BET inhibition induces synthetic lethality in PTEN deficient colorectal cancers via dual action on p21CIP1/WAF1.

Loss of PTEN tumor suppressor is an important event during colorectal cancer (CRC) development and is a target for therapeutic exploitation. This study reports that bromodomain and extra-terminal motif (BET) is a synthetic lethal partner of PTEN in CRC. BET inhibition (BETi) selectively induced G1 cell cycle arrest and apoptosis in PTEN-/- CRC. Further, BETi selectively and dose-dependently suppressed the growth of PTEN-/- CRC tumor xenografts in mice and patient-derived organoids. Mechanistically, PTEN-deficient CRC cells elevated the level of cytoplasmic p21CIP1/WAF1 that is hyper-phosphorylated at Thr145 by AKT. BETi suppressed AKT activation in PTEN-deficient CRC cells, followed by the reduction in p21 phosphorylation at Thr145, thereby promoting its nuclear translocation. In addition, BETi suppressed MYC level and this in turn increased the total p21 level in the nuclei. Over-expression of a phospho-mimetic p21 mutant (T145D) significantly rescued the BETi effect on PTEN-deficient CRC. These results suggest that BETi has a dual action on p21: elevating the level of p21 by inhibiting MYC and converting the oncogenic (cytoplasmic) p21 into the tumor-suppressive (nuclear) p21 by inhibiting AKT. Taken together, this study identified the synthetic lethal interaction between PTEN and BET, and provides a potential actionable target for CRC with PTEN loss.

Synthetic Lethality between Cohesin and WNT Signaling Pathways in Diverse Cancer Contexts.

Cohesin is a highly conserved ring-shaped complex involved in topologically embracing chromatids, gene expression regulation, genome compartmentalization, and genome stability maintenance. Genomic analyses have detected mutations in the cohesin complex in a wide array of human tumors. These findings have led to increased interest in cohesin as a potential target in cancer therapy. Synthetic lethality has been suggested as an approach to exploit genetic differences in cancer cells to influence their selective killing. In this study, we show that mutations in ESCO1, NIPBL, PDS5B, RAD21, SMC1A, SMC3, STAG2, and WAPL genes are synthetically lethal with stimulation of WNT signaling obtained following LY2090314 treatment, a GSK3 inhibitor, in several cancer cell lines. Moreover, treatment led to the stabilization of ß-catenin and affected the expression of c-MYC, probably due to the occupancy decrease in cohesin at the c-MYC promoter. Finally, LY2090314 caused gene expression dysregulation mainly involving pathways related to transcription regulation, cell proliferation, and chromatin remodeling. For the first time, our work provides the underlying molecular basis for synthetic lethality due to cohesin mutations and suggests that targeting the WNT may be a promising therapeutic approach for tumors carrying mutated cohesin.

OGDH and Bcl-xL loss causes synthetic lethality in glioblastoma.

Glioblastoma (GBM) remains an incurable disease, requiring more effective therapies. Through interrogation of publicly available CRISPR and RNAi library screens, we identified the α-ketoglutarate dehydrogenase (OGDH) gene, which encodes an enzyme that is part of the tricarboxylic acid (TCA) cycle, as essential for GBM growth. Moreover, by combining transcriptome and metabolite screening analyses, we discovered that loss of function of OGDH by the clinically validated drug compound CPI-613 was synthetically lethal with Bcl-xL inhibition (genetically and through the clinically validated BH3 mimetic, ABT263) in patient-derived xenografts as well neurosphere GBM cultures. CPI-613-mediated energy deprivation drove an integrated stress response with an upregulation of the BH3-only domain protein, Noxa, in an ATF4-dependent manner, as demonstrated by genetic loss-of-function experiments. Consistently, silencing of Noxa attenuated cell death induced by CPI-613 in model systems of GBM. In patient-derived xenograft models of GBM in mice, the combination treatment of ABT263 and CPI-613 suppressed tumor growth and extended animal survival more potently than each compound on its own. Therefore, combined inhibition of Bcl-xL along with disruption of the TCA cycle might be a treatment strategy for GBM.

