DNA Repair Deficiency Research Articles

BIN1 in cancer: biomarker and therapeutic target.

The bridging integrator 1 (BIN1) protein was originally identified as a pro-apoptotic tumor suppressor that binds to and inhibits oncogenic MYC transcription factors. BIN1 has complex physiological functions participating in endocytosis, membrane cycling, cytoskeletal regulation, DNA repair deficiency, cell-cycle arrest, and apoptosis. The expression of BIN1 is closely related to the development of various diseases such as cancer, Alzheimer's disease, myopathy, heart failure, and inflammation. Because BIN1 is commonly expressed in terminally differentiated normal tissues and is usually undetectable in refractory or metastatic cancer tissues, this differential expression has led us to focus on human cancers associated with BIN1. In this review, we discuss the potential pathological mechanisms of BIN1 during cancer development and its feasibility as a prognostic marker and therapeutic target for related diseases based on recent findings on its molecular, cellular, and physiological roles. BIN1 is a tumor suppressor that regulates cancer development through a series of signals in tumor progression and microenvironment. It also makes BIN1 a feasible early diagnostic or prognostic marker for cancer.

Pan-cancer association of DNA repair deficiencies with whole-genome mutational patterns.

DNA repair deficiencies in cancers may result in characteristic mutational patterns, as exemplified by deficiency of BRCA1/2 and efficacy prediction for PARP-inhibitors. We trained and evaluated predictive models for loss-of-function (LOF) of 145 individual DDR genes based on genome-wide mutational patterns, including structural variants, indels, and base-substitution signatures. We identified 24 genes whose deficiency could be predicted with good accuracy, including expected mutational patterns for BRCA1/2, MSH3/6, TP53, and CDK12 LOF variants. CDK12 is associated with tandem-duplications, and we here demonstrate that this association can accurately predict gene deficiency in prostate cancers (area under the ROC curve=0.97). Our novel associations include mono- or biallelic LOF variants of ATRX, IDH1, HERC2, CDKN2A, PTEN, and SMARCA4, and our systematic approach yielded a catalogue of predictive models, which may provide targets for further research and development of treatment, and potentially help guide therapy.

DNA Repair Deficiency Regulates Immunity Response in Cancers: Molecular Mechanism and Approaches for Combining Immunotherapy

Defects in DNA repair pathways can lead to genomic instability in multiple tumor types, which contributes to tumor immunogenicity. Inhibition of DNA damage response (DDR) has been reported to increase tumor susceptibility to anticancer immunotherapy. However, the interplay between DDR and the immune signaling pathways remains unclear. In this review, we will discuss how a deficiency in DDR affects anti-tumor immunity, highlighting the cGAS-STING axis as an important link. We will also review the clinical trials that combine DDR inhibition and immune-oncology treatments. A better understanding of these pathways will help exploit cancer immunotherapy and DDR pathways to improve treatment outcomes for various cancers.

Multiomic analysis of homologous recombination-deficient end-stage high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGSC) is frequently characterized by homologous recombination (HR) DNA repair deficiency and, while most such tumors are sensitive to initial treatment, acquired resistance is common. We undertook a multiomics approach to interrogate molecular diversity in end-stage disease, using multiple autopsy samples collected from 15 women with HR-deficient HGSC. Patients had polyclonal disease, and several resistance mechanisms were identified within most patients, including reversion mutations and HR restoration by other means. We also observed frequent whole-genome duplication and global changes in immune composition with evidence of immune escape. This analysis highlights diverse evolutionary changes within HGSC that evade therapy and ultimately overwhelm individual patients.

The etiology of clonal mosaicism in human aging and disease

AbstractOur DNA is consistently assaulted by a variety of intrinsic and extrinsic mutational factors. Fortunately, DNA repair provides for protective barriers that limit the full manifestation of DNA damage. Yet, DNA repair represents no panacea as DNA damage continuously slips through these erected defenses and materializes as mutation, which can have undesirable consequences as seen for cancer. Acquisition of early driver mutations can engender mutated stem cells with increased cellular fitness resulting in clonal expansion (CE) and increased risk of malignant disease. Tissue clonal mosaicism as observed in the elderly is therefore the natural outcome of continuous driver mutation acquisition in stem cells and their subsequent clonal outgrowth. Hence, a major emerging theme is that CE is an idiosyncrasy of the aging human tissue. This phenomenon can have diverse health consequences that we here divide into three categories: cancer, non‐cancer morbidity, and disease protection. This review outlines current day knowledge on clonal outgrowth, how it relates to health and aging, and how in the framework of DNA repair deficiencies these subjects are consolidated.

