Performance comparison of TCR-pMHC prediction tools reveals a strong data dependency.

The interaction of T-cell receptors with peptide-major histocompatibility complex molecules (TCR-pMHC) plays a crucial role in adaptive immune responses. Currently there are various models aiming at predicting TCR-pMHC binding, while a standard dataset and procedure to compare the performance of these approaches is still missing. In this work we provide a general method for data collection, preprocessing, splitting and generation of negative examples, as well as comprehensive datasets to compare TCR-pMHC prediction models. We collected, harmonized, and merged all the major publicly available TCR-pMHC binding data and compared the performance of five state-of-the-art deep learning models (TITAN, NetTCR-2.0, ERGO, DLpTCR and ImRex) using this data. Our performance evaluation focuses on two scenarios: 1) different splitting methods for generating training and testing data to assess model generalization and 2) different data versions that vary in size and peptide imbalance to assess model robustness. Our results indicate that the five contemporary models do not generalize to peptides that have not been in the training set. We can also show that model performance is strongly dependent on the data balance and size, which indicates a relatively low model robustness. These results suggest that TCR-pMHC binding prediction remains highly challenging and requires further high quality data and novel algorithmic approaches.

DiaDeL: An Accurate Deep Learning-Based Model With Mutational Signatures for Predicting Metastasis Stage and Cancer Types.

Mutational signatures help identify cancer-associated genes that are being involved in tumorigenesis pathways. Hence, these pathways guide precision medicine approaches to find appropriate drugs and treatments. The pattern of mutations varies in different cancer types. Some mutations dysregulate protein function so that their accumulation is responsible for cancer development and might be associated with different cancer types. Therefore, mutations as a feature set can be used as an informative candidate to distinguish various cancer types. There are several options for demonstrating mutations. One might employ binary values to demonstrate mutation regions. Another potential method for extracting features is utilizing mutation interpreters. In this study, we investigate the trinucleotide mutational pattern of each cancer type. Moreover, we extract salient NMF-based mutational signatures across various cancer types. Then, we identify cancer-associated genes of a target cancer based on its salient signatures. We evaluate the cancer-associated genes using survival and gene expression analysis in different stages of cancer. Furthermore, we introduce DiaDeL, which is a deep learning-based binary classifier. The DiaDeL model uses mutational signatures as input features and distinct a cancer type from the others. Our proposed model outperforms six state-of-the-art methods with 0.824 and 0.88 for accuracy and AUC, respectively. The source code is available at https://github.com/sabdollahi/DiaDeL.

Deciphering genes associated with diffuse large B-cell lymphoma with lymphomatous effusions: A mutational accumulation scoring approach.

INTRODUCTION: Earlier studies have shown that lymphomatous effusions in patients with diffuse large B-cell lymphoma (DLBCL) are associated with a very poor prognosis, even worse than for non-effusion-associated patients with stage IV disease. We hypothesized that certain genetic abnormalities were associated with lymphomatous effusions, which would help to identify related pathways, oncogenic mechanisms, and therapeutic targets. METHODS: We compared whole-exome sequencing on DLBCL samples involving solid organs (n = 22) and involving effusions (n = 9). We designed a mutational accumulation-based approach to score each gene and used mutation interpreters to identify candidate pathogenic genes associated with lymphomatous effusions. Moreover, we performed gene-set enrichment analysis from a microarray comparison of effusion-associated versus non-effusion-associated DLBCL cases to extract the related pathways. RESULTS: We found that genes involved in identified pathways or with high accumulation scores in the effusion-based DLBCL cases were associated with migration/invasion. We validated expression of 8 selected genes in DLBCL cell lines and clinical samples: MUC4, SLC35G6, TP53BP2, ARAP3, IL13RA1, PDIA4, HDAC1 and MDM2, and validated expression of 3 proteins (MUC4, HDAC1 and MDM2) in an independent cohort of DLBCL cases with (n = 31) and without (n = 20) lymphomatous effusions. We found that overexpression of HDAC1 and MDM2 correlated with the presence of lymphomatous effusions, and HDAC1 overexpression was associated with the poorest prognosis.  CONCLUSION: Our findings suggest that DLBCL associated with lymphomatous effusions may be associated mechanistically with TP53-MDM2 pathway and HDAC-related chromatin remodeling mechanisms.

