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.
The Mre11 complex, composed of RAD50, NBS1 and MRE11, has an essential role in the maintenance of genomic integrity and preventing cells from malignancy. Here we report the association of three Mre11 complex mutations with hereditary breast cancer susceptibility, studied by using a case-control design with 317 consecutive, newly diagnosed Northern Finnish breast cancer patients and 1000 geographically matched healthy controls (P = 0.0004). RAD50 687delT displayed significantly elevated frequency in the studied patients (8 out of 317, OR 4.3, 95% CI 1.5-12.5, P= 0.008), which indicates that it is a relatively common low-penetrance risk allele in this cohort. Haplotype analysis and the screening of altogether 512 additional breast cancer cases from Sweden, Norway and Iceland suggest that RAD50 687delT is a Finnish founder mutation, not present in the other Nordic cohorts. The RAD50 IVS3-1G>A splicing mutation leading to translational frameshift was observed in one patient, and the NBS1 Leu150Phe missense mutation affecting a conserved residue in the functionally important BRCA1 carboxy-terminal (BRCT) domain in two patients, both being absent from 1000 controls. Microsatellite marker analysis showed that loss of the wild-type allele was not involved in the tumorigenesis in any of the studied mutation carriers, but they all showed increased genomic instability assessed by cytogenetic analysis of peripheral blood T-lymphocytes (P = 0.006). In particular, the total number of chromosomal rearrangements was significantly increased (P = 0.002). These findings suggest an effect for RAD50 and NBS1 haploinsufficiency on genomic integrity and susceptibility to cancer.
A pproximately 5-10% of all breast and ovarian cancers are thought to arise from a hereditary predisposition to the disease, 1 BRCA1 and BRCA2 being the most important susceptibility genes.2 3 Genomic alterations in BRCA1 are found in 40-50% of families with a high incidence of breast cancer (six or more cases), and in a majority (75-80%) of the families that display both breast and ovarian cancers.4 5 However, a significant portion of genetic aberrations predisposing to these cancers, especially in relatively small risk families, still remains unexplained.6 7 BRCA1 interacts with a variety of proteins and is involved in multiple cellular processes including DNA repair, transcription, and checkpoint control. [8][9][10] In attempts to identify new breast and ovarian cancer susceptibility genes, much research has focused on BRCA1 associated proteins.BARD1 was originally identified through its interaction with BRCA1, with which it has a closely related domain structure.11 Both proteins possess an N-terminal RING finger motif and two BRCA1 C-terminal (BRCT) domains present in numerous proteins involved in DNA repair and cell cycle regulation. 11The functionally important BARD1/BRCA1 heterodimer formation is mediated by the RING finger motifs and has also been shown to markedly increase the stability of both proteins.11-13 The finding of breast cancer associated mutations within the RING finger domain of BRCA1, disrupting BRCA1/BARD1 interaction, 11 14 and the occurrence of BARD1 missense mutations in breast cancer patients, [15][16][17] implies participation of BARD1 in BRCA1 mediated tumour suppression. BARD1, unlike BRCA1, also contains a centrally located sequence of three ankyrin repeats 11 that are found in many proteins involved in transcriptional regulation. 18Colocalisation of BARD1 with BRCA1 and RAD51 in response to DNA damage indicates a role in DNA repair, 19 20 which is supported by the recent observation of BARD1 participation along with BRCA1 in homology directed repair of chromosome breaks. 21 Furthermore, interaction between the BARD1/BRCA1 heterodimer and cleavage stimulation factor subunit 1 (CSTF1, also called CstF-50) represses the polyadenylation machinery, presumably to prevent inappropriate mRNA processing at sites of DNA repair.22 23 The significance of BARD1/BRCA1 collaboration has also been emphasised by studies of its ubiquitin ligase activity that might contribute to tumour suppression and other biological functions of BRCA1. 24 In vivo substrates for the ubiquitination are not yet known, but involvement of the RNA polymerase-2 holoenzyme has been proposed. 25 BARD1 also regulates the subcellular localisation of BRCA1, both by translocating BRCA1 into the nucleus and by inhibiting its nuclear export. 26 The suggested role in TP53 dependent apoptotic signalling 27 and interaction with the ankyrin repeats of proto-oncoprotein BCL3, thereby possibly modulating the activity of transcription factor NFKB, 28 represent BRCA1 independent functions of BARD1. In addition, the effects of reduced...
Besides mutations in BRCA1/BRCA2, heterozygous defects in PALB2 are important in breast cancer predisposition. PALB2 heterozygosity increases the risk of malignancy about sixfold. PALB2 interacts with BRCA1 and BRCA2 to regulate homologous recombination and mediate DNA damage response. Here we show, by analysing lymphoblastoid cell lines from heterozygous female PALB2 mutation carriers, that PALB2 haploinsufficiency causes aberrant DNA replication/damage response. Mutation carrier cells show increased origin firing and shorter distance between consecutive replication forks. Carrier cell lines also show elevated ATR protein, but not phosphorylation levels, and a majority of them display aberrant Chk1-/Chk2-mediated DNA damage response. Elevated chromosome instability is observed in primary blood lymphocytes of PALB2 mutation carriers, indicating that the described mechanisms of genome destabilization operate also at the organism level. These findings provide a new mechanism for early stages of breast cancer development that may also apply to other heterozygous homologous recombination signalling pathway gene mutations in hereditary cancer predisposition.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.