Cryo-shocked tumor cells deliver CRISPR-Cas9 for lung cancer regression by synthetic lethality.

Although CRISPR-mediated genome editing holds promise for cancer therapy, inadequate tumor targeting and potential off-target side effects hamper its outcomes. In this study, we present a strategy using cryo-shocked lung tumor cells as a CRISPR-Cas9 delivery system for cyclin-dependent kinase 4 (CDK4) gene editing, which initiates synthetic lethal in KRAS-mutant non-small cell lung cancer (NSCLC). By rapidly liquid nitrogen shocking, we effectively eliminate the pathogenicity of tumor cells while preserving their structure and surface receptor activity. This delivery system enables the loaded CRISPR-Cas9 to efficiently target to lung through the capture in pulmonary capillaries and interactions with endothelial cells. In a NSCLC-bearing mouse model, the drug accumulation is increased nearly fourfold in lung, and intratumoral CDK4 expression is substantially down-regulated compared to CRISPR-Cas9 lipofectamine nanoparticles administration. Furthermore, CRISPR-Cas9 editing-mediated CDK4 ablation triggers synthetic lethal in KRAS-mutant NSCLC and prolongs the survival of mice.

The power and the promise of synthetic lethality for clinical application in cancer treatment.

Synthetic lethality is a phenomenon wherein the simultaneous deficiency of two or more genes results in cell death, while the deficiency of any individual gene does not lead to cell death. In recent years, synthetic lethality has emerged as a significant topic in the field of targeted cancer therapy, with certain drugs based on this concept exhibiting promising outcomes in clinical trials. Nevertheless, the presence of tumor heterogeneity and the intricate DNA repair mechanisms pose challenges to the effective implementation of synthetic lethality. This review aims to explore the concepts, development, and ethical quandaries surrounding synthetic lethality. Additionally, it will provide an in-depth analysis of the clinical application and underlying mechanism of synthetic lethality.

Genetic determinants of micronucleus formation in vivo.

Genomic instability arising from defective responses to DNA damage1 or mitotic chromosomal imbalances2 can lead to the sequestration of DNA in aberrant extranuclear structures called micronuclei (MN). Although MN are a hallmark of ageing and diseases associated with genomic instability, the catalogue of genetic players that regulate the generation of MN remains to be determined. Here we analyse 997 mouse mutant lines, revealing 145 genes whose loss significantly increases (n = 71) or decreases (n = 74) MN formation, including many genes whose orthologues are linked to human disease. We found that mice null for Dscc1, which showed the most significant increase in MN, also displayed a range of phenotypes characteristic of patients with cohesinopathy disorders. After validating the DSCC1-associated MN instability phenotype in human cells, we used genome-wide CRISPR-Cas9 screening to define synthetic lethal and synthetic rescue interactors. We found that the loss of SIRT1 can rescue phenotypes associated with DSCC1 loss in a manner paralleling restoration of protein acetylation of SMC3. Our study reveals factors involved in maintaining genomic stability and shows how this information can be used to identify mechanisms that are relevant to human disease biology1.

LRPPRC promotes glycolysis by stabilising LDHA mRNA and its knockdown plus glutamine inhibitor induces synthetic lethality via m6 A modification in triple-negative breast cancer.

