Genetic risk of Breast Cancer
Altogether about 20 to 30% of women who get breast cancer have a family member with the disease, meaning that 70 to 80% do not have a family history of breast cancer. Women who have a first-degree relative with breast cancer are twice as likely as the general population to develop the disease themselves. This indicates that genetic predisposition plays a significant role in determining who gets breast cancer and who does not.
Only a portion of family history-positive breast cancer patients (up to 25%; 2 to 5% of all breast cancer cases) have identifiable genetic mutations in the BRCA1, BRCA2, TP53, and PTEN genes, which, when inherited from one’s parents, are highly likely to cause breast cancer. These individuals usually have a strong family history of breast cancer, particularly of early-onset and/or ovarian cancer cases. However, each of these mutations is very rare, occurring in only a very small fraction of cases. The deCODE BreastCancerTM test does not include or detect these rare mutations. However, some of the variants in the deCODE BreastCancerTM test modify the risk of breast cancer in subjects who carry mutations in the BRCA1 and/or BRCA2 genes. The deCODE BreastCancerTM test reports a factor based on the relevant SNP genotypes by which the lifetime risk from the BRCA mutation should be multiplied in order to determine the overall lifetime genetic risk of breast cancer, given that the subject is diagnosed as a carrier of a high-penetrance BRCA1 or BRCA2 mutation.
Then there are the 15 to 20 % of breast cancer cases that have 1 or more close relatives with breast cancer but do not have mutations in the BRCA1, BRCA2, TP53, and PTEN genes. These patients may have hereto unidentified genetic variants. The risk identified by the deCODE BreastCancerTM test seems to be largely independent of immediate family history, i.e., the risk markers identified account for only a small portion (about 5%) of these familial cases. This fact makes the deCODE BreastCancerTM test all the more relevant for this group of patients since their increased baseline risk caused by their family history, and as assessed by some of the models available, can be multiplied with the test results.
The majority (70 to 80%) of breast cancer cases arise in individuals who do not have a noticeable family history of breast cancer but who may still be genetically predisposed to develop breast cancer. The genetic predisposition variants they inherit may be so common in the population, of such a number, and each with such a relatively small effect, that their contribution to breast cancer generally surfaces in sporadic cases. On an individual basis however, women who have several of these genetic risk variants are at substantially increased risk relative to the population. The deCODE BreastCancerTM test is designed to assess the genetic risk of the common form of breast cancer by testing for multiple risk variants that are common in the population.
Collectively, the deCODE BreastCancerTM markers account for about 60% of the population attributable risk, meaning that if we were able to prevent all breast cancer cases in women that have increased risk relative to the general population according to the deCODE BreastCancerTM test, 60% of breast cancer would be eliminated.
In basic terms, carrying a high-risk deCODE BreastCancerTM genetic profile does not necessarily mean that the subject will develop breast cancer, just as having a low-risk genetic profile does not eliminate the possibility of getting the disease. Rather, these genetic risk variants impact the likelihood that the subject will develop breast cancer. Nongenetic risk factors such as current age, age at menarche, age at first live birth, hormonal history and status, history of exposure of the chest wall to X-rays, and previous benign or malignant breast disease may also affect a subject’s risk of breast cancer. Genetic and nongenetic risk factors all need to be taken into account when judging the overall breast cancer risk of an individual.