A PALB2 Mutation Associated with High Risk of Breast Cancer

In In The News by Barbara Jacoby

Thumbnail for 7985From: medscape.com


Introduction: As a group, women who carry germline mutations in partner and localizer of breast cancer 2 susceptibility protein (PALB2) are at increased risk of breast cancer. Little is known about by how much or whether risk differs by mutation or family history, owing to the paucity of studies of cases unselected for family history.

Methods: We screened 1,403 case probands for PALB2 mutations in a population-based study of Australian women with invasive breast cancer stratified by age at onset. The age-specific risk of breast cancer was estimated from the cancer histories of first- and second-degree relatives of mutation-carrying probands using a modified segregation analysis that included a polygenic modifier and was conditioned on the carrier case proband. Further screening for PALB2 c.3113G > A (W1038X) was conducted for 779 families with multiple cases of breast cancer ascertained through family cancer clinics in Australia and New Zealand and 764 population-based controls.

Results: We found five independent case probands in the population-based sample with the protein-truncating mutation PALB2 c.3113G > A (W1038X); 2 of 695 were diagnosed before age 40 years and 3 of 708 were diagnosed when between ages 40 and 59 years. Both of the two early-onset carrier case probands had very strong family histories of breast cancer. Further testing found that the mutation segregated with breast cancer in these families. No c.3113G > A (W1038X) carriers were found in 764 population-based unaffected controls. The hazard ratio was estimated to be 30.1 (95% confidence interval (CI), 7.5 to 120; P < 0.0001), and the corresponding cumulative risk estimates were 49% (95% CI, 15 to 93) to age 50 and 91% (95% CI, 44 to 100) to age 70. We found another eight families carrying this mutation in 779 families with multiple cases of breast cancer ascertained through family cancer clinics.

Conclusions: The PALB2 c.3113G > A mutation appears to be associated with substantial risks of breast cancer that are of clinical relevance.


An increasing number of so-called moderate-risk[1] breast cancer susceptibility genes have been identified. Protein-truncating mutations in ataxia telangiectasia mutated (ATM), breast cancer type 1 susceptibility protein (BRCA1)-interacting protein 1 (BRIP1) and partner and localizer of the breast cancer 2 early onset protein (BRCA2) (PALB2), as well as CHK2 checkpoint homolog (CHEK2), have been observed to be nearly 10 times more likely in patients with strong breast cancer family histories than in unaffected controls.[2–4] The implications of these observations are not straightforward, so it is difficult to use the cancer histories of these families to make informative estimates of risk (penetrance) when the reason for studying them in the first place is their family cancer history.[2–5] Inference is more informative when based on testing families unselected for family history, but there is a paucity of such data for these genes.

Predicated on the assumption that the increased risk associated with a mutation multiplies a woman’s underlying familial genetic risk, for these genes it has been estimated that rare protein-truncating mutations are associated with, on average, two- to threefold increases in risk.[1–4] Therefore, this increased risk must be interpreted by taking into account a carrier’s family history. Consequently, for a given gene, the absolute risk is not the same for all carriers of such mutations.[5]

It is also possible that the increased risk is not the same for all mutations. Some mutations in moderate-risk genes are high risk. For example, population-based studies have shown that the 7217T > G variant in ATM is associated with a substantially increased risk comparable to that for mutations in BRCA1 and BRCA2,[6] as has a subset of rare substitutions in ATM.[7] Another example is the Finnish founder PALB2 mutation; on the basis of studying cases unselected for family history, it has been estimated to be associated with a sixfold increased risk and a cumulative breast cancer risk of 40% by age 70 years.[8]

We tested Australian women affected and unaffected by breast cancer and selected and unselected for family history for PALB2 mutations to estimate the prevalence and penetrance of these mutations in the Australian population.