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Somatic mutations in cancer genomes arise from distinct, context-specific mutational processes, yet their functional consequences at the protein and network level remain incompletely understood. Here, we show that mutational processes of single-nucleotide variants (SNVs) can systematically rewire signaling networks by inducing amino acid substitutions in short linear motifs (SLiMs) that mediate interactions with kinases and other signaling proteins. By analysing 11,000 cancer genomes and 144 classes of SLiMs, we identify motif-rewiring SNVs (rwSNVs) that create or disrupt SLiMs or remove phosphorylated residues. Mutational processes of methylcytosine deamination, APOBEC activity, and ultraviolet light exposure emerge as major contributors to motif rewiring. rwSNVs are enriched in cancer driver genes and pathways, linking mutation etiology to functional consequences. rwSNVs at the BRAF V600E hotspot associated with UV-related mutagenesis are predicted to generate a phosphorylation motif recognized by PLK1 kinase. Together, these findings reveal how mutational processes shape oncogenic signaling and tumor heterogeneity.Competing Interest StatementThe authors declare no competing interests. O.W. is a founder of Orb Therapeutics.Funder Information DeclaredCanadian Institutes of Health Research, https://ror.org/01gavpb45Ontario Institute for Cancer Research, https://ror.org/043q8yx54Natural Sciences and Engineering Research CouncilTerry Fox Research InstituteOntario Graduate ScholarshipAgencia Estatal de Investigación

Cancer progression involves the sequential accumulation of genetic alterations that cumulatively shape the tumour phenotype. In prostate cancer, tumours can follow divergent evolutionary trajectories that lead to distinct subtypes, but the causes of this divergence remain unclear. While causal inference could elucidate the factors involved, conventional methods are unsuitable due to the possibility of unobserved confounders and ambiguity in the direction of causality. Here, we propose a method that circumvents these issues and apply it to genomic data from 829 prostate cancer patients. We identify several genetic alterations that drive divergence as well as others that prevent this transition, locking tumours into one trajectory. Further analysis reveals that these genetic alterations may cause each other, implying a positive-feedback loop that accelerates divergence. Our findings provide insights into how cancer subtypes emerge and offer a foundation for genomic surveillance strategies aimed at monitoring the progression of prostate cancer.

Oncogenesis and tumor progression are shaped by somatic alterations in the cancer genome and features of the tumor immune microenvironment (TME). How interactions of these two systems influence tumor development and clinical outcomes remains incompletely understood. To address this challenge, we developed the multi-omics analysis framework PACIFIC to systematically integrate genetic cancer drivers and infiltration profiles of immune cells with clinical information. In an analysis of 8500 cancer samples, we report 34 immunogenomic interactions (IGXs) in 13 cancer types in which context-specific combinations of genomic alterations and immune cell activities associate with disease outcomes. Risk associations of IGXs are potentially explained by tumor-intrinsic and microenvironmental metrics of immunogenicity and differential expression of therapeutic targets. In luminal-A breast cancer, MEN1 deletion combined with reduced neutrophils is associated with poor prognosis and deregulation of immune signalling pathways. These findings help elucidate how cancer drivers interact with TME to contribute to tumorigenesis.Competing Interest StatementThe authors have declared no competing interest.

Type-II topoisomerases resolve topological stress in DNA through controlled double-strand breaks. While TOP2A is a chemotherapy target in proliferating cells, the ubiquitously expressed TOP2B is a potential off-target. Here we explore roles of TOP2B in mutagenesis by generating DNA-binding maps of TOP2B, CTCF, and RAD21 in human cancer samples and analysing these maps for driver mutations and mutational processes in 6500 whole cancer genomes. TOP2B-CTCF-RAD21 and TOP2B-RAD21 sites are enriched in somatic mutations and structural variants (SVs), especially at evolutionary conserved sites displaying high transcription and long-range chromatin interactions. TOP2B binding underlies SVs and hotspot mutations in cancer-driving genes such as TP53, MYC, FOXA1, and VHL, and many cis-regulatory elements. We show that the TOP2B-bound mutational hotspot at RMRP drives tumor initiation and growth in vivo. These data highlight TOP2B as a protector of the genome from topological challenges whose aberrant activity promotes driver and passenger mutations in cancer genomes.Competing Interest StatementThe authors have declared no competing interest.

