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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2017

Nitric oxide-dependent inflammation underlies Notch and PI3K/Akt oncogene cooperation

Concurrent activating mutations of the Notch and PI3K/Akt signalling pathways cooperate in the induction of aggressive cancers. Unfortunately, direct targeting of any of these aberrant pathways can result in severe side effects due to their broad physiological roles in multiple organs. Here, using an unbiased chemical in vivo screen in Drosophila we identified compounds that suppress the activity of the pro-inflammatory enzymes, nitric oxide synthase (NOS) and lipoxygenase (LOX), capable to block oncogenic Notch-PI3K/Akt cooperation without unwanted side effects. Genetic inactivation of NOS and LOX signalling components mirrors the anti-tumorigenic effect of the hit compounds. We show that NOS activity and immunosuppression associated to inflammation facilitates Notch-mediated tumorigenesis. Our study reveals an unnoticed immune inflammatory process underlying Notch-PI3K/Akt tumours and exposes NOS as a druggable target for anti-cancer therapeutic development.

cancer biology↗

bioRxiv2017

A subgroup of mitochondrial extracellular vesicles discovered in human melanoma tissues are detectable in patient blood

Extracellular vesicles (EVs), including exosomes and microvesicles, are secreted from all cells, and convey messages between cells in health and disease. However, the diversity of EV subpopulations are only beginning to be explored. Since EVs have been implicated in tumor microenvironmental communication, we started to determine the diversity of EVs specifically in this tissue. To do this, we isolated EVs directly from patient melanoma metastatic tissues. Using EV membrane isolation and mass spectrometry analysis, we discovered enrichment of mitochondrial membrane proteins in the melanoma tissue-derived EVs, compared to non-melanoma-derived EVs. Specifically, EVs positive for a combination of the two mitochondrial inner membrane proteins MT-CO2 (mitochondrial genome) and COX6c (nuclear genome) were detected in the plasma of melanoma patients, and in ovarian and breast cancer patients. Furthermore, this subpopulation of EVs, contains active mitochondrial enzymes. Our findings show that tumor tissues are enriched in EVs with mitochondrial proteins and enzymatic activity, and these EVs can be detected in blood.

cancer biology↗

bioRxiv2017

Copy-number signatures and mutational processes in ovarian carcinoma

Tumours with profound copy-number aberration elude molecular stratification due to their genomic complexity. By representing this complexity as a mixture of copy-number signatures, we provide molecular explanations for differing clinical outcomes. Here we present a method for copy-number signature identification, deriving eight signatures in 117 shallow whole-genome sequenced high-grade serous ovarian cancers (HGSOC), which validated on independent cohorts of 95 deep whole-genome sequenced, and 402 SNP array-profiled cases. Three copy-number signatures predicted longer overall survival, while the others predicted poorer outcome. We found evidence for the mutational processes giving rise to copy-number change for six of the eight signatures via correlations with other genomic features. Our results provide insights into the pathogenesis of HGSOC by uncovering multiple mutational processes that shape genomes following TP53 mutation. Importantly, our work shows that most HGSOC have a mixture of mutational processes suggesting that targeting a single mutator phenotype may be therapeutically suboptimal.

cancer biology↗

bioRxiv2017

Hundreds of putative non-coding cis-regulatory drivers in chronic lymphocytic leukaemia and skin cancer

Perturbations of the coding genome and their role in cancer development have been studied extensively. However, the non-coding genomes contribution in cancer is poorly understood (1), not only because it is difficult to define the non-coding regulatory regions and the genes they regulate, but also because there is limited power owing to the regulatory regions small size. In this study, we try to resolve this issue by defining modules of coordinated non-coding regulatory regions of genes (Cis Regulatory Domains or CRDs). To do so, we use the correlation between histone modifications, assayed by ChIP-seq, in population samples of immortalized B-cells and skin fibroblasts. We screen for CRDs that accumulate an excess of somatic mutations in chronic lymphocytic leukaemia (CLL) and skin cancer, which affect these cell types, after accounting for somatic mutational patterns and biases. At 5% FDR, we find 90 CRDs with significant excess somatic of mutations in CLL, 60 of which regulate 126 genes, and in skin cancer 59 significant CRDs, 25 of which regulate 37 genes. The genes these CRDs regulate include ones already implicated in tumorigenesis, and are enriched in pathways already implicated in the respective cancers, like the B-cell receptor signalling pathway in CLL and the TGF{beta} signalling pathway in skin cancer. We discover that the somatic mutations in the significant CRDs of CLL are hitting bases more likely to be functional than the mutations in non-significant CRDs. Moreover, in both cancers, mutational signatures observed in the regulatory regions of significant CRDs deviate significantly from their null sequences. Both results indicate selection acting on CRDs during tumorigenesis. Finally, we find that the transcription factor biding sites that are disturbed by the somatic mutations in significant CRDs are enriched for factors known to be involved in cancer development. We are describing a new powerful approach to discover non-coding regions involved in tumorigenesis in CLL and skin cancer and this approach could be generalized to other cancers.

