Ancestry as a potential modifier of gene expression in breast tumors from Colombian women

Background Hispanic/Latino populations are a genetically admixed and heterogeneous group, with variable fractions of European, Indigenous American and African ancestries. The molecular profile of breast cancer has been widely described in non-Hispanic Whites but equivalent knowledge is lacking in Hispanic/Latinas. We have previously reported that the most prevalent breast cancer intrinsic subtype in Colombian women was Luminal B as defined by St. Gallen 2013 criteria. In this study we explored ancestry-associated differences in molecular profiles of Luminal B tumors among these highly admixed women. Methods We performed whole-transcriptome RNA-seq analysis in 42 Luminal tumors (21 Luminal A and 21 Luminal B) from Colombian women. Genetic ancestry was estimated from a panel of 80 ancestry-informative markers (AIM). We categorized patients according to Luminal subtype and to the proportion of European and Indigenous American ancestry and performed differential expression analysis comparing Luminal B against Luminal A tumors according to the assigned ancestry groups. Results We found 5 genes potentially modulated by genetic ancestry: ERBB2 (log2FC = 2.367, padj<0.01), GRB7 (log2FC = 2.327, padj<0.01), GSDMB (log2FC = 1.723, padj<0.01, MIEN1 (log2FC = 2.195, padj<0.01 and ONECUT2 (log2FC = 2.204, padj<0.01). In the replication set we found a statistical significant association between ERBB2 expression with Indigenous American ancestry (p = 0.02, B = 3.11). This association was not biased by the distribution of HER2+ tumors among the groups analyzed. Conclusions Our results suggest that genetic ancestry in Hispanic/Latina women might modify ERBB2 gene expression in Luminal tumors. Further analyses are needed to confirm these findings and explore their prognostic value.PLoS Journal

Ancestry as a potential modifier of gene expression in breast tumors from Colombian women.

BackgroundHispanic/Latino populations are a genetically admixed and heterogeneous group, with variable fractions of European, Indigenous American and African ancestries. The molecular profile of breast cancer has been widely described in non-Hispanic Whites but equivalent knowledge is lacking in Hispanic/Latinas. We have previously reported that the most prevalent breast cancer intrinsic subtype in Colombian women was Luminal B as defined by St. Gallen 2013 criteria. In this study we explored ancestry-associated differences in molecular profiles of Luminal B tumors among these highly admixed women.MethodsWe performed whole-transcriptome RNA-seq analysis in 42 Luminal tumors (21 Luminal A and 21 Luminal B) from Colombian women. Genetic ancestry was estimated from a panel of 80 ancestry-informative markers (AIM). We categorized patients according to Luminal subtype and to the proportion of European and Indigenous American ancestry and performed differential expression analysis comparing Luminal B against Luminal A tumors according to the assigned ancestry groups.ResultsWe found 5 genes potentially modulated by genetic ancestry: ERBB2 (log2FC = 2.367, padj&lt;0.01), GRB7 (log2FC = 2.327, padj&lt;0.01), GSDMB (log2FC = 1.723, padj&lt;0.01, MIEN1 (log2FC = 2.195, padj&lt;0.01 and ONECUT2 (log2FC = 2.204, padj&lt;0.01). In the replication set we found a statistical significant association between ERBB2 expression with Indigenous American ancestry (p = 0.02, B = 3.11). This association was not biased by the distribution of HER2+ tumors among the groups analyzed.ConclusionsOur results suggest that genetic ancestry in Hispanic/Latina women might modify ERBB2 gene expression in Luminal tumors. Further analyses are needed to confirm these findings and explore their prognostic value

Ancestry as a potential modifier of gene expression in breast tumors from Colombian women

<div><p>Background</p><p>Hispanic/Latino populations are a genetically admixed and heterogeneous group, with variable fractions of European, Indigenous American and African ancestries. The molecular profile of breast cancer has been widely described in non-Hispanic Whites but equivalent knowledge is lacking in Hispanic/Latinas. We have previously reported that the most prevalent breast cancer intrinsic subtype in Colombian women was Luminal B as defined by St. Gallen 2013 criteria. In this study we explored ancestry-associated differences in molecular profiles of Luminal B tumors among these highly admixed women.</p><p>Methods</p><p>We performed whole-transcriptome RNA-seq analysis in 42 Luminal tumors (21 Luminal A and 21 Luminal B) from Colombian women. Genetic ancestry was estimated from a panel of 80 ancestry-informative markers (AIM). We categorized patients according to Luminal subtype and to the proportion of European and Indigenous American ancestry and performed differential expression analysis comparing Luminal B against Luminal A tumors according to the assigned ancestry groups.</p><p>Results</p><p>We found 5 genes potentially modulated by genetic ancestry: <i>ERBB2 (</i>log2FC = 2.367, padj<0.01), <i>GRB7 (</i>log2FC = 2.327, padj<0.01), <i>GSDMB (</i>log2FC = 1.723, padj<0.01, <i>MIEN1 (</i>log2FC = 2.195, padj<0.01 and <i>ONECUT2 (</i>log2FC = 2.204, padj<0.01). In the replication set we found a statistical significant association between <i>ERBB2</i> expression with Indigenous American ancestry (p = 0.02, B = 3.11). This association was not biased by the distribution of HER2+ tumors among the groups analyzed.</p><p>Conclusions</p><p>Our results suggest that genetic ancestry in Hispanic/Latina women might modify <i>ERBB2</i> gene expression in Luminal tumors. Further analyses are needed to confirm these findings and explore their prognostic value.</p></div

Differentially expressed genes according to IA ancestry in Luminal B vs. Luminal A tumors.

<p>Venn diagram shows the number of differentially expressed genes (padj < 0.05) between Luminal B and Luminal A tumors with low IA ancestry and high IA ancestry. “Global” refers to differentially expressed genes between Luminal tumors without stratification by ancestry.</p

Gene expression profile of 42 Luminal breast cancer samples.

<p>(A) Unsupervised hierarchical clustering with 67 differentially expressed genes between IHC defined Luminal B and Luminal A tumors. (B) Most relevant signaling pathways associated with 67 differentially expressed genes in Luminal B tumors from Colombian women. (C) Diseases associated with differentially expressed genes in Luminal B.</p

Differentially expressed genes between Luminal B and Luminal A tumors classified by St. Gallen 2013 surrogates.

<p>Differentially expressed genes between Luminal B and Luminal A tumors classified by St. Gallen 2013 surrogates.</p

Characteristic of patients analyzed by RNA-seq.

<p>Characteristic of patients analyzed by RNA-seq.</p

Expression of <i>ESR1</i>, <i>PGR</i>, <i>MKI67</i> and <i>ERBB2</i> in clusters identified in the unsupervised hierarchical clustering.

<p>Expression of <i>ESR1</i>, <i>PGR</i>, <i>MKI67</i> and <i>ERBB2</i> in clusters identified in the unsupervised hierarchical clustering.</p

Association between candidate genes expression and the interaction between European ancestry and intrinsic subtype.

<p>Association between candidate genes expression and the interaction between European ancestry and intrinsic subtype.</p

Differentially expressed genes according to European ancestry in IHC defined Luminal B vs. Luminal A tumors.

<p>Venn diagram shows the number of differentially expressed genes (padj < 0.05) between Luminal B and Luminal A tumors with low European ancestry and high European ancestry. “Global” refers to differentially expressed genes between Luminal tumors without stratification by ancestry.</p