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1. DORGE: Discovery of Oncogenes and tumoR suppressor genes using Genetic and Epigenetic features

   https://doi.org/10.1126/sciadv.aba6784  

   Lyu, Jie; Li, Jingyi Jessica; Su, Jianzhong; Peng, Fanglue; Chen, Yiling Elaine; Ge, Xinzhou; Li, Wei (November 2020, Science Advances)

   null (Ed.)

   Data-driven discovery of cancer driver genes, including tumor suppressor genes (TSGs) and oncogenes (OGs), is imperative for cancer prevention, diagnosis, and treatment. Although epigenetic alterations are important for tumor initiation and progression, most known driver genes were identified based on genetic alterations alone. Here, we developed an algorithm, DORGE (Discovery of Oncogenes and tumor suppressoR genes using Genetic and Epigenetic features), to identify TSGs and OGs by integrating comprehensive genetic and epigenetic data. DORGE identified histone modifications as strong predictors for TSGs, and it found missense mutations, super enhancers, and methylation differences as strong predictors for OGs. We extensively validated DORGE-predicted cancer driver genes using independent functional genomics data. We also found that DORGE-predicted dual-functional genes (both TSGs and OGs) are enriched at hubs in protein-protein interaction and drug-gene networks. Overall, our study has deepened the understanding of epigenetic mechanisms in tumorigenesis and revealed previously undetected cancer driver genes. 

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2. Genetic mutation and biological pathway prediction based on whole slide images in breast carcinoma using deep learning

   https://doi.org/10.1038/s41698-021-00225-9  

   Qu, Hui; Zhou, Mu; Yan, Zhennan; Wang, He; Rustgi, Vinod K.; Zhang, Shaoting; Gevaert, Olivier; Metaxas, Dimitris N. (September 2021, npj Precision Oncology)

   Abstract Breast carcinoma is the most common cancer among women worldwide that consists of a heterogeneous group of subtype diseases. The whole-slide images (WSIs) can capture the cell-level heterogeneity, and are routinely used for cancer diagnosis by pathologists. However, key driver genetic mutations related to targeted therapies are identified by genomic analysis like high-throughput molecular profiling. In this study, we develop a deep-learning model to predict the genetic mutations and biological pathway activities directly from WSIs. Our study offers unique insights into WSI visual interactions between mutation and its related pathway, enabling a head-to-head comparison to reinforce our major findings. Using the histopathology images from the Genomic Data Commons Database, our model can predict the point mutations of six important genes (AUC 0.68–0.85) and copy number alteration of another six genes (AUC 0.69–0.79). Additionally, the trained models can predict the activities of three out of ten canonical pathways (AUC 0.65–0.79). Next, we visualized the weight maps of tumor tiles in WSI to understand the decision-making process of deep-learning models via a self-attention mechanism. We further validated our models on liver and lung cancers that are related to metastatic breast cancer. Our results provide insights into the association between pathological image features, molecular outcomes, and targeted therapies for breast cancer patients. 

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3. Dr.Nod: computational framework for discovery of regulatory non-coding drivers in tissue-matched distal regulatory elements

   https://doi.org/10.1093/nar/gkac1251  

   Tomkova, Marketa; Tomek, Jakub; Chow, Julie; McPherson, John D.; Segal, David J.; Hormozdiari, Fereydoun (January 2023, Nucleic Acids Research)

   Abstract The discovery of cancer driver mutations is a fundamental goal in cancer research. While many cancer driver mutations have been discovered in the protein-coding genome, research into potential cancer drivers in the non-coding regions showed limited success so far. Here, we present a novel comprehensive framework Dr.Nod for detection of non-coding cis-regulatory candidate driver mutations that are associated with dysregulated gene expression using tissue-matched enhancer-gene annotations. Applying the framework to data from over 1500 tumours across eight tissues revealed a 4.4-fold enrichment of candidate driver mutations in regulatory regions of known cancer driver genes. An overarching conclusion that emerges is that the non-coding driver mutations contribute to cancer by significantly altering transcription factor binding sites, leading to upregulation of tissue-matched oncogenes and down-regulation of tumour-suppressor genes. Interestingly, more than half of the detected cancer-promoting non-coding regulatory driver mutations are over 20 kb distant from the cancer-associated genes they regulate. Our results show the importance of tissue-matched enhancer-gene maps, functional impact of mutations, and complex background mutagenesis model for the prediction of non-coding regulatory drivers. In conclusion, our study demonstrates that non-coding mutations in enhancers play a previously underappreciated role in cancer and dysregulation of clinically relevant target genes. 

