Presentation by: Dr. Jean-Noël Billaud and Dr. Nathan Pearson, Ingenuity Systems
Session 2: Cancer Genome Interpretation: how to make it simple?
11h20: Integrated Analysis and Interpretation of Variant and Gene Expression Data from Breast Cancer Subtypes
Molecular studies of breast cancer have defined at least five major subtypes (luminal A /B, Her2+, basal-like, and claudin-low), which inform patient prognosis, diagnosis, and management. Epithelial-to-mesenchymal-transition (EMT, types 1/2/3) is a latent embryonic program that let cells migrate and invade other tissues. In type-3 EMT, epithelial cancer cells at the invasive front of primary tumors become able to invade and metastasize through the blood, and generate a metastatic lesion at distant tissue. On reaching distal sites, these disseminated cancer cells partially revert to an epithelial phenotype allowing local adhesion and proliferation.
Here, we document molecular differences between breast cancer subtypes (claudin-low and luminal) that reflect type-3 EMT, via integrated genomic and transcriptomic analysis with Ingenuity Variant Analysis and Ingenuity Pathways Analysis (IPA). In Ingenuity Variant Analysis, we identify and functionally annotate claudin-low-distinctive genetic variants, to identify those most likely to drive EMT. We then integrate these findings into a comprehensive biological portrait of EMT, using RNA-Seq profiles from the 2 breast cancer subtypes, to highlight important molecular steps, processes, and pathways in these claudin-low cell lines. Notably, we find that isoform-specific expression patterns in multiple proteins may contribute to EMT. Finally, we computationally reconstruct a likely transcriptional program underlying EMT.
Our approach, using a sophisticated but intuitive online data analysis platform, exemplifies data-integrative methods for defining genomic events that drive processes, such as EMT, that crucially underlie tissue- and condition-specific modes of tumor emergence and spread.