Migration rather than proliferation transcriptomic signatures are strongly associated with breast cancer patient survival.

The efficacy of prospective cancer treatments is routinely estimated by in vitro cell-line proliferation screens. However, it is unclear whether tumor aggressiveness and patient survival are influenced more by the proliferative or the migratory properties of cancer cells. To address this question, we experimentally measured proliferation and migration phenotypes across more than 40 breast cancer cell-lines. Based on the latter, we built and validated individual predictors of breast cancer proliferation and migration levels from the cells' transcriptomics. We then apply these predictors to estimate the proliferation and migration levels of more than 1000 TCGA breast cancer tumors. Reassuringly, both estimates increase with tumor's aggressiveness, as qualified by its stage, grade, and subtype. However, predicted tumor migration levels are significantly more strongly associated with patient survival than the proliferation levels. We confirmed these findings by conducting siRNA knock-down experiments on the highly migratory MDA-MB-231 cell lines and deriving gene knock-down based proliferation and migration signatures. We show that cytoskeletal drugs might be more beneficial in patients with high predicted migration levels. Taken together, these results testify to the importance of migration levels in determining patient survival.

Harnessing synthetic lethality to predict the response to cancer treatment.

While synthetic lethality (SL) holds promise in developing effective cancer therapies, SL candidates found via experimental screens often have limited translational value. Here we present a data-driven approach, ISLE (identification of clinically relevant synthetic lethality), that mines TCGA cohort to identify the most likely clinically relevant SL interactions (cSLi) from a given candidate set of lab-screened SLi. We first validate ISLE via a benchmark of large-scale drug response screens and by predicting drug efficacy in mouse xenograft models. We then experimentally test a select set of predicted cSLi via new screening experiments, validating their predicted context-specific sensitivity in hypoxic vs normoxic conditions and demonstrating cSLi's utility in predicting synergistic drug combinations. We show that cSLi can successfully predict patients' drug treatment response and provide patient stratification signatures. ISLE thus complements existing actionable mutation-based methods for precision cancer therapy, offering an opportunity to expand its scope to the whole genome.

Artificial Intelligence in Cytopathology: A Neural Network to Identify Papillary Carcinoma on Thyroid Fine-Needle Aspiration Cytology Smears.

INTRODUCTION: Fine-needle aspiration cytology (FNAC) for identification of papillary carcinoma thyroid is a moderately sensitive and specific modality. The present machine learning tools can correctly classify images into broad categories. Training software for recognition of papillary thyroid carcinoma on FNAC smears will be a decisive step toward automation of cytopathology. AIM: The aim of this study is to develop an artificial neural network (ANN) for the purpose of distinguishing papillary carcinoma thyroid and nonpapillary carcinoma thyroid on microphotographs from thyroid FNAC smears. SUBJECTS AND METHODS: An ANN was developed in the Python programming language. In the training phase, 186 microphotographs from Romanowsky/Pap-stained smears of papillary carcinoma and 184 microphotographs from smears of other thyroid lesions (at ×10 and ×40 magnification) were used for training the ANN. After completion of training, performance was evaluated with a set of 174 microphotographs (66 - nonpapillary carcinoma and 21 - papillary carcinoma, each photographed at two magnifications ×10 and ×40). RESULTS: The performance characteristics and limitations of the neural network were assessed, assuming FNAC diagnosis as gold standard. Combined results from two magnifications showed good sensitivity (90.48%), moderate specificity (83.33%), and a very high negative predictive value (96.49%) and 85.06% diagnostic accuracy. However, vague papillary formations by benign follicular cells identified wrongly as papillary carcinoma remain a drawback. CONCLUSION: With further training with a diverse dataset and in conjunction with automated microscopy, the ANN has the potential to develop into an accurate image classifier for thyroid FNACs.

Distal CpG islands can serve as alternative promoters to transcribe genes with silenced proximal promoters.

DNA methylation at the promoter of a gene is presumed to render it silent, yet a sizable fraction of genes with methylated proximal promoters exhibit elevated expression. Here, we show, through extensive analysis of the methylome and transcriptome in 34 tissues, that in many such cases, transcription is initiated by a distal upstream CpG island (CGI) located several kilobases away that functions as an alternative promoter. Specifically, such genes are expressed precisely when the neighboring CGI is unmethylated but remain silenced otherwise. Based on CAGE and Pol II localization data, we found strong evidence of transcription initiation at the upstream CGI and a lack thereof at the methylated proximal promoter itself. Consistent with their alternative promoter activity, CGI-initiated transcripts are associated with signals of stable elongation and splicing that extend into the gene body, as evidenced by tissue-specific RNA-seq and other DNA-encoded splice signals. Furthermore, based on both inter- and intra-species analyses, such CGIs were found to be under greater purifying selection relative to CGIs upstream of silenced genes. Overall, our study describes a hitherto unreported conserved mechanism of transcription of genes with methylated proximal promoters in a tissue-specific fashion. Importantly, this phenomenon explains the aberrant expression patterns of some cancer driver genes, potentially due to aberrant hypomethylation of distal CGIs, despite methylation at proximal promoters.