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2022 ◽  
Malvika Sudhakar ◽  
Raghunathan Rengaswamy ◽  
Karthik Raman

The progression of tumorigenesis starts with a few mutational and structural driver events in the cell. Various cohort-based computational tools exist to identify driver genes but require a large number of samples to produce reliable results. Many studies use different methods to identify driver mutations/genes from mutations that have no impact on tumour progression; however, a small fraction of patients show no mutational events in any known driver genes. Current unsupervised methods map somatic and expression data onto a network to identify the perturbation in the network. Our method is the first machine learning model to classify genes as tumour suppressor gene (TSG), oncogene (OG) or neutral, thus assigning the functional impact of the gene in the patient. In this study, we develop a multi-omic approach, PIVOT (Personalised Identification of driVer OGs and TSGs), to train on experimentally or computationally validated mutational and structural driver events. Given the lack of any gold standards for the identification of personalised driver genes, we label the data using four strategies and, based on classification metrics, show gene-based labelling strategies perform best. We build different models using SNV, RNA, and multi-omic features to be used based on the data available. Our models trained on multi-omic data improved predictions compared to mutation and expression data, achieving an accuracy >0.99 for BRCA, LUAD and COAD datasets. We show network and expression-based features contribute the most to PIVOT. Our predictions on BRCA, COAD and LUAD cancer types reveal commonly altered genes such as TP53, and PIK3CA, which are predicted drivers for multiple cancer types. Along with known driver genes, our models also identify new driver genes such as PRKCA, SOX9 and PSMD4. Our multi-omic model labels both CNV and mutations with a more considerable contribution by CNV alterations. While predicting labels for genes mutated in multiple samples, we also label rare driver events occurring in as few as one sample. We also identify genes with dual roles within the same cancer type. Overall, PIVOT labels personalised driver genes as TSGs and OGs and also identifies rare driver genes. PIVOT is available at

PLoS Genetics ◽  
2022 ◽  
Vol 18 (1) ◽  
pp. e1009996
Alexey D. Vyatkin ◽  
Danila V. Otnyukov ◽  
Sergey V. Leonov ◽  
Aleksey V. Belikov

There is a growing need to develop novel therapeutics for targeted treatment of cancer. The prerequisite to success is the knowledge about which types of molecular alterations are predominantly driving tumorigenesis. To shed light onto this subject, we have utilized the largest database of human cancer mutations–TCGA PanCanAtlas, multiple established algorithms for cancer driver prediction (2020plus, CHASMplus, CompositeDriver, dNdScv, DriverNet, HotMAPS, OncodriveCLUSTL, OncodriveFML) and developed four novel computational pipelines: SNADRIF (Single Nucleotide Alteration DRIver Finder), GECNAV (Gene Expression-based Copy Number Alteration Validator), ANDRIF (ANeuploidy DRIver Finder) and PALDRIC (PAtient-Level DRIver Classifier). A unified workflow integrating all these pipelines, algorithms and datasets at cohort and patient levels was created. We have found that there are on average 12 driver events per tumour, of which 0.6 are single nucleotide alterations (SNAs) in oncogenes, 1.5 are amplifications of oncogenes, 1.2 are SNAs in tumour suppressors, 2.1 are deletions of tumour suppressors, 1.5 are driver chromosome losses, 1 is a driver chromosome gain, 2 are driver chromosome arm losses, and 1.5 are driver chromosome arm gains. The average number of driver events per tumour increases with age (from 7 to 15) and cancer stage (from 10 to 15) and varies strongly between cancer types (from 1 to 24). Patients with 1 and 7 driver events per tumour are the most frequent, and there are very few patients with more than 40 events. In tumours having only one driver event, this event is most often an SNA in an oncogene. However, with increasing number of driver events per tumour, the contribution of SNAs decreases, whereas the contribution of copy-number alterations and aneuploidy events increases.

