An international study led by scientists at Vanderbilt University Medical Center, division of epidemiology, Nashville, TN, and the QIMR Berghofer Medical Research Institute in Herston, Australia, has identified 48 candidate susceptibility genes for breast cancer risk, including 14 genes at loci not yet reported for breast cancer.
Their findings, published June 18 in the journal Nature Genetics, provide new insights into the biology and genetics of breast cancer, the most common cancer among women in many countries around the globe. “This study has provided substantial novel information to improve our understanding of breast cancer genetics and biology,” said Dr. Wei Zheng, the paper’s senior author and professor at the Vanderbilt Epidemiology Center.
Genetic factors play an important role in breast cancer etiology, said Dr. Zheng. To date, genetic markers in approximately 170 chromosome regions have been identified in association with breast cancer risk. However, these genetic factors explain only a small fraction of heritability for breast cancer and the genes responsible for the associations remain unknown in most of these regions.
To identify novel breast cancer risk loci and likely causal genes, the researchers conducted a transcriptome-wide association study (TWAS) of nearly 123,000 women of European descent who had been diagnosed for breast cancer and 106,000 controls (women without disease) included in the Breast Cancer Association Consortium, a large international consortium that includes studies conducted in 22 countries around the world.
The researchers first built genetic models to predict expression levels of genes across the human genome using data from a small set of women whose breast tissue samples were analyzed for gene expression. Then they used these models to predict gene expression in a large number of breast cancer patients and controls using data about their genetic make-up. Finally, genetically predictive expression levels of genes in cases and controls were compared to identify genes that were expressed differently in the two groups.
“This research design is very cost-efficient and powerful in identifying candidate risk genes for breast cancer,” said Dr. Lang Wu, a former Vanderbilt postdoctoral fellow and now research instructor in medicine, who is one of two first authors of the paper.
Of the genes identified in the study, the researchers selected 13 genes for functional analyses. In 11 cases, silencing the genes influenced cell proliferation and the ability to form colonies, two characteristics of tumor growth. This provided further evidence that the identified genes might be involved in breast cancer risk. The findings provide multiple new targets for further study and raise hopes for development of more precise risk prediction strategies for breast cancer, the researchers said.
The functional analyses were led by Dr. Georgia Chenevix-Trench, head of the Cancer Genetics Laboratory at QIMR Berghofer and the paper’s co-corresponding author with Dr. Zheng.
The research was supported in part by National Institutes of Health grants CA158473, CA148677, CA218892 and CA160056 as well as Anne Potter Wilson Chair endowment funds.