Rahman, N. et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nature Genet. 39, 165-167

University of Cambridge, Cambridge, England, United Kingdom
Nature Genetics (Impact Factor: 29.35). 03/2007; 39(2):165-7. DOI: 10.1038/ng1959
Source: PubMed

ABSTRACT PALB2 interacts with BRCA2, and biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia. We identified monoallelic truncating PALB2 mutations in 10/923 individuals with familial breast cancer compared with 0/1,084 controls (P = 0.0004) and show that such mutations confer a 2.3-fold higher risk of breast cancer (95% confidence interval (c.i.) = 1.4-3.9, P = 0.0025). The results show that PALB2 is a breast cancer susceptibility gene and further demonstrate the close relationship of the Fanconi anemia-DNA repair pathway and breast cancer predisposition.

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Available from: Sheila Seal, Sep 28, 2015
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    • "A similar pattern of incomplete segregation in affected relatives has been observed for susceptibility alleles that confer modest increased risk, and reported for variants in CHEK2, ATM, BRIP1 and PALB2 [21] [22] [23] [24]. "
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    ABSTRACT: Among breast cancers, 10 to 15% of cases would be due to hereditary risk. In these familial cases, mutations in BRCA1 and BRCA2 are found in only 15% to 20%, meaning that new susceptibility genes remain to be found. Triple-negative breast cancers represent 15% of all breast cancers, and are generally aggressive tumours without targeted therapies available. Our hypothesis is that some patients with triple negative breast cancer could share a genetic susceptibility different from other types of breast cancers. We screened 36 candidate genes, using pyrosequencing, in all the 50 triple negative breast cancer patients with familial history of cancer but no BRCA1 or BRCA2 mutation of a population of 3000 families who had consulted for a familial breast cancer between 2005 and 2013. Any mutations were also sequenced in available relatives of cases. Protein expression and loss of heterozygosity were explored in tumours. Seven deleterious mutations in 6 different genes (RAD51D, MRE11A, CHEK2, MLH1, MSH6, PALB2) were observed in one patient each, except the RAD51D mutation found in two cases. Loss of heterozygosity in the tumour was found for 2 of the 7 mutations. Protein expression was absent in tumour tissue for 5 mutations. Taking into consideration a specific subtype of tumour has revealed susceptibility genes, most of them in the homologous recombination DNA repair pathway. This may provide new possibilities for targeted therapies, along with better screening and care of patients.
    American Journal of Cancer Research 09/2015; 5(7):2113-26. · 4.17 Impact Factor
    • "This aspect is illustrated by the discovery of mutation candidates in the PALB2 and NCOR1 genes in the present study. Both PALB2 and NCOR1 are considered as predisposition factor or somatic driver in breast cancer [Rahman et al., 2007; CGAN-consortium, 2012; Stephens et al., 2012]. Here, for the first time, we present the co-occurrence of rare variants in these genes with genomic destabilization in uninvolved glandular tissue from breast cancer patients. "
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    ABSTRACT: Somatic mosaicism for DNA copy number alterations (SMC-CNAs) is defined as gain or loss of chromosomal segments in somatic cells within a single organism. As cells harboring SMC-CNAs can undergo clonal expansion, it has been proposed that SMC-CNAs may contribute to the predisposition of these cells to genetic disease including cancer. Herein, the gross genomic alterations (>500 kbp) were characterized in uninvolved mammary glandular tissue from 59 breast cancer patients and matched samples of primary tumors and lymph node metastases. Array based comparative genomic hybridization showed 10% (6/59) of patients harbored 1 - 359 large SMC-CNAs (mean: 1328 kbp; median: 961 kbp) in a substantial portion of glandular tissue cells, distal from the primary tumor site. SMC-CNAs were partially recurrent in tumors, albeit with considerable contribution of stochastic SMC-CNAs indicating genomic destabilization. Targeted resequencing of 301 known predisposition and somatic driver loci revealed mutations and rare variants in genes related to maintenance of genomic integrity: BRCA1 (p.Gln1756Profs*74, p.Arg504Cys), BRCA2 (p.Asn3124Ile), NCOR1 (p.Pro1570Glnfs*45), PALB2 (p.Ser500Pro) and TP53 (p.Arg306*). Co-occurrence of gross SMC-CNAs along with point mutations or rare variants in genes responsible for safeguarding genomic integrity highlights the temporal and spatial neoplastic potential of uninvolved glandular tissue in breast cancer patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Human Mutation 07/2015; DOI:10.1002/humu.22845 · 5.14 Impact Factor
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    • "Ablation of Rad51 paralogs leads to severe HR defects, DNA damage sensitivity, chromosome abnormalities, and defective Rad51 nuclear focus formation after DNA damage, suggestive of a major function at an early stage in the HR reaction (Chun et al., 2013; French et al., 2002; Gasior et al., 1998; Godthelp et al., 2002; Hays et al., 1995; Johnson et al., 1999; Pierce et al., 1999; Rattray and Symington, 1995; Takata et al., 2000, 2001). Like BRCA2 and PALB2, which are mutated in Fanconi anemia and breast and ovarian cancer (Howlett et al., 2002; Lancaster et al., 1996; Rahman et al., 2007; Reid et al., 2007; Wooster et al., 1995; Xia et al., 2007), biallelic germline mutations in RAD51C cause a severe form of Fanconi anemia (Vaz et al., 2010), whereas monoallelic inheritance of mutations in RAD51C and RAD51D, and RAD51B, predispose individuals to ovarian and breast cancer, respectively (Golmard et al., 2013; Loveday et al., 2011; Meindl et al., 2010), demonstrating an important tumor suppressor function for HR mediators. The budding yeast Rad55-Rad57 complex (Sung, 1997) and a sub-complex of the human BCDX2 complex, RAD51B-RAD51C (Sigurdsson et al., 2001), have been purified as heterodimers and despite lacking intrinsic recombinase activity they stimulate strand exchange by Rad51 in vitro. "
    Cell 07/2015; 162:271-286. · 32.24 Impact Factor
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