Background: Breast cancer is the most frequently diagnosed form of invasive cancer in women and the second leading cause of cancer death. Triple-negative breast cancer (TNBC) accounts for 10-20% of the disease. This aggressive subtype lacks receptors for estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2), drastically reducing treatment options. Hispanic/Latinas, who derive ancestry from European, African, and Native origins, are at least 30% more likely to be diagnosed with TNBC compared to non-Hispanic White women. However, little is known about the genomic architecture of TNBCs in Hispanic/Latinas. The goal of our study was to test the association between genetic ancestry and gene expression in TNBC samples from Hispanics/Latinas to help identify potential therapeutic targets.
Methods and Results: We obtained 41 TNBC tissues through collaboration with the National Cancer Institute in Colombia along with demographic and clinical information. Genetic ancestry proportions were estimated using a panel of 106 Ancestry Informative Markers (AIMs). RNA was extracted from FFPE tissues, qualified using Agilent chips, and used for RNA sequencing at the Translational Genomics Core at the Stanley S. Scott Cancer Center. We used an online tool (http://cbc.mc.vanderbilt.edu/tnbc/) to validate TNBC status, and 33 of the 41 samples were confirmed. Quality control procedures ensured that the samples were of acceptable quality for further analysis. Individuals were classified as having high or low genetic ancestry proportions for each of the ancestral components, based on mean ancestry proportions overall. Differential gene expression between individuals in each ancestry category was estimated utilizing DESeq2 in R-Studio. Average genetic ancestry proportions for the 33 samples analyzed were 0.52 European (18 individuals were in the high European ancestry group, 14 in the low European ancestry group), 0.36 Indigenous American (15 high, 17 low) and 0.1 African (8 high, 24 low). We observed that 91 genes were differentially expressed between high vs. low European ancestry, 21 for the Native and 12 for the African. Interestingly, 5 genes were common between the European and Native ancestries. LGALS9C and MESP1 had significant differences in normalized counts between high and low ancestry for both the Europeans and Natives, though the subgroups displayed opposite correlation patterns. These results were validated by real-time PCR. Using cBioPortal, we found that MESP1 and LGALS9C were associated with amplification in 2.8% and 1.5% of breast cancer cases, respectively. LGALS9C expression displays an inverse correlation with disease outcome in several cancers, including breast.
Conclusions: Our data suggest that expression levels of several genes, most notably MESP1 and LGALS9C, may be ancestry specific in TNBC patients from Colombia. Confirmation and further understanding of these findings are of outmost importance given that they could be therapeutic targets.
Citation Format: Laura Carrasquilla, Jone Garai, Silvia J. Serrano-Gomez, Maria C. Sanabria-Salas, Melody C. Baddoo, Laura Fejerman, Jovanny Zabaleta. Relationship between ancestry fractions and gene expression in triple-negative breast cancer in Hispanic/Latina women [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C035.