cancer biology↗

bioRxiv2017

A Low-Cost Multiplex Biomarker Assay Stratifies Colorectal Cancer Patient Samples into Clinically-Relevant Subtypes

Previously, we classified colorectal cancers (CRCs) into five CRCA subtypes with different prognoses and potential treatment responses, using a 786-gene signature. We merged our subtypes and those described by five other groups into four consensus molecular subtypes (CMS) that are similar to CRCA subtypes. Here we demonstrate the analytical development and application of a custom NanoString platform-based biomarker assay to stratify CRC into subtypes. To reduce costs, we switched from the standard protocol to a custom modified protocol (NanoCRCA) with a high Pearson correlation coefficient (>0.88) between protocols. Technical replicates were highly correlated (>0.96). The assay included a reduced robust 38-gene panel from the 786-gene signature that was selected using an in-laboratory developed computational pipeline of class prediction methods. We applied our NanoCRCA assay to untreated CRCs including fresh-frozen and formalin-fixed paraffin-embedded (FFPE) samples (n=81) with matched microarray or RNA-Seq profiles. We further compared the assay results with CMS classification, different platforms (microarrays/RNA-Seq) and gene-set classifiers (38 and 786 genes). NanoCRCA classified fresh-frozen samples (n=39; not including those showing a mixture of subtypes) into all five CRCA subtypes with overall high concordance across platforms (89.7%) and with CMS subtypes (84.6%), independent of tumour cellularity. This analytical validation of the assay shows the association of subtypes with their known molecular, mutational and clinical characteristics. Overall, our modified NanoCRCA assay with further clinical assessment may facilitate prospective validation of CRC subtypes in clinical trials and beyond.\n\nNovelty and ImpactWe previously identified five gene expression-based CRC subtypes with prognostic and potential predictive differences using a 786-gene signature and microarray platform. Subtype-driven clinical trials require a validated assay suitable for routine clinical use. This study demonstrates, for the first time, how molecular CRCA subtype can be detected using NanoString Technology-based biomarker assay (NanoCRCA) suitable for clinical validation. NanoCRCA is suitable for analysing FFPE samples, and this assay may facilitate patient stratification within clinical trials.

cancer biology↗

bioRxiv2017

The evolution of tumour composition during fractionated radiotherapy: implications for outcome

Current protocols for delivering radiotherapy are based primarily on tumour stage and nodal and metastases status, even though it is well known that tumours and their microenvironments are highly heterogeneous. It is well established that the local oxygen tension plays an important role in radiation-induced cell death, with hypoxic tumour regions responding poorly to irradiation. Therefore, to improve radiation response, it is important to understand more fully the spatiotemporal distribution of oxygen within a growing tumour before and during fractionated radiation. To this end, we have extended a spatially-resolved mathematical model of tumour growth first proposed by Greenspan (Stud. Appl. Math., 1972) to investigate the effects of oxygen heterogeneity on radiation-induced cell death. In more detail, cell death due to radiation at each location in the tumour, as determined by the well-known linear-quadratic model, is assumed also to depend on the local oxygen concentration. The oxygen concentration is governed by a reaction-diffusion equation that is coupled to an integro-differential equation that determines the size of the assumed spherically-symmetric tumour. We combine numerical and analytical techniques to investigate radiation response of tumours with different intra-tumoral oxygen distribution profiles. Model simulations reveal a rapid transient increase in hypoxia upon re-growth of the tumour spheroid post-irradiation. We investigate the response to different radiation fractionation schedules and identify a tumour-specific relationship between inter-fraction time and dose per fraction to achieve cure. The rich dynamics exhibited by the model suggest that spatial heterogeneity may be important for predicting tumour response to radiotherapy for clinical applications.

cancer biology↗

bioRxiv2017

A network modeling approach to elucidate drug resistance mechanisms and predict combinatorial drug treatments in breast cancer

