In addition to known biomarkers with a large effect such as the BRCA genes, the genetic risk for breast cancer is also determined by a number of low effect risk factors. Because of their smaller influence, it is a challenge to link such genetic variants to the disease. This requires gathering and analyzing data on DNA variations and the presence of a certain trait or disease for large patient populations. As there is power in numbers, even weaker effects can then be determined by statistical analysis. In this study, combining the data of different studies led to a better insight in the genetic risk of estrogen receptor negative (ER-) breast cancer.
The context
Some DNA regions, or “loci”, and their variations are associated with susceptibility for diseases such as cancer. Identifying these loci is important, as they can be used to estimate the hereditary risk to develop certain cancer types. Furthermore, finding the genes present in these DNA regions can give insight in the mechanism that causes the cancer.
Currently, 94 regions have been identified with variants associated with breast cancer, with only 14 of these linked to ER- breast cancer. The presence of estrogen receptors on tumor cells is an important factor for breast cancer treatment, since ER- cells are insensitive to hormone therapies. Consequently, ER- breast cancer is associated with worse short-term outcome compared to its ER+ counterpart. Breast cancers lacking the ER account for only 20-30% of all cases but are more common in young and/or African women.
The nuts and bolts
The smaller number of known loci for ER- breast cancer is partly due to the smaller availability of patients, as less patients make cancer-linked loci harder to detect. This study combined data of multiple previous studies to obtain a larger population, making the detection of subtle genetic influences more sensitive. By pooling different sources, data from more than 12.000 ER- patients, 15.000 BRCA1 mutation carriers and 56.000 controls could be analyzed.
This strategy led to the discovery of 4 new loci associated with ER- breast cancer. The percentage of the familial risk for ER- disease explained by mutations is not well defined. Assuming the estimate is similar to that of overall breast cancer, the identified mutations in the known loci explain 9.8% of the familial risk, and those in the 4 new loci account for a further 0.8%.
How will this help me?
By leveraging large amounts of patient data, new loci with a smaller effect on ER- breast cancer were identified. Further mapping and research into the function of the newly discovered loci will hopefully clarify their involvement in cancer development. The addition of new ER- loci to existing models will improve overall risk prediction models in the general population and for breast cancer among BRCA1 mutation carriers.
Source
Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer – Nature Communications (2016)