Next generation sequencing of germline DNA in 2,160 early-onset breast cancer and 1,199 ovarian cancer patients revealed nearly 2% of patients carry a very rare missense variant (MAF<0.0001) in BRIP1.
Germline DNA from 1054 BRCA-mutation-negative Hispanic women with hereditary BC (BC diagnosed at age <51 years, bilateral BC, breast and ovarian cancer, or BC diagnosed at ages 51-70 years with ≥2 first-degree or second-degree relatives who had BC diagnosed at age <70 years), 312 local controls, and 887 multiethnic cohort controls was sequenced and analyzed for 12 known and suspected, high-penetrance and moderate-penetrance cancer susceptibility genes (ataxia telangiectasia mutated [ATM], breast cancer 1 interacting protein C-terminal helicase 1 [BRIP1], cadherin 1 [CDH1], checkpoint kinase 2 [CHEK2], nibrin [NBN], neurofibromatosis type 1 [NF1], partner and localizer of BRCA2 [PALB2], phosphatase and tensin homolog [PTEN], RAD51 paralog 3 [RAD51C], RAD51D, serine/threonine kinase 11 [STK11], and TP53).
Analysis of paired specimens of primary malignant and normal tissues showed that miR-142-3p was downregulated, while Bach-1 mRNA and protein both were overexpressed in the breast cancer tumors.
Based on the negative association between BRIP1 LoF mutations and familial BC in the absence of an OC family history, we conclude that the elevated mutation prevalence in the latter cohort was driven by the occurrence of OC in these families.
Some of the tagging single-nucleotide polymorphisms of 5 genes ( PALB2, TP53, Nijmegen breakage syndrome 1, PTEN, and BRCA1-interacting protein 1) involved in the monoubiquitinated FANCD2-DNA damage repair pathway were significantly associated with breast cancer risk.
Of the 1007 probands in the study, 903 probands had no founder mutations in BRCA1 or BRCA2; of these probands, 7 (0.8%) carried another pathogenic mutation in BRCA1 or BRCA2, and 31 (3.4%) carried a pathogenic mutation in another breast cancer gene (29 in CHEK2, and 1 each in BRIP1 and NBN).
The results of pedigree analysis showed that the proband with a large deletion on RAD51C had a family history of both breast and ovarian cancer, and the families of probands with novel BRIP1 missense variants included a male patient with breast cancer or many patients with breast cancer within the second-degree relatives.
These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk.
This review will focus on the findings supporting this hypothesis, the mechanisms linking BRIP1 to the onset of BC, and the potential clinical relevance of its various inhibitors.
Enormous sequence alterations in exons and introns of FANCJ have been identified in patients, including 15 mutations in the coding region which are linked to breast cancer, 12 to FA, and two to ovarian cancer.
Characterized FANCJ missense mutations associated with breast cancer or Fanconi anemia interfere with FANCJ helicase activity required for DNA repair and the replication stress response.
Together, our data suggest that CXCR3-B mediates a growth-inhibitory signal in breast cancer cells through the modulations of nuclear translocation of Bach-1 and Nrf2 and down-regulation of HO-1.
Deleterious mutations in few genes involved in the Fanconi complex are responsible for Fanconi anemia at the homozygous state and breast cancer (BC) susceptibility at the heterozygous state (BRCA2, PALB2, BRIP1).
Furthermore, more frequent, but less penetrant, mutations have been identified in families with breast cancer clustering, in moderate or low penetrant genes, such as CHEK2, ATM, PALB2, and BRIP1.
The BRCA1-associated FANCJ helicase is among those helicases able to unwind G4 DNA in vitro, and FANCJ mutations are associated with breast cancer and linked to Fanconi anemia.
Four haplotypes within two genes (NBS1 and BRIP1) involved in the monoubiquitinated FANCD2-DNA damage-repair pathway are significantly associated with increased sporadic breast cancer risk, while one haplotype within NBS1 is correlated with an increased risk of familial or early-onset breast cancer, indicating that specific haplotypes may be distinct predictors of breast cancer.
Although investigated by fewer studies, we have also studied the risk associated with the two additional BRIP1 polymorphisms, C47G and G64A, and breast cancer riskWe conducted searches of the published literature in MEDLINE through PubMed up to October 2012.