Rahman, N., Seal, S., Thompson, D., Kelly, P., Renwick, A., Elliott, A. et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat. 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


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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    • "It binds and colocalizes with BRCA2 in the nucleus to stabilize BRCA2 foci and facilitate the intra S phase checkpoint and HR repair [184]. Germline mutations in PALB2 confer a 2–5 fold increase in breast cancer risk [185] [186] and germline mutations have been recently found in African American breast cancer patients [187] [188]. PALB2 mutations have also been observed in 1% of Chinese women with early onset breast cancer [189]. "
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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.
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    • "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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