If you have a compelling family history of breast cancer that is not explained by a BRCA1 or BRCA2 gene mutation, another gene – Abraxas – has been added to the list of possible explanations.
An international team, led by Drs. Robert Winqvist of the University of Oulu in Finland and Roger Greenberg at the University of Pennsylvania’s Abramson Family Cancer Research Institute, has shown that mutations in Abraxas (also known as CCDC98 and FAM175A) that disrupt the normal location of the Abraxas protein within the cell are associated with familial breast cancer.
A Significant Percentage of Familial Breast and Ovarian Cancer Cases are Not Explained by BRCA1 or BRCA2 Gene Mutations
Although the BRCA1 and BRCA2 genes are by far the most important of the genes that when mutated can result in a predisposition to Hereditary Breast and Ovarian Cancer, a recent steady stream of new discoveries is rounding out a group of other genes that appear to be responsible for some of the other families. We’ve covered discoveries regarding a couple of these genes, RAD51C and RAD51D, here at CancerAndYourGenes.com previously. We’ve also published a follow-up piece with more information on other types of cancer seen in the studied families with RAD51D mutations. These genes are part of a list of several other genes that – when mutated – predispose to Hereditary Breast and/or Ovarian Cancer sometimes in combination with other cancer types within the family (more on this here on the blog soon).
Abraxas is Known to Interact with the BRCA1 Protein As Part of a Protein Complex Important to the Cellular Response to DNA Damage
As the BRCA1 and BRCA2 genes are known to code for proteins that are key players in complexes that are part of the cellular DNA repair machinery, it is no surprise that several of the more recently discovered breast and/or ovarian cancer susceptibility genes are also involved in these networks. It turns out that the protein encoded by the Abraxas gene interacts with the BRCA1 protein in one of these complexes. In 2007, a team led by Dr. Stephen Elledge at Harvard was the first to demonstrate this fact. Over the last few years, several research groups – reasoning that proteins interacting with BRCA1 or BRCA2 are good cancer gene candidates – have been looking closely at these genes to assess whether they might play a role in hereditary breast and ovarian cancer.
Abraxas is a Familial Breast Cancer Susceptibility Gene
In the new study published in Science Translational Medicine, the research team sequenced the Abraxas gene in one individual chosen from each of 125 families with multiple breast and ovarian cancer cases, with the emphasis primarily on breast cancer.
73 of the families were viewed as particularly high-risk (and more likely to be harboring a mutation in a cancer susceptibility gene) as defined by the following criteria:
- 3 or more breast cancer cases in 1st (mothers, sisters, etc.) or 2nd (aunts, grandmothers, etc.) degree relatives OR
- 2 cases of breast and/or ovarian cancer in 1st or 2nd degree relatives in which at least one of the individuals has bilateral breast cancer, very early onset breast cancer (younger than 35), or multiple primary cancers including breast or ovarian cancer in the same individual
The other 52 families met more relaxed criteria:
- 2 cases of breast or ovarian cancer in 1st or 2nd degree relatives OR
- 1 individual with breast cancer diagnosed younger than age 35
In each family, they chose to sequence the gene in the woman with the youngest age of onset of breast cancer. It’s also important to note that a few of the individuals that they included had mutations in known breast cancer susceptibility genes (11 in BRCA1 or BRCA2, 3 in PALB2, and 1 in TP53).
The sequencing rapidly led to a focus on one particular recurrent mutation in Abraxas referred to as “R361Q” (it’s called this because it results in a change in the 361st amino acid in the protein from arginine to glutamine; R is the symbol for arginine and Q for glutamine). This mutation was present in heterozygous form (i.e., one copy of the Abraxas gene had this mutation in each person and the other copy did not) in the sequenced individual from 3 of the 125 families. Additionally, in the two families in which they were able to do the analysis, the mutation segregated with cancer susceptibility within the family (i.e., individuals who had available DNA and who would be expected to have the mutation based on their cancer history had the mutation).
The group then chose to look for the presence of this particular mutation in a total of 991 women with breast cancer who were unselected for likelihood of a genetic cause (i.e., no selection for family history of cancer). The mutation was identified in 1 of these 991 women with breast cancer (0.1%), but was absent from a total of 868 healthy women in whom the gene was sequenced.
The significantly higher frequency of the mutation in the familial cases in addition to the fact that the one woman from the other study with a mutation was found to have a family cancer history supports the conclusion that this Abraxis mutation is cancer risk-associated.
Also, in the two families with available DNA from other families, the mutation was found to segregate with cancer within the families. There were several non-breast cancers of note in the individuals with mutations including 1 lymphoma, 1 lip cancer, 1 endometrial cancer, 1 prostate cancer, 1 colon cancer, and 1 fibrosarcoma.
Among the notable features of the Abraxas mutation-associated breast cancer cases were the following:
- Lobular histology was more common in the breast cancers than is typically seen
- The four breast cancer cases for which data was available were all estrogen receptor-positive, progesterone receptor-positive, and HER2-negative
The Abraxas R361Q Mutation Impacts the Subcellular Location of the Abraxas Protein
The researchers bioinformatically determined that the R361Q mutation was located in a series of amino acids that is known to signal that a protein should be located in the nucleus of the cell. To investigate this further, they performed a series of experiments that showed that normal Abraxas protein is primarily located in the nucleus, while R361Q-mutant Abraxas protein is largely located outside the nucleus in an area of the cell called the cytoplasm. Based on additional experiments that they performed, it seems likely that this impacts DNA repair capacity within the cell, presumably contributing to the cancer susceptibility.
Bottom Line Implications for Women with a Significant Personal and Family History of Breast Cancer Who Have Been Tested and Found to Be BRCA Negative
1. Over the last few years, it has become increasingly clear that a handful of genes can significantly contribute to hereditary breast and/or ovarian cancer in families in which individuals affected with cancer do not have BRCA1/2 mutations despite impressive cancer family histories.
2. Based on the evidence presented in this new research paper, the Abraxas gene can be added to the list. However, a number of questions remain to be resolved both before we can really understand its potential impact and before the knowledge can be implemented in the clinic:
- Is the mutation relevant to cancer risk outside of Finland?
- If so, how common is it?
- Does it impact the risk of other cancer types (several were seen in mutation-positive individuals in the families in this study)?
- The mutation in this study may be very unique because of the way it affected the nuclear localization signal for the protein. Do other mutations in Abraxas have similar effects on cancer risk?
3. Given the cancer spectrum seen in the families in this paper, it may be especially important for BRCA negative families in which there are multiple breast cancer cases (particularly early-onset) and also either head and neck cancer, lymphoma, sarcomas, neuroblastoma, or lymphoma to pay attention to future clinical research further defining the role of Abraxas mutations in cancer risk and also to the potential future availability of clinical testing for Abraxas mutations.
If you this was helpful and you are interested in learning more, you will likely find The BRCA Negative Book to be very useful. You can order a copy or get involved in reviewing early drafts here.
Solyom S, Aressy B, Pylkäs K, et al. Breast cancer-associated Abraxas mutation disrupts nuclear localization and DNA damage response functions. Science Translational Medicine 2012; 4:122ra23.
Wang B, Matsuoka S, Ballif BA, et al. Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science 2007; 316:1194-8.
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