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Feb 23, 2012

New BRCA1-Associated Breast Cancer Susceptibility Gene Identified

  • Scientists have discovered a mutation in a gene that interacts with BRCA1 in a significant number of familial breast cancer cases studied. The Abraxas protein links BRCA1 to a protein complex involved in BRCA1-dependent DNA damage responses. A team led by researchers at Oulu University Hospital’s Institute of Clinical Medicine and Biocenter in Finland identified a functional mutation in the Abraxas protein in about 2.4% of cases of familial breast cancer. The mutation led to a change in the protein which essentially prevented the resulting BRCA1 complex from accumulating in the nucleus where it is needed to repair DNA damage and breaks.

    Reporting their findings in Science Translational Medicine, the investigators say the latest results not only support the concept of a BRCA-centered tumor suppressor network in cells, but also identifies Abraxas as a new breast cancer susceptibility gene. Their paper is titled “Breast CancerAssociated Abraxas Mutation Disrupts Nuclear Localization and DNA Damage Response Functions.”

    BRCA1 plays a number of key roles in maintaining genomic integrity, and mutations in the gene are clearly associated with hereditary predisposition to breast cancer. BRCA1 is integral to the maintenance of genomic integrity playing a key role in DNA repair by homologous recombination, and the execution of cell cycle checkpoints triggered by DNA damage. Missense mutations in BRCA1 that are clinically relevant most commonly occur at the C-terminal region of BRCA1, which contains two BRCA1 C-terminal repeats (BRCT) that are critical for its tumor suppressor function.

    Abraxas (ABRA1, CCDC98, or FAM175A) directly binds to the BRCA1 BRCT motifs via its phosphorylated C terminus, and links BRCA1 to a DNA repair protein complex that recognizes ubiquitination. Prior studies have implicated mutations in other Abaxas complex proteins in breast cancer patients, both in BRCA1 mutation carriers and those with wild-type BRCA1.

    Working with academic collaborators in Finland and at the University of Pennsylvania, the Oulu University Hospital researchers screened 125 affected patients of Northern Finnish breast cancer families for germline mutations in the Abraxas gene. The results identified four intronic and six exonic variants, five of which hadn’t previously been reported. Of these, computer analyses indicated that just one, c.1082G>A, was likely to result in functional changes in the protein. The Abraxas c.1082G>A results in an Arg361Gln (R361Q) switch that changes the last residue of a putative bipartite nuclear localization signal.

    R361Q was identified in 2.4% (3 of 125) of the studied breast cancer families but in none of 868 healthy female controls. Interestingly, the mutation was also identified in one individual in an unselected cohort of 991 breast cancer cases, and this patient also proved to have a familial cancer background. Significantly, the index patients of all four of these Abraxas mutation-positive breast cancer families tested negative for mutations in BRCA1, BRCA2, TP53, CDH1, and PALB2. A number of the R361Q-positive families also demonstrated other cancer types, including stomach, lung, and lip cancers, neuroblastoma, and lymphoma of the throat.

    Morphological evaluation of the R361Q-positive breast cancers showed that four of five demonstrated a lobular phenotype. Only one case exhibited a ductal phenotype, which is usually seen in about 75% of breast cancers, the investigators note. The four tumors also showed strong estrogen receptor and progesterone receptor expression, but a total lack of HER2 expression. “These phenotypic observations suggest that Abraxas mutation-positive breast cancer cases can deviate from the pattern of hormone receptor and HER2 negativity associated with BRCA1 tumors,” the authors state. “Tumors from patients with mutations in BRCA2 and PALB2, which, like Abraxas, encode BRCA1-associated proteins, also frequently show hormone receptor positivity.” Notably, R361Q mutation wasn’t associated with loss of heterozygosity (LOH) in any of the studied tumors.  

    The team then assessed the impact of R361Q on the subscellular localization of the protein in cell lines that stably expressed either wild-type or mutant Abraxas at near-endogenous levels. This showed that while wild-type Abraxas was predominantly localized in the nucleus, Abraxas 361Q localized in the cytoplasm. The mutant protein did, moreover, retain its interaction with BRCA1 and other components of the holoenzyme complex in the cytoplasm, while wild-type Abraxas displayed similar interactions in the nucleus.

    Critically, the R361Q mutation significantly dampened the recruitment of Abraxas to double-stranded breaks, which suggested that the mutation leads to deficiency in DNA damage response functions due to a lack of nuclear accumulation. R361Q expression in addition partially disrupted the G2 checkpoint in response to ionizing radiation, and reduced the efficiency of homology-directed DSB repair. “These results suggest that reduced nuclear accumulation by Abraxas R361Q negatively affects DSB localization of its interacting partners,” the researchers write.

    They point out that in addition to BRIP1 (FANCJ) and RAP80, Abraxas is the third BRCA1 BRCT–interacting partner with germline human breast cancer-associated mutations that has been shown to exert dominant-negative effects on BRCA1 DNA repair function. “Abraxas R361Q exerted a dominant-negative influence on BRCA1 and RAP80 by diminishing their accumulation at IR-induced DNA damage foci,” the team points out. Importantly, the findings “establish ubiquitin recognition at DNA damage sites as a bona fide tumor suppression function of BRCA1-associated protein complexes.

    The BRCA1 protein complex that contains Abraxas and RAP80 operates distinctly from BRCA1 complexes that contain breast cancer suppressors PALB2, BRCA2, and BRIP1, they continue. RAP80 targets BRCA1 and Abraxas to ubiquitinated chromatin that extends for a distance away from DSBs, whereas BRCA1 complexes containing BRCA2 and PALB2 or BRIP1 are thought to directly interact with DNA intermediates during homologous recombination-dependent DNA repair. In this instance mutations in any of the genes impacts on homologous recombination, whereas cells deficient in Abraxas or RAP80 display elevated use of homology-directed DNA repair mechanisms.

    “The identification of additional Abraxas mutation-positive families would provide the means for more reliable cancer risk assessments and evaluation of the potential use of Abraxas mutation testing in clinical diagnostics,” the authors conclude. “Similar to BRCA1 and BRCA2, mutations in Abraxas appear to be involved in susceptibility to certain other malignancy types beyond breast cancer. The present results warrant investigation of Abraxas as a new cancer susceptibility gene in other populations as well.”


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