BACKGROUND: Targeted therapy for triple-negative breast cancer (TNBC) remains a challenge. N6-methyladenosine (m6 A) is the most abundant internal mRNA modification in eukaryotes, and it regulates the homeostasis and function of modified RNA transcripts in cancer. However, the role of leucine-rich pentatricopeptide repeat containing protein (LRPPRC) as an m6 A reader in TNBC remains poorly understood. METHODS: Western blotting, reverse transcription-polymerase chain reaction (RT-qPCR) and immunohistochemistry were used to investigate LRPPRC expression levels. Dot blotting and colorimetric enzyme linked immunosorbent assay (ELISA) were employed to detect m6 A levels. In vitro functional assays and in vivo xenograft mouse model were utilised to examine the role of LRPPRC in TNBC progression. Liquid chromatography-mass spectrometry/mass spectrometry and Seahorse assays were conducted to verify the effect of LRPPRC on glycolysis. MeRIP-sequencing, RNA-sequencing, MeRIP assays, RNA immunoprecipitation assays, RNA pull-down assays and RNA stability assays were used to identify the target genes of LRPPRC. Patient-derived xenografts and organoids were employed to substantiate the synthetic lethality induced by LRPPRC knockdown plus glutaminase inhibition. RESULTS: The expressions of LRPPRC and m6 A RNA were elevated in TNBC, and the m6 A modification site could be recognised by LRPPRC. LRPPRC promoted the proliferation, metastasis and glycolysis of TNBC cells both in vivo and in vitro. We identified lactate dehydrogenase A (LDHA) as a novel direct target of LRPPRC, which recognised the m6 A site of LDHA mRNA and enhanced the stability of LDHA mRNA to promote glycolysis. Furthermore, while LRPPRC knockdown reduced glycolysis, glutaminolysis was enhanced. Moreover, the effect of LRPPRC on WD40 repeat domain-containing protein 76 (WDR76) mRNA stability was impaired in an m6 A-dependent manner. Then, LRPPRC knockdown plus a glutaminase inhibition led to synthetic lethality. CONCLUSIONS: Our study demonstrated that LRPPRC promoted TNBC progression by regulating metabolic reprogramming via m6 A modification. These characteristics shed light on the novel combination targeted therapy strategies to combat TNBC.

Evaluation of Homologous Recombination Deficiency in Ovarian Cancer.

OPINION STATEMENT: Homologous recombination deficiency (HRD) is an important biomarker guiding selection of ovarian cancer patients who will derive the most benefit from poly(ADP-ribose) polymerase inhibitors (PARPi). HRD prevents cells from repairing double-stranded DNA damage with high fidelity, PARPis limit single-stranded repair, and together these deficits induce synthetic lethality. Germline or somatic BRCA mutations represent the narrowest definition of HRD, but do not reflect all patients who will have a durable PARPi response. HRD can also be defined by its downstream consequences, which are measured by different metrics depending on the test used. Ideally, all patients will undergo genetic counseling and germline testing shortly after diagnosis and have somatic testing sent once an adequate tumor sample is available. Should barriers to one test be higher, pursuing germline testing with reflex to somatic testing for BRCA wildtype patients or somatic testing first strategies are both evidence-based. Ultimately both tests offer complementary information, germline testing should be pursued for any patient with a history of ovarian cancer, and somatic testing is valuable at recurrence if not performed in the upfront setting. There is a paucity of data to suggest superiority of one germline or somatic assay; therefore, selection should optimize turnaround time, cost to patients, preferred result format, and logistical burden. Each clinic should implement a standard testing strategy for all ovarian cancer patients that ensures HRD status is known at the time of upfront chemotherapy completion to facilitate comprehensive counseling about anticipated maintenance PARPi benefit.

Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in KrasG12D-driven tumors.

