Transcriptome and genome evolution during HER2-amplified breast neoplasia.

BACKGROUND: The acquisition of oncogenic drivers is a critical feature of cancer progression. For some carcinomas, it is clear that certain genetic drivers occur early in neoplasia and others late. Why these drivers are selected and how these changes alter the neoplasia's fitness is less understood. METHODS: Here we use spatially oriented genomic approaches to identify transcriptomic and genetic changes at the single-duct level within precursor neoplasia associated with invasive breast cancer. We study HER2 amplification in ductal carcinoma in situ (DCIS) as an event that can be both quantified and spatially located via fluorescence in situ hybridization (FISH) and immunohistochemistry on fixed paraffin-embedded tissue. RESULTS: By combining the HER2-FISH with the laser capture microdissection (LCM) Smart-3SEQ method, we found that HER2 amplification in DCIS alters the transcriptomic profiles and increases diversity of copy number variations (CNVs). Particularly, interferon signaling pathway is activated by HER2 amplification in DCIS, which may provide a prolonged interferon signaling activation in HER2-positive breast cancer. Multiple subclones of HER2-amplified DCIS with distinct CNV profiles are observed, suggesting that multiple events occurred for the acquisition of HER2 amplification. Notably, DCIS acquires key transcriptomic changes and CNV events prior to HER2 amplification, suggesting that pre-amplified DCIS may create a cellular state primed to gain HER2 amplification for growth advantage. CONCLUSION: By using genomic methods that are spatially oriented, this study identifies several features that appear to generate insights into neoplastic progression in precancer lesions at a single-duct level.

Bayesian Polytrees With Learned Deep Features for Multi-Class Cell Segmentation.

The recognition of different cell compartments, the types of cells, and their interactions is a critical aspect of quantitative cell biology. However, automating this problem has proven to be non-trivial and requires solving multi-class image segmentation tasks that are challenging owing to the high similarity of objects from different classes and irregularly shaped structures. To alleviate this, graphical models are useful due to their ability to make use of prior knowledge and model inter-class dependences. Directed acyclic graphs, such as trees, have been widely used to model top-down statistical dependences as a prior for improved image segmentation. However, using trees, a few inter-class constraints can be captured. To overcome this limitation, we propose polytree graphical models that capture label proximity relations more naturally compared to tree-based approaches. A novel recursive mechanism based on two-pass message passing was developed to efficiently calculate closed-form posteriors of graph nodes on polytrees. The algorithm is evaluated on simulated data and on two publicly available fluorescence microscopy datasets, outperforming directed trees and three state-of-the-art convolutional neural networks, namely, SegNet, DeepLab, and PSPNet. Polytrees are shown to outperform directed trees in predicting segmentation error by highlighting areas in the segmented image that do not comply with prior knowledge. This paves the way to uncertainty measures on the resulting segmentation and guide subsequent segmentation refinement.

Classification of breast lesions in ultrasonography using sparse logistic regression and morphology-based texture features.

PURPOSE: This work proposes a new reliable computer-aided diagnostic (CAD) system for the diagnosis of breast cancer from breast ultrasound (BUS) images. The system can be useful to reduce the number of biopsies and pathological tests, which are invasive, costly, and often unnecessary. METHODS: The proposed CAD system classifies breast tumors into benign and malignant classes using morphological and textural features extracted from breast ultrasound (BUS) images. The images are first preprocessed to enhance the edges and filter the speckles. The tumor is then segmented semiautomatically using the watershed method. Having the tumor contour, a set of 855 features including 21 shape-based, 810 contour-based, and 24 textural features are extracted from each tumor. Then, a Bayesian Automatic Relevance Detection (ARD) mechanism is used for computing the discrimination power of different features and dimensionality reduction. Finally, a logistic regression classifier computed the posterior probabilities of malignant vs benign tumors using the reduced set of features. RESULTS: A dataset of 104 BUS images of breast tumors, including 72 benign and 32 malignant tumors, was used for evaluation using an eightfold cross-validation. The algorithm outperformed six state-of-the-art methods for BUS image classification with large margins by achieving 97.12% accuracy, 93.75% sensitivity, and 98.61% specificity rates. CONCLUSIONS: Using ARD, the proposed CAD system selects five new features for breast tumor classification and outperforms state-of-the-art, making a reliable and complementary tool to help clinicians diagnose breast cancer.