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PALB2 Mutations Confer Increased Risk of Developing Breast Cancer

NEW YORK (GenomeWeb) – People with loss-of-function mutations in PALB2 have an increased risk of developing breast cancer, an international team of researchers reported in the New England Journal of Medicine yesterday.

On average, a person with a PALB2 mutation has a one in three chance of developing breast cancer by the age of 70, according to the consortium led by the University of Cambridge's Marc Tischkowitz. The team analyzed breast cancer risk in 362 members of 154 families with deleterious deletion, truncating, or splice mutations in the gene.

"Now that we have identified this gene, we are in a position to provide genetic counseling and advice," Tischkowitz said in a statement. "If a woman is found to carry this mutation, we would recommend additional surveillance, such as MRI breast screening."

PALB2 interacts with both BRCA1 and BRCA2, and was itself linked to breast cancer in 2007. PALB2 is also known as FANCN, the researchers noted, and biallelic germline mutations in it cause Fanconi's anemia, which is linked to an increased risk of pancreatic and breast cancer.

"Since the BRCA1 and BRCA2 mutations were discovered in the mid-90s, no other genes of similar importance have been found and the consensus in the scientific community [is] if more exist we would have found them by now," Tischkowitz added. "PALB2 is a potential candidate to be 'BRCA3.'"

Clinical testing for disease risk using approaches like next-generation sequencing and multi-gene panels relies, the researchers said, on knowing what sort of risk particular gene variants confer.

For this study, Tischkowitz and his colleague identified 154 families in which at least one family member had breast cancer, but who tested negative for BRCA1 and BRCA2 mutations while having a loss-of-function mutation in PALB2. These families included 311 women with PALB2 mutations, of whom 229 had breast cancer, and 51 men with PALB2 mutations, of whom seven had breast cancer. In total, the researchers identified 48 different loss-of-function PALB2 mutations in these families.

PALB2 mutation carriers have a more than nine-fold increase in risk of developing breast cancer, as compared to the general UK population, the researchers calculated. Likewise, they determined that the cumulative risk of breast cancer in female carriers by 70 years of age was 35 percent, though the absolute risk varied between 33 percent and 58 percent based on whether the carrier had other relatives with breast cancer.

Tischkowitz and his colleagues used two different statistical models to examine genetic susceptibility in these families. Models that took residual familial aggregation of breast cancer in addition to PALB2 mutation fit better to the data, and the best-fit model, they reported, assumed a risk that stayed constant with age or that varied slightly over decades. For instance, they noted that the mean relative risk for a female PALB2 mutation carrier decreased from about nine for 20 year olds to 24 year olds to 4.6 for 75 year olds to 79 year olds.

Additionally, the researchers noted that not all of the risk in the families was accounted for by the PALB2 mutation. It seems, they reported, that other genetic or environmental factors might modify breast cancer risk in PALB2 mutation carriers.

They also found a difference in risk based on when the carrier was born, with carriers that belong to more recent birth cohorts having a slightly higher relative risk of breast cancer than their older counterparts. This difference, the researchers said, could be in part due to changes in disease surveillance tactics.

Tischkowitz and his colleagues argued that under guidelines, such as those from the American Cancer Society and the National Institute for Health and Care Excellence, the breast cancer risk for a PALB2 mutation carrier would be classified as high and would justify the gene's inclusion in genetic testing alongside BRCA1 and BCRA2.

Addenbrooke's Hospital researchers, the University of Cambridge said, have developed such a clinical test for PALB2 that is to be incorporated into their National Health Service testing.

PARP inhibitors, which are currently being tested for treating BRCA1 and BRCA2-related breast cancers, may be an effective therapy for PALB2-related breast cancers as well, given PALB2's related activity to those genes in DNA repair, added Michele Evans and Dan Longo from the US National Institute of Aging in a related NEJM editorial.

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