We find that NUPR1, a stress-associated intrinsically disordered protein, induced droplet formation via liquid-liquid phase separation (LLPS). NUPR1-driven LLPS was crucial for the creation of NUPR1-dependent stress granules (SGs) in pancreatic cancer cells since genetic or pharmacological inhibition by ZZW-115 of NUPR1 activity impeded SGs formation. The KrasG12D mutation induced oncogenic stress, NUPR1 overexpression, and promoted SGs development. Notably, enforced NUPR1 expression induced SGs formation independently of mutated KrasG12D. Mechanistically, KrasG12D expression strengthened sensitivity to NUPR1 inactivation, inducing cell death, activating caspase 3 and releasing LDH. Remarkably, ZZW-115-mediated SG-formation inhibition hampered the development of pancreatic intraepithelial neoplasia (PanINs) in Pdx1-cre;LSL-KrasG12D (KC) mice. ZZW-115-treatment of KC mice triggered caspase 3 activation, DNA fragmentation, and formation of the apoptotic bodies, leading to cell death, specifically in KrasG12D-expressing cells. We further demonstrated that, in developed PanINs, short-term ZZW-115 treatment prevented NUPR1-associated SGs presence. Lastly, a four-week ZZW-115 treatment significantly reduced the number and size of PanINs in KC mice. This study proposes that targeting NUPR1-dependent SGs formation could be a therapeutic approach to induce cell death in KrasG12D-dependent tumors.

Genome-wide CRISPR screen reveals the synthetic lethality between BCL2L1 inhibition and radiotherapy.

Radiation therapy (RT) is one of the most commonly used anticancer therapies. However, the landscape of cellular response to irradiation, especially to a single high-dose irradiation, remains largely unknown. In this study, we performed a whole-genome CRISPR loss-of-function screen and revealed temporal inherent and acquired responses to RT. Specifically, we found that loss of the IL1R1 pathway led to cellular resistance to RT. This is in part because of the involvement of radiation-induced IL1R1-dependent transcriptional regulation, which relies on the NF-κB pathway. Moreover, the mitochondrial anti-apoptotic pathway, particularly the BCL2L1 gene, is crucially important for cell survival after radiation. BCL2L1 inhibition combined with RT dramatically impeded tumor growth in several breast cancer cell lines and syngeneic models. Taken together, our results suggest that the combination of an apoptosis inhibitor such as a BCL2L1 inhibitor with RT may represent a promising anticancer strategy for solid cancers including breast cancer.

Two mitochondrial DNA polymorphisms modulate cardiolipin binding and lead to synthetic lethality.

Genetic screens have been used extensively to probe interactions between nuclear genes and their impact on phenotypes. Probing interactions between mitochondrial genes and their phenotypic outcome, however, has not been possible due to a lack of tools to map the responsible polymorphisms. Here, using a toolkit we previously established in Drosophila, we isolate over 300 recombinant mitochondrial genomes and map a naturally occurring polymorphism at the cytochrome c oxidase III residue 109 (CoIII109) that fully rescues the lethality and other defects associated with a point mutation in cytochrome c oxidase I (CoIT300I). Through lipidomics profiling, biochemical assays and phenotypic analyses, we show that the CoIII109 polymorphism modulates cardiolipin binding to prevent complex IV instability caused by the CoIT300I mutation. This study demonstrates the feasibility of genetic interaction screens in animal mitochondrial DNA. It unwraps the complex intra-genomic interplays underlying disorders linked to mitochondrial DNA and how they influence disease expression.

Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.

Metabolic reprogramming is key for cancer development, yet the mechanism that sustains triple-negative breast cancer (TNBC) cell growth despite deficient pyruvate kinase M2 (PKM2) and tumor glycolysis remains to be determined. Here, we find that deficiency in tumor glycolysis activates a metabolic switch from glycolysis to fatty acid ß-oxidation (FAO) to fuel TNBC growth. We show that, in TNBC cells, PKM2 directly interacts with histone methyltransferase EZH2 to coordinately mediate epigenetic silencing of a carnitine transporter, SLC16A9. Inhibition of PKM2 leads to impaired EZH2 recruitment to SLC16A9, and in turn de-represses SLC16A9 expression to increase intracellular carnitine influx, programming TNBC cells to an FAO-dependent and luminal-like cell state. Together, these findings reveal a new metabolic switch that drives TNBC from a metabolically heterogeneous-lineage plastic cell state to an FAO-dependent-lineage committed cell state, where dual targeting of EZH2 and FAO induces potent synthetic lethality in TNBC.

