2. Large structural variations in inflammatory breast cancer identifies possible pathognomonic alterations

      Inflammatory breast cancer (IBC) is a clinical diagnosis that spans all breast cancer clinical and molecular subtypes. The clinical course of IBC is associated with poorer outcomes than molecular subtype-matched non-IBC and represents an unmet need in breast cancer therapy. IBC is characterized by invasive dermal lymphatic tumor emboli resulting in erythema and edema of the breast. These features suggest a pathognomonic common molecular theme or alteration, which if identified and targeted, could help reduce the mortality related to this highly aggressive breast cancer type. We performed whole-genome imaging on human IBC cell lines, PDX models, and tumors, as well as several non-IBC control tumors using the Saphyr technology (Bionano Genomics) which permits the detection of large structural variations that are difficult to detect by NGS. We identified novel somatic exon deletions in the AUTS2 gene in IBC samples, but not in non-IBCs. Similar deletions have been noted rarely in the germline of humans, resulting in autistic spectral disorders, neurocognitive defects, and microcephaly. Interestingly, the C-terminal deletions identified result in overexpression of truncated protein isoforms of AUTS2 by western blot analysis. Thus, whole genome imaging is a useful tool to identify large structural variations in cancer genomes that may be missed upon typical NGS analyses. We have identified AUTS2 C-terminus deletions as a possible biomarker of IBC, which could aid in a molecular diagnosis, and potentially new therapies targeted at AUTS2 once function and biological significance are identified. Functional and murine studies are underway.
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