Single-cell landscape in mammary epithelium reveals bipotent-like cells associated with breast cancer risk and outcome

Adult stem-cells may serve as the cell-of-origin for cancer, yet their unbiased identification in single cell RNA sequencing data is challenging due to the high dropout rate. In the case of breast, the existence of a bipotent stem-like state is also controversial. Here we apply a marker-free algorithm to scRNA-Seq data from the human mammary epithelium, revealing a high-potency cell-state enriched for an independent mammary stem-cell expression module. We validate this stem-like state in independent scRNA-Seq data. Our algorithm further predicts that the stem-like state is bipotent, a prediction we are able to validate using FACS sorted bulk expression data. The bipotent stem-like state correlates with clinical outcome in basal breast cancer and is characterized by overexpression of YBX1 and ENO1, two modulators of basal breast cancer risk. This study illustrates the power of a marker-free computational framework to identify a novel bipotent stem-like state in the mammary epithelium

Robust prediction of clinical outcomes using cytometry data.

MotivationFlow cytometry and mass cytometry are widely used to diagnose diseases and to predict clinical outcomes. When associating clinical features with cytometry data, traditional analysis methods require cell gating as an intermediate step, leading to information loss and susceptibility to batch effects. Here, we wish to explore an alternative approach that predicts clinical features from cytometry data without the cell-gating step. We also wish to test if such a gating-free approach increases the accuracy and robustness of the prediction.ResultsWe propose a novel strategy (CytoDx) to predict clinical outcomes using cytometry data without cell gating. Applying CytoDx on real-world datasets allow us to predict multiple types of clinical features. In particular, CytoDx is able to predict the response to influenza vaccine using highly heterogeneous datasets, demonstrating that it is not only accurate but also robust to batch effects and cytometry platforms.Availability and implementationCytoDx is available as an R package on Bioconductor (bioconductor.org/packages/CytoDx). Data and scripts for reproducing the results are available on bitbucket.org/zichenghu_ucsf/cytodx_study_code/downloads.Supplementary informationSupplementary data are available at Bioinformatics online

Radiomics strategies for risk assessment of tumour failure in head-and-neck cancer

Quantitative extraction of high-dimensional mineable data from medical images is a process known as radiomics. Radiomics is foreseen as an essential prognostic tool for cancer risk assessment and the quantification of intratumoural heterogeneity. In this work, 1615 radiomic features (quantifying tumour image intensity, shape, texture) extracted from pre-treatment FDG-PET and CT images of 300 patients from four different cohorts were analyzed for the risk assessment of locoregional recurrences (LR) and distant metastases (DM) in head-and-neck cancer. Prediction models combining radiomic and clinical variables were constructed via random forests and imbalance-adjustment strategies using two of the four cohorts. Independent validation of the prediction and prognostic performance of the models was carried out on the other two cohorts (LR: AUC = 0.69 and CI = 0.67; DM: AUC = 0.86 and CI = 0.88). Furthermore, the results obtained via Kaplan-Meier analysis demonstrated the potential of radiomics for assessing the risk of specific tumour outcomes using multiple stratification groups. This could have important clinical impact, notably by allowing for a better personalization of chemo-radiation treatments for head-and-neck cancer patients from different risk groups.Comment: (1) Paper: 33 pages, 4 figures, 1 table; (2) SUPP info: 41 pages, 7 figures, 8 table

Development of a multivariable risk model integrating urinary cell DNA methylation and cell-free RNA data for the detection of significant prostate cancer

Background: Prostate cancer exhibits severe clinical heterogeneity and there is a critical need for clinically implementable tools able to precisely and noninvasively identify patients that can either be safely removed from treatment pathways or those requiring further follow up. Our objectives were to develop a multivariable risk prediction model through the integration of clinical, urine-derived cell-free messenger RNA (cf-RNA) and urine cell DNA methylation data capable of noninvasively detecting significant prostate cancer in biopsy naïve patients. Methods: Post-digital rectal examination urine samples previously analyzed separately for both cellular methylation and cf-RNA expression within the Movember GAP1 urine biomarker cohort were selected for a fully integrated analysis (n = 207). A robust feature selection framework, based on bootstrap resampling and permutation, was utilized to find the optimal combination of clinical and urinary markers in a random forest model, deemed ExoMeth. Out-of-bag predictions from ExoMeth were used for diagnostic evaluation in men with a clinical suspicion of prostate cancer (PSA ≥ 4 ng/mL, adverse digital rectal examination, age, or lower urinary tract symptoms). Results: As ExoMeth risk score (range, 0-1) increased, the likelihood of high-grade disease being detected on biopsy was significantly greater (odds ratio = 2.04 per 0.1 ExoMeth increase, 95% confidence interval [CI]: 1.78-2.35). On an initial TRUS biopsy, ExoMeth accurately predicted the presence of Gleason score ≥3 + 4, area under the receiver-operator characteristic curve (AUC) = 0.89 (95% CI: 0.84-0.93) and was additionally capable of detecting any cancer on biopsy, AUC = 0.91 (95% CI: 0.87-0.95). Application of ExoMeth provided a net benefit over current standards of care and has the potential to reduce unnecessary biopsies by 66% when a risk threshold of 0.25 is accepted. Conclusion: Integration of urinary biomarkers across multiple assay methods has greater diagnostic ability than either method in isolation, providing superior predictive ability of biopsy outcomes. ExoMeth represents a more holistic view of urinary biomarkers and has the potential to result in substantial changes to how patients suspected of harboring prostate cancer are diagnosed