Biology and Development of DNA-Targeted Drugs, Focusing on Synthetic Lethality, DNA Repair, and Epigenetic Modifications for Cancer: A Review.

DNA-targeted drugs constitute a specialized category of pharmaceuticals developed for cancer treatment, directly influencing various cellular processes involving DNA. These drugs aim to enhance treatment efficacy and minimize side effects by specifically targeting molecules or pathways crucial to cancer growth. Unlike conventional chemotherapeutic drugs, recent discoveries have yielded DNA-targeted agents with improved effectiveness, and a new generation is anticipated to be even more specific and potent. The sequencing of the human genome in 2001 marked a transformative milestone, contributing significantly to the advancement of targeted therapy and precision medicine. Anticipated progress in precision medicine is closely tied to the continuous development in the exploration of synthetic lethality, DNA repair, and expression regulatory mechanisms, including epigenetic modifications. The integration of technologies like circulating tumor DNA (ctDNA) analysis further enhances our ability to elucidate crucial regulatory factors, promising a more effective era of precision medicine. The combination of genomic knowledge and technological progress has led to a surge in clinical trials focusing on precision medicine. These trials utilize biomarkers for identifying genetic alterations, molecular profiling for potential therapeutic targets, and tailored cancer treatments addressing multiple genetic changes. The evolving landscape of genomics has prompted a paradigm shift from tumor-centric to individualized, genome-directed treatments based on biomarker analysis for each patient. The current treatment strategy involves identifying target genes or pathways, exploring drugs affecting these targets, and predicting adverse events. This review highlights strategies incorporating DNA-targeted drugs, such as PARP inhibitors, SLFN11, methylguanine methyltransferase (MGMT), and ATR kinase.

An 19F NMR fragment-based approach for the discovery and development of BRCA2-RAD51 inhibitors to pursuit synthetic lethality in combination with PARP inhibition in pancreatic cancer.

The BRCA2-RAD51 interaction remains an intriguing target for cancer drug discovery due to its vital role in DNA damage repair mechanisms, which cancer cells become particularly reliant on. Moreover, RAD51 has many synthetically lethal partners, including PARP1-2, which can be exploited to induce synthetic lethality in cancer. In this study, we established a 19F-NMR-fragment based approach to identify RAD51 binders, leading to two initial hits. A subsequent SAR program identified 46 as a low micromolar inhibitor of the BRCA2-RAD51 interaction. 46 was tested in different pancreatic cancer cell lines, to evaluate its ability to inhibit the homologous recombination DNA repair pathway, mediated by BRCA2-RAD51 and trigger synthetic lethality in combination with the PARP inhibitor talazoparib, through the induction of apoptosis. Moreover, we further analyzed the 46/talazoparib combination in 3D pancreatic cancer models. Overall, 46 showed its potential as a tool to evaluate the RAD51/PARP1-2 synthetic lethality mechanism, along with providing a prospect for further inhibitors development.

A systematic analysis of the landscape of synthetic lethality-driven precision oncology.

BACKGROUND: Synthetic lethality (SL) denotes a genetic interaction between two genes whose co-inactivation is detrimental to cells. Because more than 25 years have passed since SL was proposed as a promising way to selectively target cancer vulnerabilities, it is timely to comprehensively assess its impact so far and discuss its future. METHODS: We systematically analyzed the literature and clinical trial data from the PubMed and Trialtrove databases to portray the preclinical and clinical landscape of SL oncology. FINDINGS: We identified 235 preclinically validated SL pairs and found 1,207 pertinent clinical trials, and the number keeps increasing over time. About one-third of these SL clinical trials go beyond the typically studied DNA damage response (DDR) pathway, testifying to the recently broadening scope of SL applications in clinical oncology. We find that SL oncology trials have a greater success rate than non-SL-based trials. However, about 75% of the preclinically validated SL interactions have not yet been tested in clinical trials. CONCLUSIONS: Dissecting the recent efforts harnessing SL to identify predictive biomarkers, novel therapeutic targets, and effective combination therapy, our systematic analysis reinforces the hope that SL may serve as a key driver of precision oncology going forward. FUNDING: Funded by the Samsung Research Funding & Incubation Center of Samsung Electronics, the Institute of Information & Communications Technology Planning & Evaluation (IITP) grant funded by the Republic of Korea government (MSIT), the Kwanjeong Educational Foundation, the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), and Center for Cancer Research (CCR).