BackgroundMechanistic models of within-cell signal transduction networks can explain how these networks integrate internal and external inputs to give rise to the appropriate cellular response. These models can be fruitfully used in cancer cells, whose aberrant decision-making regarding their survival or death, proliferation or quiescence can be connected to errors in the state of nodes or edges of the signal transduction network.\n\nResultsHere we present a comprehensive network, and discrete dynamic model, of signal transduction in breast cancer based on the literature of ER+, HER2+, and PIK3CA-mutant breast cancers. The network model recapitulates known resistance mechanisms to PI3K inhibitors and suggests other possibilities for resistance. The model also reveals known and novel combinatorial interventions that are more effective than PI3K inhibition alone.\n\nConclusionsThe use of a logic-based, discrete dynamic model enables the identification of results that are mainly due to the organization of the signaling network, and those that also depend on the kinetics of individual events. Network-based models such as this will play an increasing role in the rational design of high-order therapeutic combinations.

cancer biology↗

bioRxiv2017

The Complex Ecosystem in Non Small Cell Lung Cancer Invasion

Many tumors are characterized by genetic instability, producing an assortment of genetic variants of tumor cells called subclones. These tumors and their surrounding environments form complex multi-cellular ecosystems, where subclones compete for resources and cooperate to perform multiple tasks, including cancer invasion. Our recent empirical studies revealed existence of such distinct phenotypes of cancer cells, leaders and followers, in lung cancer. These two cellular subclones exchange a complex array of extracellular signals demonstrating a symbiotic relationship at the cellular level. Here, we develop a computational model of the microenvironment of the lung cancer ecosystem to explore how the interactions between subclones can advance or inhibit invasion. We found that, due to the complexity of the ecosystem, invasion may have very different dynamics characterized by the different levels of aggressiveness. By altering the signaling environment, we could alter the ecological relationship between the cell types and the overall ecosystem development. Competition between leader and follower cell populations (defined by the limited amount of resources), positive feedback within the leader cell population (controlled by the focal adhesion kinase and fibronectin signaling), and impact of the follower cells to the leaders (represented by yet undetermined proliferation signal) all had major effects on the outcome of the collective dynamics. Specifically, our analysis revealed a class of tumors (defined by the strengths of fibronectin signaling and competition) that are particularly sensitive to manipulations of the signaling environment. This class can undergo irreversible changes to the tumor ecosystem that outlast these manipulations of feedbacks and have a profound impact on invasive potential. Our study predicts a complex division of labor between cancer cell subclones and suggests new treatment strategies targeting signaling within the tumor ecosystem.\n\nAuthor SummaryCancer is an elusive disease due to the wide variety of cancer types and adaptability to treatment. How is this adaptability accomplished? Loss of genetic stability, a hallmark of cancer, leads to the emergence of many different types of cancer cells within a tumor. This creates a complex ecosystem where cancer cell types can cooperate, compete, and exploit each other. We have previously used an image-guided technology to isolatedistinct cancer subclones and identify how they interact. Here, we have employed mathematical modeling to understand how the dynamic feedbacks between different cancer cell types can impact the success of invasion in lung cancer. We found that successful invasion required for feedbacks to support the less viable but more invasive cell types. These predictions may have implications for novel clinical treatment options and emphasize the need to visualize and probe cancer as a tumor ecosystem.

cancer biology↗

bioRxiv2017

Variable dose analysis: A novel RNAi-based method for detection of synthetic lethal interactions

Synthetic sick or synthetic lethal (SS/L) screens are a powerful way to identify candidate drug targets to specifically kill tumor cells but such screens generally suffer from low reproducibility. We found that many SS/L interactions involve essential genes and are therefore detectable within a limited range of knockdown efficiency. Such interactions are often missed by overly efficient RNAi reagents. We therefore developed an assay that measures viability over a range of knockdown efficiency within a cell population. This method, called variable dose analysis (VDA), is highly sensitive to viability phenotypes and reproducibly detects SS/L interactions. We applied the VDA method to search for SS/L interactions with TSC1 and TSC2, the two tumor suppressors underlying tuberous sclerosis complex (TSC) and generated a SS/L network for TSC. Using this network, we identified four FDA-approved drugs that selectively affect viability of TSC deficient cells, representing promising candidates for repurposing to treat TSC-related tumors.