PARP Inhibitors and Proteins Interacting with SLX4.

PARP inhibitors are small molecules currently used with success in the treatment of certain cancer patients. Their action was first shown to be specific to cells with DNA repair deficiencies, such as BRCA-mutant cancers. However, recent work has suggested clinical interest of these drugs beyond this group of patients. Preclinical data on relationships between the activity of PARP inhibitors and other proteins involved in DNA repair exist, and this review will only highlight findings on the SLX4 protein and its interacting protein partners. As suggested from these available data and depending on further validations, new treatment strategies could be developed in order to broaden the use for PARP inhibitors in cancer patients.

CRISPR metabolic screen identifies ATM and KEAP1 as targetable genetic vulnerabilities in solid tumors

Cancer treatments targeting DNA repair deficiencies often encounter drug resistance, possibly due to alternative metabolic pathways that counteract the most damaging effects. To identify such alternative pathways, we screened for metabolic pathways exhibiting synthetic lethality with inhibition of the DNA damage response kinase Ataxia-telangiectasia-mutated (ATM) using a metabolism-centered Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 library. Our data revealed Kelch-like ECH-associated protein 1 (KEAP1) as a key factor involved in desensitizing cancer cells to ATM inhibition both invitro and invivo. Cells depleted of KEAP1 exhibited an aberrant overexpression of the cystine transporter SLC7A11, robustly accumulated cystine inducing disulfide stress, and became hypersensitive to ATM inhibition. These hallmarks were reversed in a reducing cellular environment indicating that disulfide stress was a crucial factor. In The Cancer Genome Atlas (TCGA) pan-cancer datasets, we found that ATM levels negatively correlated with KEAP1 levels across multiple solid malignancies. Together, our results unveil ATM and KEAP1 as new targetable vulnerabilities in solid tumors.

ATM or CHEK2 alterations: Potential biomarkers of improved outcomes with irinotecan-containing chemotherapy in advanced pancreatic ductal adenocarcinoma.

754 Background: ATM and CHEK2 mutations are linked to homologous recombination DNA repair deficiency, with the potential for improved therapeutic response to DNA damaging agents. To investigate our clinical observation of improved outcomes with irinotecan (IRI) based chemotherapy in advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) patients (pts) with somatic or germline ATM/ CHEK2 mutations, we examined our institutional real world experience. Methods: Between 2015-2021, 33 pts with ATM or CHEK2 mutations treated with chemotherapy were identified, of which 16 pts had advanced/metastatic disease. Progression-free survival (PFS) was calculated and compared (Kaplan Meier, log-rank test) in several ways to assess the impact of IRI vs platinum or other regimens. The event for PFS was progression (or death), and pts without progression were censored at treatment end, or at last follow up if treatment was ongoing. Results: Among 16 pts with advanced/metastatic PDAC, 8 (50%) had ATM (5 germline, 3 somatic) and 8 (50%), CHEK2 alterations (4 germline, 4 somatic). Overall, pts received 48 lines of chemotherapy (platinum-based-(No-IRI) N=14; IRI-based-(No-Platinum) N=8; both N=4; none N=22). For best-PFS among pts analysis, median line of best-PFS therapy for IRI-Ever (N=9 pts) was 2nd line (range 1-7) and for IRI-Never (N=7 pts) was 1st (range, 1-1); median PFS was 13 vs 3 months (mo) (IRI-Ever vs IRI-Never; p=0.0076). For PFS analysis within lines of treatment of each pt, median therapy line for both IRI-containing and No-IRI lines was 2nd line (range 1-7); median PFS for IRI-containing (N=12 lines of therapy) vs No-IRI (N=36) was 12.1 vs 3 mo (p<0.001). Median PFS for best IRI-based-(No-Platinum) line (N=7) was 13 mo; for best platinum-based-(No-IRI) line (N=9) was 2.8 mo; and for best treatment containing no IRI or platinum (N=13) was 5.1 mo (P= 0.003) (median therapy line for each was 3, 2 and 1.5, respectively). Conclusions: Irinotecan is a topoisomerase 1 inhibitor that induces DNA strand breaks, potentially causing synthetic lethality in tumors with DNA damage repair deficits due to ATM or CHEK2 alterations. IRI-containing therapy out-performed other treatment types, including platinum-containing regimens, in pts with ATM or CHEK2-mutated advanced/metastatic PDAC. Prospective trials are warranted.

