No more than Ϸ30% of hereditary breast cancer has been accounted for by mutations in known genes. Most of these genes, such as BRCA1, BRCA2, TP53, CHEK2, ATM, and FANCJ/BRIP1, function in DNA repair, raising the possibility that germ line mutations in other genes that contribute to this process also predispose to breast cancer. Given its close relationship with BRCA2, PALB2 was sequenced in affected probands from 68 BRCA1/BRCA2-negative breast cancer families of Ashkenazi Jewish, French Canadian, or mixed ethnic descent. The average BRCAPRO score was 0.58. A truncating mutation (229delT) was identified in one family with a strong history of breast cancer (seven breast cancers in three female mutation carriers). This mutation and its associated breast cancers were characterized with another recently reported but unstudied mutation (2521delA) that is also associated with a strong family history of breast cancer. There was no loss of heterozygosity in tumors with either mutation. Moreover, comparative genomic hybridization analysis showed major similarities to that of BRCA2 tumors but with some notable differences, especially loss of 18q, a change that was previously unknown in BRCA2 tumors and less common in sporadic breast cancer. This study supports recent observations that PALB2 mutations are present, albeit not frequently, in breast cancer families. The apparently high penetrance noted in this study suggests that at least some PALB2 mutations are associated with a substantially increased risk for the disease.DNA repair ͉ FANCN ͉ Fanconi anemia ͉ hereditary predisposition T he presence of a family history is the most important predisposing factor for development of breast cancer. Among the genes known to be linked to familial breast cancer, BRCA1, BRCA2, CHK2, TP53, and ATM all participate in DNA damage responses (1), suggesting that familial breast cancer is, at least partly, a consequence of impaired genome stability control. PALB2 is a recently identified BRCA2-interacting protein, and a high fraction of each protein interacts with the other (2). Their association is essential for BRCA2 anchorage to nuclear structures and for its function in double strand break repair (DSBR) by homologous recombination (HR). Furthermore, introduction of PALB2 siRNAs sensitized cells to mitomycin C like BRCA2 siRNA (2). PALB2-depleted cells, therefore, display a Fanconi anemia (FA)/ BRCA2-deficient phenotype (3).Recent evidence shows that PALB2 is, in fact, another FA gene (known as FANCN), and that FANCN disease resembles FA arising from biallelic BRCA2 mutations in that the affected children are prone to develop embryonal tumors (medulloblastoma, Wilms tumor) and experience early bone marrow failure (4, 5). In other respects, FA-N cases have a typical FA phenotype. Their cells reveal increased chromosome breakage after interstrand cross-linking agent exposure, and these patients reveal growth retardation and various congenital malformations (4, 5). It is unclear why a different cancer predisposition phenotype exists in FA c...

There is considerable interest for genetic testing among Jewish women at low risk of carrying a mutation. However, many women with mutations are ineligible for genetic testing under current guidelines. Approximately 1% of Jewish women carry a BRCA mutation, and these women should be considered to be candidates for genetic testing.

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.