cancer biology↗

bioRxiv2017

Hydrogen peroxide formation by Nox4 limits malignant transformation

Reactive oxygen species (ROS) can cause cellular damage and are thought to promote cancer-development. Nevertheless, under physiological conditions, all cells constantly produce ROS, either as chemical by-products or for signaling purpose. During differentiation cells induce the NADPH oxidase Nox4, which constitutively produces low amounts of H2O2. We infer that this constitutive H2O2 is unlikely to be carcinogenic and may rather maintain basal activity of cellular surveillance systems.\n\nUtilizing two different murine tumor models we demonstrate that Nox4 prevents malignant transformation and facilitated the recognition of DNA-damage. Upon DNA-damage repair is initiated as consequence of phosphorylation of H2AX ({gamma}H2AX). Repair only occurs if nuclear activity of the {gamma}H2AX-dephosphorylating phosphatase PP2A is kept sufficiently low, a task fulfilled by Nox4: Nox4 continuously oxidizes AKT, and once oxidized AKT captures PP2A in the cytosol. Absence of Nox4 facilitates nuclear PP2A translocation and dephosphorylation of {gamma}H2AX. Simultaneously the proportion of active, phosphorylated AKT is increased. Thus, DNA-damage is not recognized and the increase in AKT activity promotes proliferation. The combination of both events resulted in genomic instability and tumor initiation.\n\nWith the identification of the first cancer-protective source of reactive oxygen species, Nox4, the paradigm of reactive-oxygen species-induced initiation of malignancies should be revised.\n\nSignificanceThe stereotype of ROS produced by NADPH oxidases as cause of malignant diseases persists generalized since decades. We demonstrate that the NADPH oxidase Nox4, as constitutive source of ROS, prevents malignant transformation and that its pharmacological inhibition as currently aspired by several companies will potentially increase the risk of malignant cell transformation and eventually tumor formation.\n\nPrecisBy oxidizing AKT and keeping PP2A in the cytosol, the NADPH oxidase Nox4 allows proper DNA damage repair and averts cancer development.

cancer biology↗

bioRxiv2017

LIM Protein Ajuba associates with the RPA complex through direct and cell cycle-dependent interaction with the RPA70 subunit.

DNA damage response pathways are essential for genome stability and cell survival. Specifically, the ATR kinase is activated by DNA replication stress. An early event in this activation is the recruitment and phosphorylation of RPA, a single stranded DNA binding complex composed of three subunits, RPA70,RPA32 and RPA14. We have previously shown that the LIM protein Ajuba associates with RPA, and that depletion of Ajuba leads to potent activation of ATR. In this study, we show evidence that the Ajuba-RPA interaction occurs through direct protein contact with RPA70, and that their association is cell cycle-regulated and is reduced upon DNA replication stress. We propose a model in which Ajuba negatively regulates the ATR pathway by directly interacting with RPA70, thereby preventing an inappropriate ATR activation. Our results provide a framework to understand the mechanism of regulation of ATR in human cells, which is important to prevent cellular transformation and tumorigenesis.

cancer biology↗

bioRxiv2017

SPIN1 promotes tumorigenesis by blocking the uL18-MDM2-p53 pathway

Ribosomal proteins (RPs) play important roles in modulating the MDM2-p53 pathway. However, less is known about the upstream regulators of the RPs. Here we identify SPIN1 (Spindlin 1) as a novel binding partner of human RPL5/uL18 that is important for this pathway. SPIN1 ablation activates p53, suppresses cell growth, reduces clonogenic ability, and induces apoptosis of cancer cells by sequestering uL18 in the nucleolus, preventing it from interacting with MDM2, and thereby alleviating uL18-mediated inhibition of MDM2 ubiquitin ligase activity towards p53. SPIN1 deficiency increases ribosome-free uL18 and uL5 (human RPL11), which are required for SPIN1 depletion-induced p53 activation. Analysis of cancer genomic databases suggests that SPIN1 is highly expressed in several human cancers, and its overexpression is positively correlated with poor prognosis in cancer patients. Altogether, our findings reveal that the oncogenic property of SPIN1 is highly attributed to its negative regulation of uL18, leading to p53 inactivation.

cancer biology↗

bioRxiv2017

BCL-3 enhances β-catenin signalling in colorectal tumour cells promoting a cancer stem cell phenotype

