Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women

Abstract

Background: PALB2 has recently been identified as a breast cancer susceptibility gene. PALB2 mutations are rare causes of hereditary breast cancer but may be important in countries such as Finland where a founder mutation is present. We sought to estimate the contribution of PALB2 mutations to the burden of breast cancer in French Canadians from Quebec.

Methods: We screened all coding exons of PALB2 in a sample of 50 French-Canadian women diagnosed with either early-onset breast cancer or familial breast cancer at a single Montreal hospital. The genetic variants identified in this sample were then studied in 356 additional women with breast cancer diagnosed before age 50 and in 6,448 newborn controls.

Results: We identified a single protein-truncating mutation in PALB2 (c.2323 C>T, resulting in Q775X) in 1 of the 50 high-risk women. This variant was present in 2 of 356 breast cancer cases and in none of 6,440 newborn French-Canadian controls (P = 0.003). We also identified two novel new non-synonymous single nucleotide polymorphisms in exon 4 of PALB2 (c.5038 A>G [I76V] and c.5156 G>T [G115V]). G115V was found in 1 of 356 cases and in 15 of 6,442 controls (P = 0.6). The I76V variant was not identified in either the extended case series or the controls.

Conclusion: We have identified a novel truncating mutation in PALB2. The mutation was found in approximately 0.5% of unselected French-Canadian women with early-onset breast cancer and appears to have a single origin. Although mutations are infrequent, PALB2 can be added to the list of breast cancer susceptibility genes for which founder mutations have been identified in the French-Canadian population.

Figure 1

Pedigree of the P28031 family, whose index case carried a Q775X mutation. The proband was diagnosed with breast cancer at age 54. She has female relatives on both sides of the family who have been diagnosed with breast cancer (n = 2 on paternal side, n = 4 on maternal side), and the mutation was shown to segregate on the maternal side, with a 46-year-old affected cousin also found to be a carrier. Remarkably, there appear to be five relatives, including her mother, who have been diagnosed with colorectal cancer. Plus sign indicates Q775X mutation carrier. PSU, primary site unknown.

Figure 2

Pedigree of the P31030 family, whose index case carried a Q775X mutation. The proband was diagnosed with breast cancer at age 49. She reports two relatives diagnosed with breast cancer on her mother's side. She reports that her mother was diagnosed with colorectal cancer at age 32. Plus sign indicates Q775X mutation carrier. PSU, primary site unknown.

Figure 3

Pedigree of the P26007 family, whose index case carried a Q775X mutation. The proband was diagnosed with breast cancer at age 36. She does not report any breast tumors on her father's side of the family, but her mother (who was also found to carry the mutation) was diagnosed with breast cancer at age 62. There are also cases of leukemia, colon cancer, and thyroid cancer reported on this side of the family. Plus sign indicates Q775X mutation carrier.