Study Quantifies Risk of Hereditary Breast Cancer in Carriers of PALB2 Mutations

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Antonis C. Antoniou, PhD

Loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them.

—Antonis C. Antoniou, PhD, and colleagues

In a study reported in The New England Journal of Medicine, Antonis C. Antoniou, PhD, Reader in Cancer Risk Prediction and Cancer Research UK Senior Cancer Research Fellow at the University of Cambridge, and colleagues identified lifetime risk of breast cancer in families with germline loss-of-function mutations in PALB2.1 Estimated cumulative risk among female mutation carriers was 14% by 50 years of age and 35% by 70 years of age. Compared with risk in the general UK population, risk was increased eight- to ninefold in mutation carriers aged < 40 years, six- to eightfold in those aged 40 to 60 years, and fivefold in those aged > 60 years.

PALB2 (partner and localizer of BRCA2) was first identified as a protein integral to BRCA2 genome caretaker functions and was also found to interact with BRCA1. Monoallelic loss-of-function mutations have been associated with increased risks of breast and pancreatic cancers. These loss-of-function mutations have been identified in persons from many countries and have been found in 0.6% to 3.9% of families with a history of breast cancer.

Study Details

The study involved analysis of risk of breast cancer among 362 members of 154 families with truncating, splice, or deletion mutations in PALB2. Age-specific risk was estimated using a modified segregation analysis that accounted for effects of PALB2 genotype and residual familial aggregation.

Cumulative and Age-Related Risk

The estimated cumulative risk of breast cancer among female mutation carriers was 14% (95% confidence interval [CI] = 9%–20%) by 50 years of age and 35% (95% CI = 26%–46%) by 70 years of age.

Mean annual breast cancer incidence in mutation carriers and relative risk of breast cancer compared with the general population by age group were 0.01% and 9.01 for 20 to 24 years of age, 0.07% and 8.97 for 25 to 29 years, 0.23% and 8.85 for 30 to 34 years, 0.50% and 8.54 for 35 to 39 years , 0.85% and 8.02 for 40 to 44 years, 1.27% and 7.31 for 45 to 49 years, 1.60% and 6.55 for 50 to 54 years, 1.45% and 5.92 for 55 to 59 years, 1.47% and 5.45 for 60 to 64 years, 1.19% and 5.10 for 65 to 69 years, 1.34% and 4.82 for 70 to 74 years, and 1.34% and 4.56 for 75 to 79 years.

Effects of Birth Cohort and Family History

As has been observed among carriers of loss-of-function mutations in BRCA1 and BRCA2, there is an increase in risk PALB2 mutation carriers in later birth cohorts. Compared with risk in those born before 1940, relative risk was 2.84 (95% CI = 1.64–4.93) in those born between 1940 and 1959 and 6.29 (95% CI = 2.81–14.10) in those born in 1960 or later (P < .001).

Risk was also increased by family history of breast cancer, with absolute risk by age 70 years among mutation carriers ranging from 33% (95% CI = 25%–44%) in those with no family history of breast cancer to 58% (95% CI = 50%–66%) in those with two or more first-degree relatives with breast cancer by age 50 years.

Receptor Status

Among 129 affected PALB2 mutation carriers with known estrogen receptor status, 95 (74%) had estrogen receptor–positive tumors, a rate similar to that in patients with BRCA2 mutations and those with sporadic breast cancer. Among 63 affected patients with known progesterone receptor and HER2 status, 19 (30%) had triple-negative disease, a rate higher than the 12% to 17% prevalence found in unselected populations of breast cancer patients.

Other Associations?

The investigators noted that they also found a nonsignificant 2.3-fold increased risk of ovarian cancer in PALB2 mutation carriers and that larger studies would be required to adequately address the potential association. Risk of male breast cancer was increased by approximately eightfold in mutation carriers, although the confidence interval for the estimate was very large. PALB2 mutations have also been associated with increased risk of pancreatic cancer, but lifetime risks have yet to be assessed.

The investigators concluded, “Loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them. Our data suggest the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers.”

They noted:

Our study includes most of the reported families with PALB2 mutation carriers, as well as many not previously reported, but it is still based on small numbers. Because of the widespread availability of multigene panels and whole-exome sequencing, screening for inherited loss-of-function mutations in PALB2 has begun to enter clinical practice. As families with PALB2 mutations are identified, it will be valuable to collect family history and other data for future analysis, in order to refine estimates of the cancer risks for PALB2 mutation carriers. ■

Disclosure: The study was funded by the European Research Council and many others. For full disclosures of the study authors, visit


1. Antoniou AC, Casadei S, Heikkinen T, et al: Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371:497-506, 2014.

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