Increased nuclear BCL-3 (a key regulator of inflammation and NF-{kappa}B signalling when associated with p50 or p52 homodimers) has been reported in a subset of colorectal cancers, but its role in colorectal tumorigenesis remains poorly understood. Interestingly, recent studies have highlighted the importance of the interplay between NF-{kappa}B signalling and the Wnt/{beta}-catenin pathway in colorectal epithelial cells, reporting that non-stem cells engineered to undergo high levels of Wnt and NF-{kappa}B signalling can de-differentiate, initiating tumours in mice. Here we show that BCL-3 is an important co-activator of {beta}-catenin/TCF-mediated transcriptional activity in colorectal cancer cells, increasing expression of Wnt-regulated intestinal stem cell genes. We demonstrate RNAi-mediated BCL-3 suppression reduced {beta}-catenin/TCF-dependent transcription and the expression of intestinal stem cell genes and Wnt targets LGR5 and ASCL2. Further we show that BCL-3 promotes the stem cell phenotype in colorectal cancer cells by increasing colorectal spheroid and tumoursphere formation in 3D culture conditions. Our data suggest that targeting BCL-3 may represent an exciting new approach for CRC treatment, particularly as it acts downstream of frequently mutated APC and {beta}-catenin.

cancer biology↗

bioRxiv2017

NSD1 inactivation defines an immune cold, DNA hypomethylated subtype in squamous cell carcinoma

Chromatin modifying enzymes are frequently mutated in cancer, resulting in a cascade of epigenetic deregulation. Recent reports indicate that inactivating mutations in the histone methyltransferase NSD1 define an intrinsic subtype of head and neck squamous cell carcinoma (HNSC) that features widespread DNA hypomethylation. Here, we describe a similar DNA hypomethylated subtype of lung squamous cell carcinoma (LUSC) that is enriched for both inactivating mutations and deletions in NSD1. The NSD1 subtype of HNSC and LUSC are highly correlated at the DNA methylation and gene expression levels, with concordant DNA hypomethylation and overexpression of a strongly overlapping set of genes, a subset of which are also hypomethylated in Sotos syndrome, a congenital growth disorder caused by germline NSD1 mutations. Further, the NSD1 subtype of HNSC displays an immune cold phenotype characterized by low infiltration of tumor-associated leukocytes, particularly macrophages and CD8+ T cells, as well as low expression of genes encoding the immunotherapy target PD-1 immune checkpoint receptor and its ligands PD-L1 and PD-L2. Using an in vivo model, we demonstrate that NSD1 inactivation results in a reduction in the degree of T cell infiltration into the tumor microenvironment, implicating NSD1 as a tumor cell-intrinsic driver of an immune cold phenotype. These data have important implications for immunotherapy and reveal a general role of NSD1 in maintaining epigenetic repression.

cancer biology↗

bioRxiv2017

Cancer associated fibroblasts and alectinib switch the evolutionary games that non-small cell lung cancer plays

Heterogeneity in strategies for survival and proliferation among the cells which constitute a tumour is a driving force behind the evolution of resistance to cancer therapy. The rules mapping the tumours strategy distribution to the fitness of individual strategies can be represented as an evolutionary game. We develop a game assay to measure effective evolutionary games in co-cultures of non-small cell lung cancer cells which are sensitive and resistant to the anaplastic lymphoma kinase inhibitor Alectinib. The games are not only quantitatively different between different environments, but targeted therapy and cancer associated fibroblasts qualitatively switch the type of game being played by the in-vitro population from Leader to Deadlock. This observation provides empirical confirmation of a central theoretical postulate of evolutionary game theory in oncology: we can treat not only the player, but also the game. Although we concentrate on measuring games played by cancer cells, the measurement methodology we develop can be used to advance the study of games in other microscopic systems by providing a quantitative description of non-cell-autonomous effects.

cancer biology↗

bioRxiv2017

Novel Magnetic Resonance Imaging strategy targeting Neurotensin Receptors in detection of Prostate Cancer