High G protein subunit beta 4 protein level is correlated to poor prognosis of urothelial carcinoma.

Data mining on a public domain detected eight potential transcripts which were upregulated in advanced UBUCs, suggesting that they may take part in UC development or/and progression. Retrospectively, immunohistochemistry along with H-score recording was carried out to evaluate the GNB4 protein levels on tissues from UC patients. Correlations between GNB4 H-score and imperative clinicopathological factors, as well as the implication of GNB4 protein level on disease-specific and metastasis-free survivals were assessed. In UTUCs (n = 340) and UBUCs (n = 295), 170 (50.0%) and 148 (50.0%) cases, respectively, were identified to be of high GNB4 expression. The GNB4 protein levels were correlated to numerous clinicopathological features and patients' survivals. Upregulation of the GNB4 protein was significantly associated with primary tumor, nodal metastasis, histological grade, vascular invasion and mitotic rate. High GNB4 protein levels independently and significantly predicted poor disease-specific and metastasis-free in UTUC and UBUC, respectively. Ingenuity pathway analysis furthermore showed that multiple signaling pathways were enriched including 'Communication between Innate and Adaptive Immune Cells' and 'NFκB Signaling'. Our findings demonstrated that the upregulation of the GNB4 protein is an independent unfavorable prognosticator in UC. High GNB4 gene expression plays an important role in UC progression.

WinBinVec: Cancer-Associated Protein-Protein Interaction Extraction and Identification of 20 Various Cancer Types and Metastasis Using Different Deep Learning Models.

Biophysical protein-protein interactions perform dominant roles in the initiation and progression of many cancer-related pathways. A protein-protein interaction might play different roles in diverse cancer types. Hence, prioritizing the PPIs in each cancer type would help detect cancer-associated pathways, find a better understanding of cancer biology, and facilitate drug discovery. Several studies to date have proposed computational methods for extracting the PPI essentiality of different cancer types based on the PPI network. The main drawback of these studies is not using a rich source such as genomics variant data. An amino acid sequence encodes useful information about protein structure and behavior. We represent each amino acid sequence based on its variants/mutations in seven different ways: binary vectors, pathogenicity scores, binding affinity changes upon mutations, gene expression-based network of the interactions, biophysicochemical properties, g-gap dipeptide, and one-hot vectors. Based on these representations, we design and consider seven different deep learning models. Then, we compare the accuracy of these models in predicting 20 different cancer types from the TCGA cohort. WinBinVec is a window-based model that outperforms the other models. Moreover, WinBinVec contains a PPI essentiality module that helps extract the essentiality probability of each PPI for every cancer type. Source code and Data: https://github.com/sabdollahi/WinBinVec.

Precise uncertain significance prediction using latent space matrix factorization models: genomics variant and heterogeneous clinical data-driven approaches.

Several studies to date have proposed different types of interpreters for measuring the degree of pathogenicity of variants. However, in predicting the disease type and disease-gene associations, scholars face two essential challenges, namely the vast number of existing variants and the existence of variants which are recognized as variant of uncertain significance (VUS). To tackle these challenges, we propose algorithms to assign a significance to each gene rather than each variant, describing its degree of pathogenicity. Since the interpreters identified most of the variants as VUS, most of the gene scores were identified as uncertain significance. To predict the uncertain significance scores, we design two matrix factorization-based models: the common latent space model uses genomics variant data as well as heterogeneous clinical data, while the single-matrix factorization model can be used when heterogeneous clinical data are unavailable. We have managed to show that the models successfully predict the uncertain significance scores with low error and high accuracy. Moreover, to evaluate the effectiveness of our novel input features, we train five different multi-label classifiers including a feedforward neural network with the same feature set and show they all achieve high accuracy as the main impact of our approach comes from the features. Availability: The source code is freely available at https://github.com/sabdollahi/CoLaSpSMFM.