Fanconi anemia is associated with a defect in the BRCA2 partner PALB2

Abstract

The Fanconi anemia and BRCA networks are considered interconnected, as BRCA2 gene defects have been discovered in individuals with Fanconi anemia subtype D1. Here we show that a defect in the BRCA2-interacting protein PALB2 is associated with Fanconi anemia in an individual with a new subtype. PALB2-deficient cells showed hypersensitivity to cross-linking agents and lacked chromatin-bound BRCA2; these defects were corrected upon ectopic expression of PALB2 or by spontaneous reversion.

Routine testing for PALB2 mutations in familial pancreatic cancer families and breast cancer families with pancreatic cancer is not indicated

“…Primer pairs that were used have been previously described. 12 The presence of large genomic deletions in PALB2 was analysed by MLPA using the MLPA P057 kit of MRC-Holland (Amsterdam, The Netherlands) as previously described. 13 As a positive control, genomic DNA from the previously described PALB2 FA patient EUFA1341 was included in the analysis.…”

“…13 As a positive control, genomic DNA from the previously described PALB2 FA patient EUFA1341 was included in the analysis. 12 RESULTS PALB2 mutation analysis was performed in a total of 64 patients from 56 distinct families (28 FPC families, 28 FBC families; Table 1). In total, 31 patients (48%) originated from FPC families; 24 were FPC patients (77%), 6 had a personal history of BC (19%) and 1 was a suspected carrier (3.2%).…”

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

“…Consistent with this, certain point mutations in BRCA2 that disrupt its interaction with PALB2 are also implicated in breast/ovarian cancer predisposition. BRCA2 and, very recently, PALB2 have been shown to undergo biallelic mutation in some cases of Fanconi Anemia [143][144][145][146]. Rad51 focus formation is defective in cells from some FA complementation groups, including those harboring mutations in BRCA2 or PALB2.…”

DNA double-strand break repair and development

“…In humans bi-allelic hypomorphic mutations of BRCA2 are responsible for some cases of Fanconi anemia (FANC-D1 subgroup; Howlett et al, 2002), a rare autosomal recessive cancer susceptibility syndrome characterized by congenital abnormalities, progressive bone narrow failure and cellular hypersensitivity to DNA crosslinking agents (D'Andrea and Grompe, 2003;Kennedy and D'Andrea, 2005;Reid et al, 2007). Defects in the BRCA2 partner-protein PALB2 can also result in FA (Reid et al, 2007;Xia et al, 2007). Brca2 also functions as an important tumor suppressor as its loss confers susceptibility to breast, ovarian and brain tumors (Hughes-Davies et al, 2003;Offit et al, 2003;Shivji and Venkitaraman, 2004).…”