Morphological signatures and genomic correlates in glioblastoma

Large multimodal datasets such as The Cancer Genome Atlas present an opportunity to perform correlative studies of tissue morphology and genomics to explore the morphological phenotypes associated with gene expression and genetic alterations. In this paper we present an investigation of Cancer Genome Atlas data that correlates morphology with recently discovered molecular subtypes of glioblastoma. Using image analysis to segment and extract features from millions of cells, we calculate high-dimensional morphological signatures to describe trends of nuclear morphology and cytoplasmic staining in whole-slide images. We illustrate the similarities between the analysis of these signatures and predictive studies of gene expression, both in terms of limited sample size and high-dimensionality. Our top-down analysis demonstrates the power of morphological signatures to predict clinically-relevant molecular tumor subtypes, with 85.4% recognition of the proneural subtype. A complementary bottom-up analysis shows that self-aggregating clusters have statistically significant associations with tumor subtype and reveals the existence of remarkable structure in the morphological signature space of glioblastomas.