DNA repair deficiency as circulating biomarker in prostate cancer.

Deleterious aberrations in DNA repair genes are actionable in approximately 25% of metastatic castration-resistant prostate cancers (mCRPC) patients. Homology recombination repair (HRR) is the DNA damage repair (DDR) mechanism most frequently altered in prostate cancer; of note BRCA2 is the most frequently altered DDR gene in this tumor. Poly ADP-ribose polymerase inhibitors showed antitumor activity with a improvement in overall survival in mCRPC carrying somatic and/or germline alterations of HHR. Germline mutations are tested on peripheral blood samples using DNA extracted from peripheral blood leukocytes, while the somatic alterations are assessed by extracting DNA from a tumor tissue sample. However, each of these genetic tests have some limitations: the somatic tests are related to the sample availability and tumor heterogeneity, while the germline testing are mainly related to the inability to detect somatic HRR mutations. Therefore, the liquid biopsy, a non-invasive and easily repeatable test compared to tissue test, could identified somatic mutation detected on the circulating tumor DNA (ctDNA) extracted from a plasma. This approach should better represent the heterogeneity of the tumor compared to the primary biopsy and maybe helpful in monitoring the onset of potential mutations involved in treatment resistance. Furthermore, ctDNA may inform about timing and potential cooperation of multiple driver genes aberration guiding the treatment options in patients with mCRPC. However, the clinical use of ctDNA test in prostate cancer compared to blood and tissue testing are currently very limited. In this review, we summarize the current therapeutic indications in prostate cancer patients with DDR deficiency, the recommendation for germline and somatic-genomic testing in advanced PC and the advantages of the use liquid biopsy in clinical routine for mCRPC.

Pathological consequences of DNA damage in the kidney.

DNA lesions that evade repair can lead to mutations that drive the development of cancer, and cellular responses to DNA damage can trigger senescence and cell death, which are associated with ageing. In the kidney, DNA damage has been implicated in both acute and chronic kidney injury, and in renal cell carcinoma. The susceptibility of the kidney to chemotherapeutic agents that damage DNA is well established, but an unexpected link between kidney ciliopathies and the DNA damage response has also been reported. In addition, human genetic deficiencies in DNA repair have highlighted DNA crosslinks, DNA breaks and transcription-blocking damage as lesions that are particularly toxic to the kidney. Genetic tools in mice, as well as advances in kidney organoid and single-cell RNA sequencing technologies, have provided important insights into how specific kidney cell types respond to DNA damage. The emerging view is that in the kidney, DNA damage affects the local microenvironment by triggering a damage response and cell proliferation to replenish injured cells, as well as inducing systemic responses aimed at reducing exposure to genotoxic stress. The pathological consequences of DNA damage are therefore key to the nephrotoxicity of DNA-damaging agents and the kidney phenotypes observed in human DNA repair-deficiency disorders.

DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities.

The DNA damage response (DDR), a set of signaling pathways for DNA damage detection and repair, maintains genomic stability when cells are exposed to endogenous or exogenous DNA-damaging agents. Alterations in these pathways are strongly associated with cancer development, including ovarian cancer (OC), the most lethal gynecologic malignancy. In OC, failures in the DDR have been related not only to the onset but also to progression and chemoresistance. It is known that approximately half of the most frequent subtype, high-grade serous carcinoma (HGSC), exhibit defects in DNA double-strand break (DSB) repair by homologous recombination (HR), and current evidence indicates that probably all HGSCs harbor a defect in at least one DDR pathway. These defects are not restricted to HGSCs; mutations in ARID1A, which are present in 30% of endometrioid OCs and 50% of clear cell (CC) carcinomas, have also been found to confer deficiencies in DNA repair. Moreover, DDR alterations have been described in a variable percentage of the different OC subtypes. Here, we overview the main DNA repair pathways involved in the maintenance of genome stability and their deregulation in OC. We also recapitulate the preclinical and clinical data supporting the potential of targeting the DDR to fight the disease.

