Many studies have been conducted over the past 15 years of the genetic factors for breast cancer risk. Led by researchers at Vanderbilt University, the largest genetic study in breast cancer risk included data from more than 386,000 women from Asian and European ancestry to provide the latest understanding of the genetic variants linked with the disease. Results were published in the American Journal of Human Genetics.
In this analysis, the team included data from 160,500 women with breast cancer and more than 226,000 women of Asian and European ancestry. Most genetic studies of breast cancer have been conducted among women of European ancestry so the addition of a significant number of Asian women in this study provided key insights.
“This was not just a study to look at genetic variants but also to do transcriptome-wide association studies to identify risk,” said senior author Wei Zheng, MD, PhD, MPH of Vanderbilt University Medical Center. “We wanted not just to tell the difference between the two populations—Asian and European—but also gain some new insights about the genetic variants, whether they are causal or not, or whether it could be a target gene.”
The data used in this study was collected from the Asia Breast Cancer Consortium (ABCC) and the Breast Cancer Association Consortium(BCAC), including 386,696 women (139,523 of Asian ancestry and 247,173 of European ancestry). In addition, the team analyzed two types of breast cancer according to estrogen receptor status: negative and positive. They identified 222 risk loci and 137 genes associated with breast cancer risk. Of these, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants.
The results also indicated significant differences between the women of Asian and European ancestry in terms of risk variants and their frequency. “Some variants are only found in Asian populations and some only in European,” said Zheng. “And there are a pretty large number of variants that show differences in association with breast cancer risk.”
Once key genes were identified, Zheng and colleagues pursued pathway analysis to identify multiple signaling pathways. They found that germline alterations in TP53, RAS, and MAPK pathways may play a more significant role in the etiology of breast cancer than what is currently appreciated. “This will be helpful in the future to design target therapies, or perhaps for early detection or monitoring treatment response,” added Zheng.
The team believes this study represents the most comprehensive data on genetic breast cancer risk. “We hope this can be used as a reference so that everyone in the field can see the different loci and genes identified so far in one place and use it for future studies,” said Zheng.