gene mutations disrupt DNA repair pathways, by inhibiting the homologous recombination process. Past studies have linkedPALB2mutations with a higher risk of developing breast and pancreatic cancer; however, the exact risk had not been quantified prior to this study.
In the analysis, 154 families with a least one member who had breast cancer and a germlinePALB2mutation were analyzed. These families included 311 women (229 with breast cancer) and 51 men (7 with breast cancer) withPALB2mutations. Altogether, 48 different loss-of-function mutations were detected in thePALB2gene, which is located on chromosome 16p12.2 and contains 13 exons.
The level of risk varied based on family history for femalePALB2mutation carriers. For women with a mother who developed breast cancer at 35 or younger, the risk at age 50 was 23% and was 52% at 70. The highest risk was seen in women with both a mother and sister diagnosed with breast cancer by agent 50. For these patients, the risk of developing breast cancer was 27% and 58% at age 50 and 70, respectively. For those without a family history of breast cancer, the estimated risk of developing breast cancer at age 50 was 14% and reached 35% by age 70.
Traditionally,BRCA1/2mutations have also been connected with an increased risk of ovarian cancer. At age 70, the risk forBRCA1mutation carriers is 39% and 11-17% withBRCA2. In theNEJMstudy, the risk of developing ovarian cancer was increased by a factor of 2.31 in thePALB2carriers (95% CI, 0.77-6.97;P= .18). However, this finding was not deemed statistically significant. The authors noted that a larger study will be needed to determine whetherPALB2mutations increases a women's risk of developing ovarian cancer.
"On the basis of our estimates, the breast cancer risk for aPALB2mutation carrier, even in the absence of a family history of breast cancer, would be classified as high according to various guidelines," the authors of the study wrote. "This level of risk may justify addingPALB2to genetic testing forBRCA1andBRCA2."
Based on these promising results and those demonstrated in previous trials, a number of studies are exploringPALB2in patients with cancer. One study is looking at the incidence ofBRCA1/2, PALB2, andPTENmutations in patients with triple-negative breast cancer. Additionally, a phase II study is exploring treatment with gemcitabine and cisplatin with or without the PARP inhibitor veliparib in patients with pancreas adenocarcinoma harboring aBRCAorPALB2mutation.
"Loss of heterozygosity at thePALB2locus is likely to result in increased sensitivity to cell death with PARP inhibition, given that synthetic lethality is seen with other proteins that are involved in homologous recombination," Michele K. Evans, MD, and Dan L. Longo, MD, wrote in an editorial published along with the research article inNEJM.