Cancer driver events refer to key genetic aberrations that drive oncogenesis; however, their exact molecular mechanisms remain insufficiently understood. Here, our multi-omics pan-cancer analysis ...uncovers insights into the impacts of cancer drivers by identifying their significant cis-effects and distal trans-effects quantified at the RNA, protein, and phosphoprotein levels. Salient observations include the association of point mutations and copy-number alterations with the rewiring of protein interaction networks, and notably, most cancer genes converge toward similar molecular states denoted by sequence-based kinase activity profiles. A correlation between predicted neoantigen burden and measured T cell infiltration suggests potential vulnerabilities for immunotherapies. Patterns of cancer hallmarks vary by polygenic protein abundance ranging from uniform to heterogeneous. Overall, our work demonstrates the value of comprehensive proteogenomics in understanding the functional states of oncogenic drivers and their links to cancer development, surpassing the limitations of studying individual cancer types.
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•Multi-omic clusters reveal shared oncogenic driver pathways across ten cancer types•Genetic changes correlate with altered, tumor-specific protein-protein interactions•cis/trans-effects and kinase activities show driver heterogeneity and druggability•Proteomic integration with genomic drivers resolves distinct cancer hallmark patterns
A multi-omics analysis-based resource across ten cancer types from more than 1,000 patients provides pan-cancer insights into shared oncogenic driver mechanisms and pathways.
Post-translational modifications (PTMs) play key roles in regulating cell signaling and physiology in both normal and cancer cells. Advances in mass spectrometry enable high-throughput, accurate, and ...sensitive measurement of PTM levels to better understand their role, prevalence, and crosstalk. Here, we analyze the largest collection of proteogenomics data from 1,110 patients with PTM profiles across 11 cancer types (10 from the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium CPTAC). Our study reveals pan-cancer patterns of changes in protein acetylation and phosphorylation involved in hallmark cancer processes. These patterns revealed subsets of tumors, from different cancer types, including those with dysregulated DNA repair driven by phosphorylation, altered metabolic regulation associated with immune response driven by acetylation, affected kinase specificity by crosstalk between acetylation and phosphorylation, and modified histone regulation. Overall, this resource highlights the rich biology governed by PTMs and exposes potential new therapeutic avenues.
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•Unsupervised clustering reveals 33 pan-cancer multi-omic signatures•PTM dysregulation is associated with distinct DNA damage repair mechanisms•Changes in acetylation of metabolic proteins correlate with tumor immune state•Phosphorylation of Thr/Ser kinases is affected by proximal acetylation
An analytical resource of post-translational modifications from over 1,000 patients across 11 cancer types reveals pan-cancer changes involved in hallmark cancer processes and reveals potential new therapeutic avenues.
DNA methylation plays a critical role in establishing and maintaining cellular identity. However, it is frequently dysregulated during tumor development and is closely intertwined with other genetic ...alterations. Here, we leveraged multi-omic profiling of 687 tumors and matched non-involved adjacent tissues from the kidney, brain, pancreas, lung, head and neck, and endometrium to identify aberrant methylation associated with RNA and protein abundance changes and build a Pan-Cancer catalog. We uncovered lineage-specific epigenetic drivers including hypomethylated FGFR2 in endometrial cancer. We showed that hypermethylated STAT5A is associated with pervasive regulon downregulation and immune cell depletion, suggesting that epigenetic regulation of STAT5A expression constitutes a molecular switch for immunosuppression in squamous tumors. We further demonstrated that methylation subtype-enrichment information can explain cell-of-origin, intra-tumor heterogeneity, and tumor phenotypes. Overall, we identified cis-acting DNA methylation events that drive transcriptional and translational changes, shedding light on the tumor’s epigenetic landscape and the role of its cell-of-origin.
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•Pan-cancer epigenetic aberrations and their transcriptional and translational changes•FGFR2 and EGFR hypomethylation are bona fide driver DNA methylation events•STAT5A methylation is a potential switch for immunosuppression in squamous tumors•Methylation subtypes illuminate cell origin, tumor heterogeneity, and tumor phenotype
Liang et al. catalog pan-cancer DNA methylation with concordant transcriptional and translational changes, revealing lineage-specific epigenetic driver FGFR2 hypomethylation in uterine corpus endometrial carcinoma, and STAT5 hypermethylation as an immunosuppression switch in squamous tumors. They also identify methylation-driven subtypes associated with cell-of-origin, tumor heterogeneity, tumor phenotype, and links to therapeutic potential.