Circular RNAs in Clear Cell Renal Cell Carcinoma: Their Microarray-Based Identification, Analytical Validation, and Potential Use in a Clinico-Genomic Model to Improve Prognostic Accuracy

Circular RNAs (circRNAs) may act as novel cancer biomarkers. However, a genome-wide evaluation of circRNAs in clear cell renal cell carcinoma (ccRCC) has yet to be conducted. Therefore, the objective of this study was to identify and validate circRNAs in ccRCC tissue with a focus to evaluate their potential as prognostic biomarkers. A genome-wide identification of circRNAs in total RNA extracted from ccRCC tissue samples was performed using microarray analysis. Three relevant differentially expressed circRNAs were selected (circEGLN3, circNOX4, and circRHOBTB3), their circular nature was experimentally confirmed, and their expression-along with that of their linear counterparts-was measured in 99 malignant and 85 adjacent normal tissue samples using specifically established RT-qPCR assays. The capacity of circRNAs to discriminate between malignant and adjacent normal tissue samples and their prognostic potential (with the endpoints cancer-specific, recurrence-free, and overall survival) after surgery were estimated by C-statistics, Kaplan-Meier method, univariate and multivariate Cox regression analysis, decision curve analysis, and Akaike and Bayesian information criteria. CircEGLN3 discriminated malignant from normal tissue with 97% accuracy. We generated a prognostic for the three endpoints by multivariate Cox regression analysis that included circEGLN3, circRHOBT3 and linRHOBTB3. The predictive outcome accuracy of the clinical models based on clinicopathological factors was improved in combination with this circRNA-based signature. Bootstrapping as well as Akaike and Bayesian information criteria confirmed the statistical significance and robustness of the combined models. Limitations of this study include its retrospective nature and the lack of external validation. The study demonstrated the promising potential of circRNAs as diagnostic and particularly prognostic biomarkers in ccRCC patients

Using Similarity Metrics on Real World Data and Patient Treatment Pathways to Recommend the Next Treatment

Non-small-cell lung cancer (NSCLC) is one of the most prevalent types of lung cancer and continues to have an ominous five year survival rate. Considerable work has been accomplished in analyzing the viability of the treatments offered to NSCLC patients; however, while many of these treatments have performed better over populations of diagnosed NSCLC patients, a specific treatment may not be the most effective therapy for a given patient. Coupling both patient similarity metrics using the Gower similarity metric and prior treatment knowledge, we were able to demonstrate how patient analytics can complement clinical efforts in recommending the next best treatment. Our retrospective and exploratory results indicate that a majority of patients are not recommended the best surviving therapy once they require a new therapy. This investigation lays the groundwork for treatment recommendation using analytics, but more investigation is required to analyze patient outcomes beyond survival

Patients With Kidney Cancer

To develop a preoperative prognostic model in order to predict recurrence-free survival in patients with nonmetastatic kidney cancer.A multi-institutional data base of 1889 patients who underwent surgical resection between 1987 and 2007 for kidney cancer was retrospectively analyzed. Preoperative variables were defined as age, gender, presentation, size, presence of radiological lymph nodes and clinical stage. Univariate and multivariate analyses of the variables were performed using the Cox proportional hazards regression model. A model was developed with preoperative variables as predictors of recurrence after nephrectomy. Internal validation was performed by Harrells concordance index.The median follow-up was 23.6 months (1222 months). During the follow-up, 258 patients (13.7) developed cancer recurrence. The median follow-up for patients who did not develop recurrence was 25 months. The median time from surgery to recurrence was 13 months. The 5-year freedom from recurrence probability was 78.6. All variables except age were associated with freedom from recurrence in multivariate analyses (P 0.05). Age was marginally significant in the univariate analysis. All variables were included in the predictive model. The calculated c-index was 0.747.This preoperative model utilizes easy to obtain clinical variables and predicts the likelihood of development of recurrent disease in patients with kidney tumors