Breast cancer susceptibility: New tests look for gene variations to assess risk

For most women who have a personal and/or family history of breast cancer, genetic testing for BRCA1 and BRCA2 (the two genes known to be responsible for the majority of hereditary breast and ovarian cancer) is found to be negative.  Several of these families are said to fit more into the category of “familial” breast cancer, meaning that there is more breast cancer present in a family, or at a younger age of diagnosis, than would be expected by chance alone.  However, these families do not typically fit the striking characteristics seen with hereditary cancer.*  It is suspected that in these families, cancer is not caused by a single gene mutation that is passed from generation to generation, but rather by a complicated interaction of multiple genetic and environmental factors that together pose an increased risk to develop breast cancer. 

SNPs: What are they and what do they mean to me?
These other genetic “factors,” for the most part, are yet to be discovered.  However, recent studies have identified a number of genetic changes that may alter the risk to develop breast cancer.  These changes, referred to as single nucleotide polymorphisms, or SNPs, can be thought of as single letter spelling differences in the DNA code.  Each SNP may occur commonly in the general population and are found in healthy individuals.  In other words, they represent normal variations in DNA.  However, depending on where they are located, they may slightly increase the risk for certain diseases, including cancer.

By itself, a single SNP is unlikely to significantly modify the risk to develop breast cancer.  However, if an individual were to carry several specific SNPs in combination, this may have a noticeable impact on his/her risk of developing cancer.  Two large studies have found four different SNPs that can increase the risk for breast cancer.  For any woman in the general population, the lifetime risk to develop breast cancer is around 13%, and for a woman who carries these SNPs that risk may be as high as 20%.

These SNPs may explain why some women may be more susceptible to breast cancer because of their genetic make-up, even if they do not carry a BRCA gene mutation.  Even for women who do carry a BRCA mutation, the lifetime risk to develop breast cancer is not 100%, and is quoted to range anywhere from 40% up to 87% in a lifetime.  The reason for such variation among families with BRCA mutations may also be explained by these modifying genetic changes.  One study has found two SNPs that increase the risk for breast cancer in the general population may also modify the risk in BRCA carriers. 

So where are we going with this new information?
Following these discoveries, new tests are starting to become available on the market that will look for the presence of several of these SNPs in an individual blood sample and then provide a modified risk for that person to develop cancer.  Already, there are SNP tests clinically available for breast cancer risk assessment.  These tests claim to provide risk information for women who have a family history of cancer, as well as women who have no family history of cancer.  The hope is that eventually these tests will provide useful information to help guide screening and management decisions by providing individualized, or personalized, cancer risk assessment. 

Further studies are needed before theses tests become mainstream to learn how SNP tests can improve risk assessment and clinical care for women in the general population, and for those women who carry a BRCA gene mutation.  Currently, there is not a lot of evidence that these SNP tests improve risk assessment much more than a thorough, accurate family history evaluation.  There are no published guidelines how to use the information obtained from a SNP test to modify breast cancer screening.  In addition, the rate of insurance reimbursement and coverage for such testing is unclear since it has become only recently available. 

There is much that is still not known about how SNPs can interact with one another and with other genes in the body to alter the risk for different cancers.  Additionally, the risk to develop cancer is further complicated by other environmental and lifestyle factors such as diet, weight, exercise, age at first pregnancy, number of pregnancies, use of birth control pills, and other environmental exposures that have yet to be clarified.  Cancer is obviously complicated and we still have much to learn, but SNP testing is a fascinating breakthrough in the field of cancer risk assessment that with further research may offer the opportunity to learn how to improve an individual’s screening guidelines.

AC Antoniou, et al on behalf of CIMBA. Common Breast Cancer-Predisposition Alleles are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. The American Journal of Human Genetics, 2008; 82: 937–948.

DF Easton, et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature, 2007; 447: 1087-1095

PDP Pharoah, AC Antoniou, DF Easton and Ponder, BAJ.  Polygenes, risk prediction, and targeted prevention of breast cancer.  The New England Journal of Medicine, 2008; 358: 2797-2803.