A PALB2 mutation associated with high risk of breast cancer

Abstract

Ntroduction: 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.

Figure 1

Women diagnosed with breast cancer under age 40 years: The Australian Breast Cancer Family Registry. The majority of breast cancer patients diagnosed before the age of 40 years have no affected family members (zero affected; the "sporadic" breast cancer group), some probands have one affected family member (one affected), and ~8% have a stronger family history (the "familial" breast cancer group). A strong family history is defined as the case proband having two or more first- or second-degree relatives affected by breast or ovarian cancer. x represents the 22 partner and localizer of the breast cancer 2 early onset protein (BRCA2) mutation carriers identified by previous testing in the ABCFR [13,19]. The filled black stars represent the two probands found to carry PALB2 c.3113G > A who both have a very strong family history of breast cancer. Adapted from Hopper [42].

Figure 2

Pedigrees of the PALB2 c.3113G > A mutation-carrying families. Pedigrees of the PALB2 c.3113G > A mutation carrying families with (a) probands (indicated by arrows) and (b) families with probands diagnosed under the age of 40 years identified in the population-based study. (c) Family with probands diagnosed under the age of 50 years and (d) families diagnosed under the age of 60 years. Breast cancer is indicated by black filled symbols, and other cancers are indicated by gray filled symbols. All primary cancer diagnoses are indicated for each individual. Numbers within symbols represent multiple individuals. Breast, breast cancer; V, cancer verified; +, PALB2 c.3113G > A-positive; -, PALB2 c.3113G > A-negative; (+), obligate carrier;/, deceased.

Figure 3

Age-specific cumulative risks for PALB2 c.3113G > A mutation carriers. Age-specific cumulative risks of breast cancer for women carrying the PALB2 c.3113G > A mutation (unbroken lines) and for women in the general Australian population (dotted line).

Figure 4

The Kaplan-Meier survival curves for PALB2 c.3113G > A mutation carriers. The Kaplan-Meier survival curve with breast cancer as the outcome for female first- and second-degree relatives of the probands with the fitted survival curve overlaid. The fitted survival curve was calculated as the average of the survival curves for carriers and noncarriers, each of these being equal to the exponential minus the appropriate cumulative incidences. For the averaging of survival curves, we used age-specific weights equal to the expected proportion of relatives at risk of breast cancer at a given age who carry (for the carrier survival curve) or do not carry (for the noncarrier survival curve) the partner and localizer of breast cancer 2 susceptibility protein (PALB2) mutation. Carrier probabilities for the relatives were calculated from known genotypes and family relationships, but not from affected status or other phenotypes, using a modified version of Mendel 3.2 software [28].