MANGO: pipeline for identifying genomic translocations with key biological significance in inflammatory breast cancer

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Genomic instability in cancer is essential for aberrant gene expression and translocation events that potentiate oncogenesis. Thus gene fusions, nonsense mutations and gene deregulation are key contributors to oncogenic phenotypes. Certain genomic translocations have been linked to cancer subtypes, such BCR-ABL1 for chronic myeloid leukemia (CML) serving as potential onco-biomarkers. Inflammatory breast cancer (IBC) is the rarest and most lethal subtype of breast cancer with a 5-year survival rate below 50%. Ethnic disparities for breast cancer exist; negative estrogen (ER) and progesterone (PR) hormone receptor status is more frequent in Hispanic and African American women. In addition, inflammatory breast cancer lacks defined molecular markers limiting its early onset detection which leads to poorer overall prognosis. Thus, we hypothesized that profiling IBC translocations, including its subtypes, show valuable insights to better understand this complex disease. We developed MANGO, a pipeline that leverages STAR, STAR-Fusion, FusionInspector, and Trinity to identify, visualize and assemble gene fusions from IBC sequencing data. Using the SUM149PT cell line as a model for IBC, we identified and experimentally validated a model fusion gene ZDHHC5-EPB41L5. Fusion unaware sequence assemblies cross-validated the fusion and its multiple splice sites, one of which encodes a fusion peptide. Differential gene expression between SUM149PT and SUM190PT, an IBC cell line without evidence for the identified translocation, showed loss of expression of ZDHHC5 but no change in EPB41L5, suggesting the latter retained its expression in its new genomic localization. Furthermore, in-silico functional predictions for experimental results reveals an in-frame fusion peptide with transmembrane signals in EPB41L5. Genomic translocation mapping reveals triple-negative IBC diverges from traditional breast cancer translocation patterns. In short, MANGO serves as a powerful tool to identify biologically significant translocations involved in IBC and other cancer classifications.

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