Prostate cancer is the second leading cause of all male cancer deaths. One of the factors present in malignant prostate cells and shown to support its metastatic growth is the neuropeptide neurotensin (NT). The primary goal of the present study was to establish the feasibility of using a newly developed paramagnetic receptor ligand for NT and non-invasive ultrahigh-field magnetic resonance (MR) imaging to visualize prostate cancer in rodents. Orthotropic xenografts were initiated in six-week old male BALB/c nu/nu athymic mice (n = 28) by intra-prostatic (ventral lobe) inoculation of human prostate cancer cells (10L of PC3 cells (106 /100l)). Palpable tumors developed within 30-60 days. A micro-imager utilized in these studies was an actively shielded 9.4T, 89 mm bore, Oxford superconducting magnet with a 100 gauss/cm gradient system. Prior to contrast injection, T2 weighted anatomy scans were done to localize the tumor with a spin-echo multi-slice sequence with TR: 2000 TE: 40 and NEX: 1 in both coronal and axial planes. The paramagnetic ligand data sets were collected with a spin-echo, T1 weighted pulse sequence (MSME): TR 300 msec; TE 5 msec; NEX 4 in both axial and coronal planes. The data sets were taken initially at 5-min intervals post contrast injection for the first half hour and then at 15 min intervals for the next 1.5-2 hours for a time series analyses. The temporal distribution of MR signal intensity in various regions were determined in the absence and presence of NT. Our results confirm that the novel NT molecule was protected from enzymatic degradation and capable of forming a high affinity paramagnetic NT ligand with an extended half-life. During the imaging studies, the signal intensity increased by 200 % in the region of the tumor. This increase in signal intensity approached maximum binding within 30 minutes and remained visible for 1 hour post-injection of the contrast agent. Taken together, these findings suggest that it is feasible to detect and image prostate cancer using a paramagnetic NT ligand and the emergence of the NT receptor ligand that may be used as a diagnostic marker for prostate cancer in humans.

cancer biology↗

bioRxiv2017

Low Perfusion Compartments in Glioblastoma Quantified by Advanced Magnetic Resonance Imaging: Correlation with Patient Survival

BackgroundGlioblastoma exhibits profound intratumoral heterogeneity in blood perfusion, which may cause inconsistent therapy response. Particularly, low perfusion may create hypoxic microenvironment and induce resistant clones. Thus, developing validated imaging approaches that define low perfusion compartments is crucial for clinical management.\n\nMethodsA total of 112 newly-diagnosed supratentorial glioblastoma patients were prospectively recruited for maximal safe resection. Preoperative MRI included anatomical, dynamic susceptibility contrast (DSC), diffusion tensor imaging (DTI) and chemical shift imaging (CSI). The apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) were calculated from DTI and DSC respectively. Using thresholding methods, two low perfusion compartments (ADCH-rCBVL and ADCL-rCBVL) were identified. Volumetric analysis was performed. Lactate and macromolecule/lipid levels were determined from multivoxel spectroscopy. Progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan-Meier and multivariate Cox regression analyses.\n\nResultsTwo compartments displayed higher lactate and macromolecule/lipid levels than normal controls (each P < 0.001), suggesting hypoxic and pro-inflammatory microenvironment. The proportional volume of ADCL-rCBVL compartment was associated with a larger infiltration area (P < 0.001, rho = 0.42). Lower lactate in this compartment was associated with a less invasive phenotype visualized on DTI. Multivariate Cox regression showed higher lactate level in the ADCL-rCBVL compartment was associated with a worse survival (PFS: HR 2.995, P = 0.047; OS: HR 4.974, P = 0.005).\n\nConclusionsThe ADCL-rCBVL compartment represent a treatment resistant sub-region associated with glioblastoma invasiveness. This approach was based on clinically available imaging modalities and could thus provide crucial pretreatment information for clinical decision making.

cancer biology↗

bioRxiv2017

Germline loss of MBD4 predisposes to leukaemia due to a mutagenic cascade driven by 5mC

Cytosine methylation is essential for normal mammalian development, yet also provides a major mutagenic stimulus. Methylcytosine (5mC) is prone to spontaneous deamination, which introduces cytosine to thymine transition mutations (C>T) upon replication1. Cells endure hundreds of 5mC deamination events each day and an intricate repair network is engaged to restrict this damage. Central to this network are the DNA glycosylases MBD42 and TDG3,4, which recognise T:G mispairing and initiate base excision repair (BER). Here we describe a novel cancer predisposition syndrome resulting from germline biallelic inactivation of MBD4 that leads to the development of acute myeloid leukaemia (AML). These leukaemias have an extremely high burden of C>T mutations, specifically in the context of methylated CG dinucleotides (CG>TG). This dependence on 5mC as a source of mutations may explain the remarkable observation that MBD4-deficient AMLs share a common set of driver mutations, including biallelic mutations in DNMT3A and hotspot mutations in IDH1/IDH2. By assessing serial samples taken over the course of treatment, we highlight a critical interaction with somatic mutations in DNMT3A that accelerates leukaemogenesis and accounts for the conserved path to AML. MBD4-deficiency was also detected, rarely, in sporadic cancers, which display the same mutational signature. Collectively these cancers provide a model of 5mC-dependent hypermutation and reveal factors that shape its mutagenic influence.

cancer biology↗