SL-Miner: a web server for mining evidence and prioritization of cancer-specific synthetic lethality.

SUMMARY: Synthetic lethality (SL) refers to a type of genetic interaction in which the simultaneous inactivation of two genes leads to cell death, while the inactivation of a single gene does not affect cell viability. It significantly expands the range of potential therapeutic targets for anti-cancer treatments. SL interactions are primarily identified through experimental screening and computational prediction. Although various computational methods have been proposed, they tend to ignore providing evidence to support their predictions of SL. Besides, they are rarely user-friendly for biologists who likely have limited programming skills. Moreover, the genetic context specificity of SL interactions is often not taken into consideration. Here, we introduce a web server called SL-Miner, which is designed to mine the evidence of SL relationships between a primary gene and a few candidate SL partner genes in a specific type of cancer, and to prioritize these candidate genes by integrating various types of evidence. For intuitive data visualization, SL-Miner provides a range of charts (e.g. volcano plot and box plot) to help users get insights from the data. AVAILABILITY AND IMPLEMENTATION: SL-Miner is available at https://slminer.sist.shanghaitech.edu.cn.

SLKB: synthetic lethality knowledge base.

Emerging CRISPR-Cas9 technology permits synthetic lethality (SL) screening of large number of gene pairs from gene combination double knockout (CDKO) experiments. However, the poor integration and annotation of CDKO SL data in current SL databases limit their utility, and diverse methods of calculating SL scores prohibit their comparison. To overcome these shortcomings, we have developed SL knowledge base (SLKB) that incorporates data of 11 CDKO experiments in 22 cell lines, 16,059 SL gene pairs and 264,424 non-SL gene pairs. Additionally, within SLKB, we have implemented five SL calculation methods: median score with and without background control normalization (Median-B/NB), sgRNA-derived score (sgRNA-B/NB), Horlbeck score, GEMINI score and MAGeCK score. The five scores have demonstrated a mere 1.21% overlap among their top 10% SL gene pairs, reflecting high diversity. Users can browse SL networks and assess the impact of scoring methods using Venn diagrams. The SL network generated from all data in SLKB shows a greater likelihood of SL gene pair connectivity with other SL gene pairs than non-SL pairs. Comparison of SL networks between two cell lines demonstrated greater likelihood to share SL hub genes than SL gene pairs. SLKB website and pipeline can be freely accessed at https://slkb.osubmi.org and https://slkb.docs.osubmi.org/, respectively.

Leveraging synthetic lethality to uncover potential therapeutic target in gastric cancer.

Since trastuzumab was approved in 2012 for the first-line treatment of gastric cancer (GC), no significant advancement in GC targeted therapies has occurred. Synthetic lethality refers to the concept that simultaneous dysfunction of a pair of genes results in a lethal effect on cells, while the loss of an individual gene does not cause this effect. Through exploiting synthetic lethality, novel targeted therapies can be developed for the individualized treatment of GC. In this study, we proposed a computational strategy named Gastric cancer Specific Synthetic Lethality inference (GSSL) to identify synthetic lethal interactions in GC. GSSL analysis was used to infer probable synthetic lethality in GC using four accessible clinical datasets. In addition, prediction results were confirmed by experiments. GSSL analysis identified a total of 34 candidate synthetic lethal pairs, which included 33 unique targets. Among the synthetic lethal gene pairs, TP53-CHEK1 was selected for further experimental validation. Both computational and experimental results indicated that inhibiting CHEK1 could be a potential therapeutic strategy for GC patients with TP53 mutation. Meanwhile, in vitro experimental validation of two novel synthetic lethal pairs TP53-AURKB and ARID1A-EP300 further proved the universality and reliability of GSSL. Collectively, GSSL has been shown to be a reliable and feasible method for comprehensive analysis of inferring synthetic lethal interactions of GC, which may offer novel insight into the precision medicine and individualized treatment of GC.

