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Major Study Provides New Insight into Breast Cancer Genetics

BCRF investigator Fergus Couch and colleagues identify 72 new genetic variants that contribute to breast cancer risk.
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Studies released today in Nature and Nature Genetics, supported in part by BCRF, reported findings by a major international consortium identifying 72 previously unknown common genetic variants that predispose individuals to breast cancer and seven others that are specific for triple negative breast cancer- a highly aggressive form of the disease.

BCRF investigator Fergus Couch is a member of two international consortia, the Breast Cancer Association Consortium (BCAC) and The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) that conducted the OncoArray breast cancer study. Over 500 researchers from 300 institutions in six continents contributed genetic data from 275,000 women, 146,000 of whom had been diagnosed with breast cancer.

Many of us have heard of the breast cancer genes, BRCA1 and BRCA2, both of which confer a significantly increased risk of breast and ovarian cancer in women and breast, prostate and pancreatic cancer in men. While mutations in the BRCA genes are uncommon in the general population, scientists have discovered many other, more common genetic variants (changes to genes) that individually harbor much lower risk of breast cancer but when combined may yield a strong influence on risk of this disease. The challenge facing scientists is in understanding how to interpret risk of these variants and most importantly, how to use the information to guide risk assessment and prevention.

BCRF had an opportunity to discuss the potential clinical implications of the findings with Dr. Couch.

BCRF. Dr. Couch, can you put these findings into context of the subject of genetic risk for breast cancer?

Dr. Couch: First of all, the findings are important in that we were able to corroborate the gene variants we identified in earlier studies in a much larger population. By combining new data with results from earlier, smaller studies, we were also able to identify new risk variants that were not previously known.

Following ten years of research on genetic risk of breast cancer that has culminated in these two papers, work is already in progress to develop what we call a polygenic risk score (PRS). This is essentially a statistical analysis that allows us to predict risk based on combining the variants in a composite score. For each individual there will be a unique score that can be used in addition to other risk measures, such as breast density, family history, etc. to refine a person’s risk of breast cancer.

BCRF: Would the PRS replace mammographic screening in the general population as a way to establish a risk-based screening schedule?

Dr. Couch: The initial utility of the PRS will be in assessing the risk in women already at high risk. For instance, when a woman has a biopsy for a mass found on a screening mammogram, she is placed in a high-risk group, even if the biopsy is benign (not cancerous). Currently all women in this group will undergo more frequent screening, but we know they don’t all have the same level of risk and some will never go on to get invasive cancer. The PRS can be used to identify those who are at high risk, for whom more frequent screening and prevention surveillance would be appropriate, as well as those women at very low risk, who maybe do not need to be screened as frequently.

From the patient perspective, the PRS personalizes risk assessment. For some women, that may reduce the stress and anxiety of worrying about cancer and for other women, it may provide the opportunity for early intervention that can be lifesaving. From a health economics level, the PRS relieves the health care system by reserving resources for those at high risk.

As far as using PRS as a primary screening tool, I think that will come, but we need to learn from those affected by breast cancer to refine the PRS for screening the general, “normal” population.

BCRF: The Nature Genetics article pointed to a group of variants that were specific for triple negative and BRCA1 breast cancers. Was this an unexpected finding?

Dr. Couch: By pooling data from two large consortia, we were able to identify genetic variants that were missed in smaller studies. The findings support what we’ve already known, i.e. that triple negative (and BRCA1) breast cancer is clearly a different disease from those breast cancers that have the estrogen receptor. We know now that we will need a PRS for the general (non-BRCA1) population and a PRS for the triple negative/BRCA1 populations.

BCRF: We know that women of African descent have a higher risk of being diagnosed with triple negative breast cancer. Does the PRS help us identify those women?

Dr. Couch: These results are from a predominantly European Caucasian population, so the PRS may not translate to other populations. There are ongoing efforts to examine the gene variants we found in this study in the African American population, including work by BCRF investigators, Christine Ambrosone and Funmi Olopade.  Our own group is starting to look at this in some African American studies, but the number of patients is still very small. We know that there will be differences in the common genetic variants between racial groups, but that we will also find a subset of the variants that behave similarly in all populations and we can use these to begin to develop an African American-specific PRS. Similar work is ongoing for Hispanic and Asian populations.

BCRF: Other than the PRS, what else do these findings tell us?

Dr. Couch: In addition to the PRS applicability, we have uncovered new genes that will increase our understanding of the biology of breast cancer. While these genes are in pathways that are well known in cancer biology, the genes themselves have not previously been implicated in breast cancer biology. This information will open new areas of prevention research, that I am equally excited about.

You can read more about Dr. Couch’s BCRF research here.

The articles appeared in Nature and Nature Genetics October 23

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