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Team IDs Familial Breast Cancer Risk Gene in BRCA1-Containing DNA Damage Response Pathway

NEW YORK (GenomeWeb News) – Researchers from the US and Finland have tracked down a new gene contributing to familial breast cancer risk in a DNA damage response pathway that also relies on the well known breast and ovarian cancer gene BRCA1.

Through a candidate gene sequencing and genotyping study involving hundreds of Finnish women with or without breast cancer, including women from more than 100 moderate- or high-risk families, the team found a recurrent mutation in Abraxas, a gene coding for a component in a checkpoint that kicks in when cells face ionizing radiation or other sources of DNA damage.

As they reported online today in Science Translational Medicine, researchers found that the recurrent Abraxas alteration seems to predispose women to inherited breast cancer by interfering with the resulting protein's ability to localize to the nucleus. That compromises the DNA damage pathway, which also contains a protein encoded by BRCA1.

"These findings contribute to the concept of a BRCA-centered tumor suppressor network and provide the identity of Abraxas as a new breast cancer susceptibility gene," co-corresponding authors Robert Winqvist, a clinical geneticist from the University of Oulu, and Roger Greenberg, a University of Pennsylvania cancer biology researcher, and colleagues wrote.

Both BRCA1 and BRCA2 have been linked to hereditary forms of breast and ovarian cancer risk. Despite the importance of these two genes, only around one-fifth of familial breast cancer cases around the world are explained by BRCA1 or BRCA2 germline mutations, authors of the new study explained.

As such, they argued that there may yet be unidentified genes that can significantly influence breast and ovarian cancer risk, along with lower penetrance genes and environmental risk factors.

For the current study, researchers focused on Abraxas, a gene coding for a DNA damage checkpoint component that interacts with BRCA1 and other members of a complex that responds to DNA damage, most often caused by ionizing radiation. Given its central role in this complex, the team speculated that Abraxas mutations might elevate cancer risk.

To test that notion, they screened for alterations in the Abraxas gene in individuals from families enrolled at Oulu University Hospital in northern Finland that had a history of breast cancer or of both breast and ovarian cancer.

Using conformation-sensitive gel electrophoresis and targeted Sanger sequencing of Abraxas exons, the team screened for mutations in one individual each from 125 Finnish families classified as being at high or moderate cancer risk. Of these, 15 individuals had tested positive for mutations in known cancer risk genes such as BRCA1, BRCA2, TP53, or PALB2.

Using this screening approach, the team unearthed several changes to Abraxas in individuals from at-risk families. But just one of these alterations was predicted to produce functional changes to the resulting protein.

That same mutation — a guanine to adenine change at position 1,083 of the Abraxas gene — occurred in individuals from three of the families tested.

And when researchers genotyped 991 more unrelated women with breast cancer and 868 unaffected controls at three informative SNPs in Abraxas, they found another woman with the same mutation. That individual was tested in the unselected group, but also came from a family with a history of breast cancer.

None of the four affected women carried mutations in cancer-related genes such as BRCA1/2, TP53, PALB2 or CDH1. Moreover, the Abraxas mutation appeared to co-segregate with cancer cases in the two families for which additional samples were available.

Because the recurrent mutation leads to an amino acid swap within a predicted nuclear localization signal in the Abraxas protein, researchers suspected that this change might have serious functional consequences.

Indeed, results of their follow-up immunofluorescence experiments in several cell lines suggest that the mutation hinders Abraxas protein localization to the nucleus, affecting its ability to participate in the DNA damage checkpoint.

In addition, they found that cell lines expressing mutant versions of the Abraxas gene showed impaired nuclear localization of BRCA1 and another DNA damage checkpoint component, RAP80, and were more prone to ionizing radiation-induced damage.

The pathway affected by the Abraxas mutation appears to be independent of the DNA repair pathways comprised of BRCA1, BRCA2, PALB2, and other proteins, the study authors noted, suggesting tumors with Abraxas or RAP80 alterations might respond to different treatments than tumors harboring mutations in other BRCA-related pathways.

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