Co-Leads: Hua Zhao, PhD, Jie Shen, PhD, Aakrosh Ratan, PhD and Todd Stukenberg, PhD

Research

It is well established that African American(AA)/Blacks have higher mortality and more aggressive Breast Cancers than European Ancestry(EA)/Whites, but the underlying mechanisms are poorly understood.  Project 1 of SASCO studies mechanisms that lower the fidelity of mitosis to generate Chromosomal Instability (CIN) to generate highly aneuploid tumors.  Using a 100-gene transcriptional signature known as the Breast Functional Aneuploidy signature (BrFA100) that specifies highly aneuploid tumors, we explored the TCGA-BRCA datasets to determine if there is a racial disparity between Black and White patients.  While genes were equally likely to be overexpressed in either white or black patient’s tumors, we found that all of the BrFA100 genes were more highly expressed in black patients (Figure).  In fact, 85 of the 100 genes were significantly higher.  We saw a similar disparity in an independent signature of CIN (CIN70) that only has ~35% overlap with the BrFA100.  Since both signatures have several genes involved in mitosis, we asked if three different proliferation signatures showed such a disparity.  There was little to no disparity of any of the three proliferation signatures (only one is shown in the figure) and this important control argues the disparity is specific to CIN/Aneuploidy.  We also found the disparity in nontransformed tumor-adjacent breast tissue from patients.  Together, these data argue that the BRCA of black patients are more likely to have underlying CIN, and the mechanisms that are the focus of SASCO project 1 underlie this difference. To further support our findings, we propose the addition of three new laboratories into SASCO.  While the TCGA analysis revealed the disparity in ER+ tumors (not shown), it lacks the statistical power to test whether it exists in triple-negative breast tumors.  Hua Zhao (UVA, Public Health), who is an expert in racial disparities of Breast cancer, has a well-annotated dataset of ~40 white and 40 black triple-negative BRCA, including RNA sequence.  It is also unclear if the disparity is caused by genetic or environmental differences.  Therefore, we have initiated collaborations with Jie Shen (UVA Public Health), an expert in environmental factors underlying BRCA, and Aakrosh Ratan (UVA, Center of Public Health Genomics), an expert in the identification of germline variants that drive cancers.  Finally, we will bring in Brett Jones, a senior research associate in Todd Stukenberg’s lab for bioinformatic and machine learning expertise.  Even though highly aneuploid tumors are found in all four BRCA tumor subtypes, we currently do not have separate treatments for patients with high or low aneuploidy.  The long-term goal of Project 1 is to identify treatments that are specific to highly aneuploid tumors, and this subproject could establish if these treatments will benefit a higher percentage of black patients.