African American (AA) families have the highest risk of prostate cancer. However, the genetic factors contributing to prostate cancer susceptibility in AA families remain poorly understood. We ...performed whole-exome sequencing of one affected and one unaffected brother in an AA family with hereditary prostate cancer. The novel non-synonymous variants discovered only in the affected individuals were further analyzed in all affected and unaffected men in 20 AA-PC families. Here, we report one rare recurrent ADPRHL1 germline mutation (c.A233T; p.D78V) in four of the 20 families affected by prostate cancer. The mutation co-segregates with prostate cancer in two families and presents in two affected men in the other two families, but was absent in 170 unrelated healthy AA men. Functional characterization of the mutation in benign prostate cells showed aberrant promotion of cell proliferation, whereas expression of the wild-type ADPRHL1 in prostate cancer cells suppressed cell proliferation and oncogenesis. Mechanistically, the ADPRHL1 mutant activates PARP1, leading to an increased H2O2 or cisplatin-induced DNA damage response for prostate cancer cell survival. Indeed, the PARP1 inhibitor, olaparib, suppresses prostate cancer cell survival induced by mutant ADPRHL1. Given that the expression levels of ADPRHL1 are significantly high in normal prostate tissues and reduce stepwise as Gleason scores increase in tumors, our findings provide genetic, biochemical, and clinicopathological evidence that ADPRHL1 is a tumor suppressor in prostate tissue. A loss of function mutation in ADPRHL1 induces prostate tumorigenesis and confers prostate cancer susceptibility in high-risk AA families.
This study highlights a potential strategy for ADPRHL1 mutation detection in prostate cancer-risk assessment and a potential therapeutic application for individuals with prostate cancer in AA families.
We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can ...predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of β-catenin, which may render Wnt-FZD antagonists ineffective. Deep learning accurately predicts EC subtypes and mutations from histopathology images, which may be useful for rapid diagnosis. Overall, this study identified molecular and imaging markers that can be further investigated to guide patient stratification for more precise treatment of EC.
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•APM status can be accurately predicted using a targeted proteomic assay•MYC activity is a potential biomarker for metformin treatment•PIK3R1 in-frame indels are associated with upregulated AKT1 phosphorylation•CTNNB1 exon 3 hotspot mutations block pS45 induced β-catenin degradation
Dou et al. report the characterization of a prospective endometrial carcinoma (EC) cohort using 10 different omics platforms. They identify potential molecular and imaging markers for guiding patient stratification for more precise treatment of EC.
Despite widespread use of formalin-fixed, paraffin-embedded (FFPE) tissue in clinical and research settings, potential effects of variable tissue processing remain largely unknown.
To elucidate ...molecular effects associated with clinically relevant preanalytical variability, the National Cancer Institute initiated the Biospecimen Preanalytical Variables (BPV) program.
The BPV program, a well-controlled series of systematic, blind and randomized studies, investigated whether a delay to fixation (DTF) or time in fixative (TIF) affects the quantity and quality of DNA and RNA isolated from FFPE colon, kidney, and ovarian tumors in comparison to case-matched snap-frozen controls.
DNA and RNA yields were comparable among FFPE biospecimens subjected to different DTF and TIF time points. DNA and RNA quality metrics revealed assay- and time point-specific effects of DTF and TIF. A quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay was superior when assessing RNA quality, consistently detecting differences between FFPE and snap-frozen biospecimens and among DTF and TIF time points. RNA Integrity Number and DV
(representing the percentage of RNA fragments longer than 200 nucleotides) displayed more limited sensitivity. Differences in DNA quality (Q-ratio) between FFPE and snap-frozen biospecimens and among DTF and TIF time points were detected with a qPCR-based assay.
DNA and RNA quality may be adversely affected in some tumor types by a 12-hour DTF or a TIF of 72 hours. Results presented here as well as those of additional BPV molecular analyses underway will aid in the identification of acceptable delays and optimal fixation times, and quality assays that are suitable predictors of an FFPE biospecimen's fit-for-purpose.