PP2A inhibition causes synthetic lethality in BRCA2-mutated prostate cancer models via spindle assembly checkpoint reactivation.

Mutations in the BRCA2 tumor suppressor gene have been associated with an increased risk of developing prostate cancer. One of the paradoxes concerning BRCA2 is the fact that its inactivation affects genetic stability and is deleterious for cellular and organismal survival, while BRCA2-mutated cancer cells adapt to this detriment and malignantly proliferate. Therapeutic strategies for tumors arising from BRCA2 mutations may be discovered by understanding these adaptive mechanisms. In this study, we conducted forward genetic synthetic viability screenings in Caenorhabditis elegans brc-2 (Cebrc-2) mutants and found that Ceubxn-2 inactivation rescued the viability of Cebrc-2 mutants. Moreover, loss of NSFL1C, the mammalian ortholog of CeUBXN-2, suppressed the spindle assembly checkpoint (SAC) activation and promoted the survival of BRCA2-deficient cells. Mechanistically, NSFL1C recruited USP9X to inhibit the polyubiquitination of AURKB and reduce the removal of AURKB from the centromeres by VCP, which is essential for SAC activation. SAC inactivation is common in BRCA2-deficient prostate cancer patients, but PP2A inhibitors could reactivate the SAC and achieve BRCA2-deficient prostate tumor synthetic lethality. Our research reveals the survival adaptation mechanism of BRCA2-deficient prostate tumor cells and provides different angles for exploring synthetic lethal inhibitors in addition to targeting DNA damage repair pathways.

Expression of "DNA damage response" pathway genes in diffuse large B-cell lymphoma: The potential for exploiting synthetic lethality.

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are two of the most prevalent non-Hodgkin's lymphoma subtypes. Despite advances, treatment resistance and patient relapse remain challenging issues. Our study aimed to scrutinize gene expression distinctions between DLBCL and FL, employing a cohort of 53 DLBCL and 104 FL samples that underwent rigorous screening for genetic anomalies. The NanoString nCounter assay evaluated 730 cancer-associated genes, focusing on densely tumorous areas in diagnostic samples. Employing the Lymph2Cx method, we determined the cell-of-origin (COO) for DLBCL cases. Our meticulous analysis, facilitated by Qlucore Omics Explorer software, unveiled a substantial 37% of genes with significantly differential expression patterns between DLBCL and FL, pointing to nuanced mechanistic disparities. Investigating the impact of FL disease stage and DLBCL COO on gene expression yielded minimal differences, prompting us to direct our attention to consistently divergent genes in DLBCL. Intriguingly, our Gene Set Enrichment Analysis spotlighted 21% of these divergent genes, converging on the DNA damage response (DDR) pathway, vital for cell survival and cancer evolution. Strong positive correlations among most DDR genes were noted, with key genes like BRCA1, FANCA, FEN1, PLOD1, PCNA, and RAD51 distinctly upregulated in DLBCL compared to FL and normal tissue controls. These findings were subsequently validated using RNA seq data on normal controls and DLBCL samples from public databases like The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases, enhancing the robustness of our results. Considering the established significance of these DDR genes in solid cancer therapies, our study underscores their potential applicability in DLBCL treatment strategies. In conclusion, our investigation highlights marked gene expression differences between DLBCL and FL, with particular emphasis on the essential DDR pathway. The identification of these DDR genes as potential therapeutic targets encourages further exploration of synthetic lethality-based approaches for managing DLBCL.