2022 ◽  
Sarah Jafrin ◽  
Md. Abdul Aziz ◽  
Mohammad Safiqul Islam

Review question / Objective: TP73 G4C14-A4T14 variant has been suspected of elevating the risk of cancer for many years. The available evidence was unsatisfactory and could not provide a reliable conclusion. Therefore, we performed this meta-analysis to re-evaluate the previous findings and illustrate the actual role of TP73 G4C14-A4T14 variant on cancer development. Condition being studied: The association of the G4C14-A4T14 variant with cancer risk was studied. Information sources: PubMed, Google Scholar, EMBASE, Cochrane Library, and Web of Science, CNKI.

2022 ◽  
Vol 12 ◽  
Yiran Zhou ◽  
Qinghua Cui ◽  
Yuan Zhou

tRNA-derived fragments (tRFs) constitute a novel class of small non-coding RNA cleaved from tRNAs. In recent years, researches have shown the regulatory roles of a few tRFs in cancers, illuminating a new direction for tRF-centric cancer researches. Nonetheless, more specific screening of tRFs related to oncogenesis pathways, cancer progression stages and cancer prognosis is continuously demanded to reveal the landscape of the cancer-associated tRFs. In this work, by combining the clinical information recorded in The Cancer Genome Atlas (TCGA) and the tRF expression profiles curated by MINTbase v2.0, we systematically screened 1,516 cancer-associated tRFs (ca-tRFs) across seven cancer types. The ca-tRF set collectively combined the differentially expressed tRFs between cancer samples and control samples, the tRFs significantly correlated with tumor stage and the tRFs significantly correlated with patient survival. By incorporating our previous tRF-target dataset, we found the ca-tRFs tend to target cancer-associated genes and onco-pathways like ATF6-mediated unfolded protein response, angiogenesis, cell cycle process regulation, focal adhesion, PI3K-Akt signaling pathway, cellular senescence and FoxO signaling pathway across multiple cancer types. And cell composition analysis implies that the expressions of ca-tRFs are more likely to be correlated with T-cell infiltration. We also found the ca-tRF expression pattern is informative to prognosis, suggesting plausible tRF-based cancer subtypes. Together, our systematic analysis demonstrates the potentially extensive involvements of tRFs in cancers, and provides a reasonable list of cancer-associated tRFs for further investigations.

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 415
Limin Jiang ◽  
Hui Yu ◽  
Scott Ness ◽  
Peng Mao ◽  
Fei Guo ◽  

Somatic mutations are one of the most important factors in tumorigenesis and are the focus of most cancer-sequencing efforts. The co-occurrence of multiple mutations in one tumor has gained increasing attention as a means of identifying cooperating mutations or pathways that contribute to cancer. Using multi-omics, phenotypical, and clinical data from 29,559 cancer subjects and 1747 cancer cell lines covering 78 distinct cancer types, we show that co-mutations are associated with prognosis, drug sensitivity, and disparities in sex, age, and race. Some co-mutation combinations displayed stronger effects than their corresponding single mutations. For example, co-mutation TP53:KRAS in pancreatic adenocarcinoma is significantly associated with disease specific survival (hazard ratio = 2.87, adjusted p-value = 0.0003) and its prognostic predictive power is greater than either TP53 or KRAS as individually mutated genes. Functional analyses revealed that co-mutations with higher prognostic values have higher potential impact and cause greater dysregulation of gene expression. Furthermore, many of the prognostically significant co-mutations caused gains or losses of binding sequences of RNA binding proteins or micro RNAs with known cancer associations. Thus, detailed analyses of co-mutations can identify mechanisms that cooperate in tumorigenesis.