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4. Network propagation-based prioritization of long tail genes in 17 cancer types

   https://doi.org/10.1186/s13059-021-02504-x  

   Mohsen, Hussein; Gunasekharan, Vignesh; Qing, Tao; Seay, Montrell; Surovtseva, Yulia; Negahban, Sahand; Szallasi, Zoltan; Pusztai, Lajos; Gerstein, Mark B. (October 2021, Genome Biology)

   Abstract BackgroundThe diversity of genomic alterations in cancer poses challenges to fully understanding the etiologies of the disease. Recent interest in infrequent mutations, in genes that reside in the “long tail” of the mutational distribution, uncovered new genes with significant implications in cancer development. The study of cancer-relevant genes often requires integrative approaches pooling together multiple types of biological data. Network propagation methods demonstrate high efficacy in achieving this integration. Yet, the majority of these methods focus their assessment on detecting known cancer genes or identifying altered subnetworks. In this paper, we introduce a network propagation approach that entirely focuses on prioritizing long tail genes with potential functional impact on cancer development. ResultsWe identify sets of often overlooked, rarely to moderately mutated genes whose biological interactions significantly propel their mutation-frequency-based rank upwards during propagation in 17 cancer types. We call these sets “upward mobility genes” and hypothesize that their significant rank improvement indicates functional importance. We report new cancer-pathway associations based on upward mobility genes that are not previously identified using driver genes alone, validate their role in cancer cell survival in vitro using extensive genome-wide RNAi and CRISPR data repositories, and further conduct in vitro functional screenings resulting in the validation of 18 previously unreported genes. ConclusionOur analysis extends the spectrum of cancer-relevant genes and identifies novel potential therapeutic targets. 

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5. Lift the Veil of Breast Cancers Using 4 or Fewer Critical Genes

   https://doi.org/10.1177/11769351221076360  

   Zhang, Zhengjun (January 2022, Cancer Informatics)

   Known genes in the breast cancer study literature could not be confirmed whether they are vital to breast cancer formations due to lack of convincing accuracy, although they may be biologically directly related to breast cancer based on present biological knowledge. It is hoped vital genes can be identified with the highest possible accuracy, for example, 100% accuracy and convincing causal patterns beyond what has been known in breast cancer. One hope is that finding gene-gene interaction signatures and functional effects may solve the puzzle. This research uses a recently developed competing linear factor analysis method in differentially expressed gene detection to advance the study of breast cancer formation. Surprisingly, 3 genes are detected to be differentially expressed in TNBC and non-TNBC (Her2, Luminal A, Luminal B) samples with 100% sensitivity and 100% specificity in 1 study of triple-negative breast cancers (TNBC, with 54 675 genes and 265 samples). These 3 genes show a clear signature pattern of how TNBC patients can be grouped. For another TNBC study (with 54 673 genes and 66 samples), 4 genes bring the same accuracy of 100% sensitivity and 100% specificity. Four genes are found to have the same accuracy of 100% sensitivity and 100% specificity in 1 breast cancer study (with 54 675 genes and 121 samples), and the same 4 genes bring an accuracy of 100% sensitivity and 96.5% specificity in the fourth breast cancer study (with 60 483 genes and 1217 samples). These results show the 4-gene-based classifiers are robust and accurate. The detected genes naturally classify patients into subtypes, for example, 7 subtypes. These findings demonstrate the clearest gene-gene interaction patterns and functional effects with the smallest numbers of genes and the highest accuracy compared with findings reported in the literature. The 4 genes are considered to be essential for breast cancer studies and practice. They can provide focused, targeted researches and precision medicine for each subtype of breast cancer. New breast cancer disease types may be detected using the classified subtypes, and hence new effective therapies can be developed. 

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