Despite a vast expansion in the availability of epigenomic data, our knowledge of the chromatin landscape at interspersed repeats remains highly limited by difficulties in mapping short-read sequencing data to these regions. In particular, little is known about the locus-specific regulation of evolutionarily young transposable elements (TEs), which have been implicated in genome stability, gene regulation and innate immunity in a variety of developmental and disease contexts. Here we propose an approach for generating locus-specific protein-DNA binding profiles at interspersed repeats, which leverages information on the spatial proximity between repetitive and non-repetitive genomic regions. We demonstrate that the combination of HiChIP and a newly developed mapping tool (PAtChER) yields accurate protein enrichment profiles at individual repetitive loci. Using this approach, we reveal previously unappreciated variation in the epigenetic profiles of young TE loci in mouse and human cells. Insights gained using our method will be invaluable for dissecting the molecular determinants of TE regulation and their impact on the genome. Competing Interest Statement The authors have declared no competing interest. Footnotes * Added an analysis of the effects of long-range interactions on PAtChER's mapping accuracy. Added supplementary tables. Other minor modifications. * https://github.com/MBrancoLab/PAtChER * https://github.com/MBrancoLab/Taylor_2021_PAtChER * https://ncbi.xyz/geo/query/acc.cgi?acc=GSE182304

Cancer progression involves the sequential accumulation of genetic alterations that cumulatively shape the tumour phenotype. In prostate cancer, tumours can follow divergent evolutionary trajectories that lead to distinct subtypes, but the causes of this divergence remain unclear. While causal inference could elucidate the factors involved, conventional methods are unsuitable due to the possibility of unobserved confounders and ambiguity in the direction of causality. Here, we propose a method that circumvents these issues and apply it to genomic data from 829 prostate cancer patients. We identify several genetic alterations that drive divergence as well as others that prevent this transition, locking tumours into one trajectory. Further analysis reveals that these genetic alterations may cause each other, implying a positive-feedback loop that accelerates divergence. Our findings provide insights into how cancer subtypes emerge and offer a foundation for genomic surveillance strategies aimed at monitoring the progression of prostate cancer.

Binding of the transcription factor NF-κB subunit RelA activates proinflammatory gene expression. Gozani and colleagues show that basal expression of RelA target genes is suppressed by methylation of RelA by SETD6, which triggers repressive histone methylation by GLP. Signaling via the methylation of lysine residues in proteins has been linked to diverse biological and disease processes, yet the catalytic activity and substrate specificity of many human protein lysine methyltransferases (PKMTs) are unknown. We screened over 40 candidate PKMTs and identified SETD6 as a methyltransferase that monomethylated chromatin-associated transcription factor NF-κB subunit RelA at Lys310 (RelAK310me1). SETD6-mediated methylation rendered RelA inert and attenuated RelA-driven transcriptional programs, including inflammatory responses in primary immune cells. RelAK310me1 was recognized by the ankryin repeat of the histone methyltransferase GLP, which under basal conditions promoted a repressed chromatin state at RelA target genes through GLP-mediated methylation of histone H3 Lys9 (H3K9). NF-κB-activation–linked phosphorylation of RelA at Ser311 by protein kinase C-ζ (PKC-ζ) blocked the binding of GLP to RelAK310me1 and relieved repression of the target gene. Our findings establish a previously uncharacterized mechanism by which chromatin signaling regulates inflammation programs.