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 383
Jianlin Zhu ◽  
Lu Wang ◽  
Fan Liu ◽  
Jinghua Pan ◽  
Zhimeng Yao ◽  

Abnormal angiogenesis is one of the important hallmarks of colorectal cancer as well as other solid tumors. Optimally, anti-angiogenesis therapy could restrain malignant angiogenesis to control tumor expansion. PELP1 is as a scaffolding oncogenic protein in a variety of cancer types, but its involvement in angiogenesis is unknown. In this study, PELP1 was found to be abnormally upregulated and highly coincidental with increased MVD in CRC. Further, treatment with conditioned medium (CM) from PELP1 knockdown CRC cells remarkably arrested the function of human umbilical vein endothelial cells (HUVECs) compared to those treated with CM from wildtype cells. Mechanistically, the STAT3/VEGFA axis was found to mediate PELP1-induced angiogenetic phenotypes of HUVECs. Moreover, suppression of PELP1 reduced tumor growth and angiogenesis in vivo accompanied by inactivation of STAT3/VEGFA pathway. Notably, in vivo, PELP1 suppression could enhance the efficacy of chemotherapy, which is caused by the normalization of vessels. Collectively, our findings provide a preclinical proof of concept that targeting PELP1 to decrease STAT3/VEGFA-mediated angiogenesis and improve responses to chemotherapy due to normalization of vessels. Given the newly defined contribution to angiogenesis of PELP1, targeting PELP1 may be a potentially ideal therapeutic strategy for CRC as well as other solid tumors.

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 352
Anyou Wang ◽  
Rong Hai ◽  
Paul J. Rider ◽  
Qianchuan He

Detecting cancers at early stages can dramatically reduce mortality rates. Therefore, practical cancer screening at the population level is needed. To develop a comprehensive detection system to classify multiple cancer types. We integrated an artificial intelligence deep learning neural network and noncoding RNA biomarkers selected from massive data. Our system can accurately detect cancer vs. healthy objects with 96.3% of AUC of ROC (Area Under Curve of a Receiver Operating Characteristic curve), and it surprisingly reaches 78.77% of AUC when validated by real-world raw data from a completely independent data set. Even validating with raw exosome data from blood, our system can reach 72% of AUC. Moreover, our system significantly outperforms conventional machine learning models, such as random forest. Intriguingly, with no more than six biomarkers, our approach can easily discriminate any individual cancer type vs. normal with 99% to 100% AUC. Furthermore, a comprehensive marker panel can simultaneously multi-classify common cancers with a stable 82.15% accuracy rate for heterogeneous cancerous tissues and conditions.: This detection system provides a promising practical framework for automatic cancer screening at population level. Key points: (1) We developed a practical cancer screening system, which is simple, accurate, affordable, and easy to operate. (2) Our system binarily classify cancers vs. normal with >96% AUC. (3) In total, 26 individual cancer types can be easily detected by our system with 99 to 100% AUC. (4) The system can detect multiple cancer types simultaneously with >82% accuracy.

2022 ◽  
Vol 11 ◽  
Jayesh Kumar Tiwari ◽  
Shloka Negi ◽  
Manju Kashyap ◽  
Sheikh Nizamuddin ◽  
Amar Singh ◽  

Epithelial–mesenchymal transition (EMT) is a highly dynamic process that occurs under normal circumstances; however, EMT is also known to play a central role in tumor progression and metastasis. Furthermore, role of tumor immune microenvironment (TIME) in shaping anticancer immunity and inducing the EMT is also well recognized. Understanding the key features of EMT is critical for the development of effective therapeutic interventions. Given the central role of EMT in immune escape and cancer progression and treatment, we have carried out a pan-cancer TIME analysis of The Cancer Genome Atlas (TCGA) dataset in context to EMT. We have analyzed infiltration of various immune cells, expression of multiple checkpoint molecules and cytokines, and inflammatory and immune exhaustion gene signatures in 22 cancer types from TCGA dataset. A total of 16 cancer types showed a significantly increased (p < 0.001) infiltration of macrophages in EMT-high tumors (mesenchymal samples). Furthermore, out of the 17 checkpoint molecules we analyzed, 11 showed a significant overexpression (p < 0.001) in EMT-high samples of at least 10 cancer types. Analysis of cytokines showed significant enrichment of immunosuppressive cytokines—TGFB1 and IL10—in the EMT-high group of almost all cancer types. Analysis of various gene signatures showed enrichment of inflammation, exhausted CD8+ T cells, and activated stroma signatures in EMT-high tumors. In summary, our pan-cancer EMT analysis of TCGA dataset shows that the TIME of EMT-high tumors is highly immunosuppressive compared to the EMT-low (epithelial) tumors. The distinctive features of EMT-high tumors are as follows: (i) the enrichment of tumor-associated macrophages, (ii) overexpression of immune checkpoint molecules, (iii) upregulation of immune inhibitory cytokines TGFB1 and IL10, and (iv) enrichment of inflammatory and exhausted CD8+ T-cell signatures. Our study shows that TIMEs of different EMT groups differ significantly, and this would pave the way for future studies analyzing and targeting the TIME regulators for anticancer immunotherapy.