We introduce a pioneering approach that integrates pathology imaging with transcriptomics and proteomics to identify predictive histology features associated with critical clinical outcomes in ...cancer. We utilize 2,755 H&E-stained histopathological slides from 657 patients across 6 cancer types from CPTAC. Our models effectively recapitulate distinctions readily made by human pathologists: tumor vs. normal (AUROC = 0.995) and tissue-of-origin (AUROC = 0.979). We further investigate predictive power on tasks not normally performed from H&E alone, including TP53 prediction and pathologic stage. Importantly, we describe predictive morphologies not previously utilized in a clinical setting. The incorporation of transcriptomics and proteomics identifies pathway-level signatures and cellular processes driving predictive histology features. Model generalizability and interpretability is confirmed using TCGA. We propose a classification system for these tasks, and suggest potential clinical applications for this integrated human and machine learning approach. A publicly available web-based platform implements these models.
Background Inflammation and immune activation of the cervicovaginal mucosa are considered factors that increase susceptibility to HIV infection. Therefore, it is essential to screen candidate ...anti-HIV microbicides for potential mucosal immunomodulatory/inflammatory effects prior to further clinical development. The goal of this study was to develop an in vitro method for preclinical evaluation of the inflammatory potential of new candidate microbicides using a microarray gene expression profiling strategy. Methods To this end, we compared transcriptomes of human vaginal cells (Vk2/E6E7) treated with well-characterized pro-inflammatory (PIC) and non-inflammatory (NIC) compounds. PICs included compounds with different mechanisms of action. Gene expression was analyzed using Affymetrix U133 Plus 2 arrays. Data processing was performed using GeneSpring 11.5 (Agilent Technologies, Santa Clara, CA). Results Microarraray comparative analysis allowed us to generate a panel of 20 genes that were consistently deregulated by PICs compared to NICs, thus distinguishing between these two groups. Functional analysis mapped 14 of these genes to immune and inflammatory responses. This was confirmed by the fact that PICs induced NFkB pathway activation in Vk2 cells. By testing microbicide candidates previously characterized in clinical trials we demonstrated that the selected PIC-associated genes properly identified compounds with mucosa-altering effects. The discriminatory power of these genes was further demonstrated after culturing vaginal cells with vaginal bacteria. Prevotella bivia, prevalent bacteria in the disturbed microbiota of bacterial vaginosis, induced strong upregulation of seven selected PIC-associated genes, while a commensal Lactobacillus gasseri associated to vaginal health did not cause any changes. Conclusions In vitro evaluation of the immunoinflammatory potential of microbicides using the PIC-associated genes defined in this study could help in the initial screening of candidates prior to entering clinical trials. Additional characterization of these genes can provide further insight into the cervicovaginal immunoinflammatory and mucosal-altering processes that facilitate or limit HIV transmission with implications for the design of prevention strategies.
Nicotine is a known risk factor for cancer development and has been shown to alter gene expression in cells and tissue upon exposure. We used Illumina registered Next Generation Sequencing (NGS) ...technology to gain unbiased biological insight into the transcriptome of normal epithelial cells (MCF-10A) to nicotine exposure. We generated expression data from 54,699 transcripts using triplicates of control and nicotine stressed cells. As a result, we identified 138 differentially expressed transcripts, including 39 uncharacterized genes. Additionally, 173 transcripts that are primarily associated with DNA replication, recombination, and repair showed evidence for alternative splicing. We discovered the greatest nicotine stress response by HPCAL4 (up-regulated by 4.71 fold) and NPAS3 (down-regulated by -2.73 fold); both are genes that have not been previously implicated in nicotine exposure but are linked to cancer. We also discovered significant down-regulation (-2.3 fold) and alternative splicing of NEAT1 (lncRNA) that may have an important, yet undiscovered regulatory role. Gene ontology analysis revealed nicotine exposure influenced genes involved in cellular and metabolic processes. This study reveals previously unknown consequences of nicotine stress on the transcriptome of normal breast epithelial cells and provides insight into the underlying biological influence of nicotine on normal cells, marking the foundation for future studies.
Abstract
The antidiabetic, hypolipidemic, and antioxidant properties of Phyllanthus niruri. (L) (Euphorbiaceae) were compared in normal, insulin-dependent diabetes mellitus (IDDM), and ...non-insulin-dependent diabetes mellitus (NIDDM) animals through evaluating the effects on carbohydrate and lipid metabolism and antioxidant activities. The alcohol extract of Phyllanthus niruri. produced significant antidiabetic effect in IDDM alone but lowered lipid profiles and improved body antioxidant activities in both IDDM and NIDDM animals. This investigation revealed that the lipid-lowering effect of Phyllanthus niruri. is independent from its antidiabetic action.
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