A recurrent mutation in PALB2 in Finnish cancer families

Abstract

BRCA1, BRCA2 and other known susceptibility genes account for less than half of the detectable hereditary predisposition to breast cancer. Other relevant genes therefore remain to be discovered. Recently a new BRCA2-binding protein, PALB2, was identified. The BRCA2-PALB2 interaction is crucial for certain key BRCA2 DNA damage response functions as well as its tumour suppression activity. Here we show, by screening for PALB2 mutations in Finland that a frameshift mutation, c.1592delT, is present at significantly elevated frequency in familial breast cancer cases compared with ancestry-matched population controls. The truncated PALB2 protein caused by this mutation retained little BRCA2-binding capacity and was deficient in homologous recombination and crosslink repair. Further screening of c.1592delT in unselected breast cancer individuals revealed a roughly fourfold enrichment of this mutation in patients compared with controls. Most of the mutation-positive unselected cases had a familial pattern of disease development. In addition, one multigenerational prostate cancer family that segregated the c.1592delT truncation allele was observed. These results indicate that PALB2 is a breast cancer susceptibility gene that, in a suitably mutant form, may also contribute to familial prostate cancer development.

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

“…2 Mutations in this gene may be associated with familial clustering of PC and BC. [1][2][3][4][5][6][7][8][9][10] Previous studies have shown that PALB2-mutation-positive familial BC (FBC) patients were significantly more likely to have a relative with PC, 5 and that nearly all PALB2-mutation positive familial PC (FPC) families were affected by at least one BC case. 4 Given these findings and the fact that the prevalence of gene mutations varies between different populations, we aimed to determine the prevalence of PALB2 mutations in Dutch cohorts of non-BRCA1/2 FPC patients and of non-BRCA1/2 FBC patients with a personal or family history of PC.…”

Cancer predisposing missense and protein truncatingBARD1mutations in non-BRCA1orBRCA2breast cancer families

“…Limitations of currently used mutation screening methods may explain the low recovery rates [Teugels et al, 2005]. It is generally accepted that mutations in other genes like CHEK2, ATM, PALB2 and BRIP1 could be the cancer predisposing factor in some breast cancer families [Meijers-Heijboer et al, 2002;Erkko et al, 2006;Rahman et al, 2006;Renwick et al, 2006;Seal et al, 2006], but the observed lower penetrance of these mutations and a less obvious cosegregation pattern with the disease suggest that these mutations act according to a polygenic model [Antoniou et al, 2001Ponder, 2001;Pharoah et al, 2002]. The search for additional breast cancer susceptibility genes is still ongoing and candidate genes can be found among those that interact in the same molecular pathways as BRCA1/2.…”

Surveying germline genomic landscape of breast cancer

“…1). For some of the moderate-penetrance genes, ATM, BRIP1, CHEK2 and PALB2, the data are still limited to single populations [12][13][14][15][16]. For CHEK2*del1100delC and ATM variants the PAF estimates are about 0.5% each; adding up the other CHEK2 variants, BRIP1 and PALB2 mutations the sum PAF would be around 1.5% (Fig.…”