Sacroiliac (SI) joint pain is an often overlooked cause of low back pain. SI joint arthrodesis has been reported to relieve pain and improve quality of life in patients suffering from degeneration or disruption of the SI joint who have failed non-surgical care. We report herein early results of a multicenter prospective single-arm cohort of patients with SI joint degeneration or disruption who underwent minimally invasive fusion using the iFuse Implant System®. The safety cohort includes 94 subjects at 23 sites with chronic SI joint pain who met study eligibility criteria and underwent minimally invasive SI joint fusion with the iFuse Implant System® between August 2012 and September 2013. Subjects underwent structured assessments preoperatively, immediately postoperatively, and at 1, 3, and 6 months postoperatively, including SI joint and back pain visual analog scale (VAS), Oswestry Disability Index (ODI), Short Form-36 (SF-36), and EuroQoL-5D (EQ-5D). Patient satisfaction with surgery was assessed at 6 months. The effectiveness cohort includes the 32 subjects who have had 6-month follow-up to date. Mean subject age was 51 years (n=94, safety cohort) and 66% of patients were women. Subjects were highly debilitated at baseline (mean VAS pain score 78, mean ODI score 54). Three implants were used in 80% of patients; two patients underwent staged bilateral implants. Twenty-three adverse events occurred within 1 month of surgery and 29 additional events occurred between 30 days and latest follow-up. Six adverse events were severe but none were device-related. Complete 6-month postoperative follow-up was available in 26 subjects. In the effectiveness cohort, mean (± standard deviation) SI joint pain improved from a baseline score of 76 (±16.2) to a 6-month score of 29.3 (±23.3, an improvement of 49 points, P<0.0001), mean ODI improved from 55.3 (±10.7) to 38.9 (±18.5, an improvement of 15.8 points, P<0.0001) and SF-36 PCS improved from 30.7 (±4.3) to 37.0 (±10.7, an improvement of 6.7 points, P=0.003). Ninety percent of subjects who were ambulatory at baseline regained full ambulation by month 6; median time to full ambulation was 30 days. Satisfaction with the procedure was high at 85%. Minimally invasive SI joint fusion using the iFuse Implant System® is safe. Mid-term follow-up indicates a high rate of improvement in pain and function with high rates of patient satisfaction.

To gain insight into melanoma pathogenesis, we characterized an insertional mouse mutant, TG3, that is predisposed to develop multiple melanomas 1 , 2 . Physical mapping identified multiple tandem insertions of the transgene into intron 3 of Grm1 (encoding metabotropic glutamate receptor 1) with concomitant deletion of 70 kb of intronic sequence. To assess whether this insertional mutagenesis event results in alteration of transcriptional regulation, we analyzed Grm1 and two flanking genes for aberrant expression in melanomas from TG3 mice. We observed aberrant expression of only Grm1. Although we did not detect its expression in normal mouse melanocytes, Grm1 was ectopically expressed in the melanomas from TG3 mice. To confirm the involvement of Grm1 in melanocytic neoplasia, we created an additional transgenic line with Grm1 expression driven by the dopachrome tautomerase promoter. Similar to the original TG3, the Tg( Grm1 )EPv line was susceptible to melanoma. In contrast to human melanoma, these transgenic mice had a generalized hyperproliferation of melanocytes with limited transformation to fully malignant metastasis. We detected expression of GRM1 in a number of human melanoma biopsies and cell lines but not in benign nevi and melanocytes. This study provides compelling evidence for the importance of metabotropic glutamate signaling in melanocytic neoplasia.

Two Pseudomonas strains, P. putida Fl and P. putida TVA8, were used to evaluate biodegradation of toluene and cometabolism of trichloroethylene (TCE) in batch systems. Both organisms effectively utilized toluene although at different rates. The extent of TCE cometabolism was dependent upon the initial mass of toluene present. A relationship between toluene/TCE degradation and bioluminescence production for P. putida TVA8 was explored. A linear relationship between the total amount of toluene degraded and total bioluminescence was found. The slope of this straight line, however, was found to vary between experiments. To overcome this problem, a normalization method was proposed and successful tested.