2022 ◽  
Emre Yekedüz ◽  
Güngör Utkan ◽  
Yüksel Ürün

HIV-infected patients are more susceptible to cancer due to their immune-compromised condition and HIV infection. Chronic inflammation and immune dysregulation are the main causes of cancer development in these patients. Because of lymphopenia and an immune-compromised condition, most HIV-infected patients with cancer were not considered for cytotoxic therapies, such as chemotherapy and radiotherapy. Immune checkpoint inhibitors (ICIs) have become a game-changer in many cancer types. However, not enough prospective data is available regarding the use of ICIs in HIV-infected patients with cancer. Retrospective data from case reports/series showed that ICIs are safe in HIV-infected patients with cancer.

2022 ◽  
Vol 2022 ◽  
pp. 1-21
Jinhui Liu ◽  
Yuanyuan Wang ◽  
Jian Yin ◽  
Yan Yang ◽  
Rui Geng ◽  

Background. Serine/arginine-rich splicing factor 9 (SRSF9) is one of the members of SRSF gene family and related to the tumorigenesis and the progression of tumor. However, whether SRSF9 has a crucial role across pan-cancer is still unknown. Methods. In this study, we used public databases, such as The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), and Genotype-Tissue Expression (GTEx), to analyze SRSF9 expression level among tumor and normal cells. Survival analysis, K-M plotter, and PrognoScan were used to analyze the prognosis value of SRSF9, regarding to overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI). Moreover, we performed the correlation between SRSF9 and clinical characteristics (including the outcome of prognosis), as well as molecular events of tumor mutation burden (TMB), microsatellite instability (MSI), immune checkpoint gene, tumor microenvironment (TME), immune infiltrating cells, mismatch repair (MMR) genes, m6A genes, DNA methyltransferases, and neoantigen with bioinformatics methods and TISIDB, TIMER, and Sangerbox websites. Results. In general, SRSF9 expression was upregulated in most cancers, such as BLCA, CHOL, and UCEC, which SRSF9 was associated with short survival and severe progression. In COAD, STAD, and UCEC, SRSF9 expression was positively related to both TMB and MSI. In BRCA, BLCA, ESCA, GBM, HNSC, LUSC, LUAD, OV, PRAD, TGCT, THCA, and UCEC, both immune score and stomal score showed a negative relationship with SRSF9 expression. Immune score showed a positive relationship with SRSF9 expression in LGG. SRSF9 expression had a significant and positive correlation with six types of immune infiltration cells in LGG, KIRC, LIHC, PCPG, PRAD, SKCM, THCA, and THYM, except in LUSC. In LIHC, SRSF9 was highly significant correlated with most immune checkpoint genes. For neoantigens, correlation between SRSF9 and the quantity of neoantigens was significantly positive in some cancer types. SRSF9 was also correlated with MMR genes, m6A genes, and DNA methyltransferases. In the 33 cancer types, gene set enrichment analysis (GSEA) demonstrated that SRSF9 was correlated with multiple functions and signaling pathways. Conclusion. These findings demonstrated that SRSF9 may be a new biomarker for the prognosis and immunotherapy in various cancers. As a result, it will be beneficial to provide new therapies for cancer patients, thereby improving the treatment and prognosis of cancer patients.

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