Abstract P015: Mechanisms of mitochondrial dysfunction in development of mismatch repair-deficient endometrial cancer

Abstract Background: Lynch syndrome (LS) is a hereditary cancer syndrome carrying roughly 60% lifetime risk of endometrial cancer (EC) development. LS-EC is caused by mutations in mismatch repair genes (most commonly MSH2), which lead to DNA repair deficiency and hypermutability. Identifying mechanisms that impact cancer development could provide novel opportunities for EC prevention. Our recent studies in Msh2-deficient mice identified mitochondrial dysfunction in EC pathogenesis. The objective of this study is to define the impact of MSH2 loss on mitochondrial function and oxidative DNA damage to identify targets for EC prevention. We hypothesized that MSH2 loss disrupts mitochondrial function and increases oxidative DNA damage in EC cells. Methods: The effects of MSH2 loss on EC pathogenesis were evaluated using our novel mouse model for EC development (PR-Cre+Msh2flox/flox, abbreviated Msh2KO) and primary cell lines derived from this model. Mitochondrial stress tests (MSTs) compared mitochondrial function in murine and human MSH2-deficient and -intact EC cell lines. Western blots compared mitochondrial protein expression between cell lines. Transcriptomic data of human ECs from The Cancer Genome Atlas (TCGA) were probed using cBioPortal. To examine direct effects of MSH2 loss on oxidative stress and mitochondrial function, we performed lentiviral shRNA knockdown (KD) of MSH2 in two human EC cell lines (KLE, Hec1a) and MSH2 overexpression (MSH2++) in MFE280 cells. MSTs and Western blots were utilized as above. Immunofluorescent staining compared oxidative DNA damage in MSH2-KD, MSH2++, and control cell lines after pharmacologically induced oxidative stress via H2O2. RESULTS Transcriptomic signatures of histologically normal endometrium and EC from Msh2KO mice versus control mice reveal mitochondrial dysfunction as a key aberrant pathway. MSTs show reduced baseline and induced mitochondrial function in murine and human MSH2-deficient EC cells compared to MSH2-intact (p<0.0001). Western blots show that MSH2-deficient EC cells exhibit loss of mitochondrial complex II compared to MSH2-intact cells (p<0.05). TCGA data confirm MSH2-deficient human ECs have reduced complex II subunits (p<0.05). Isogenic in vitro studies show MSH2-KD reduces complex II expression yet has variable effects on mitochondrial function. MSH2 overexpression increases complex II expression and mitochondrial function. Oxidative DNA damage did not differ at baseline, but H2O2-induced DNA damage increased after MSH2-KD in one of two cell lines. Conclusions: MSH2 and complex II loss are strongly associated in EC. Further studies on the downstream effects of complex II loss are necessary to determine the contribution to LS-EC development. Complex II loss could result in disruptions to oxidative phosphorylation, the citric acid cycle, metabolic reprogramming, and oncometabolite production. Defining direct effects of MSH2 loss on these potential cancer susceptibility mechanisms will open new avenues for LS-associated EC prevention. Citation Format: Diana L. Moreno, Mikayla S. Borthwick, Leah Peralta, Wai Kin Chan, Brenda Melendez, Qian Zhang, Nisha Gokul, Melinda S. Yates. Mechanisms of mitochondrial dysfunction in development of mismatch repair-deficient endometrial cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P015.

Optimized detection of homologous recombination deficiency improves the prediction of clinical outcomes in cancer

Homologous recombination DNA-repair deficiency (HRD) is a common driver of genomic instability and confers a therapeutic vulnerability in cancer. The accurate detection of somatic allelic imbalances (AIs) has been limited by methods focused on BRCA1/2 mutations and using mixtures of cancer types. Using pan-cancer data, we revealed distinct patterns of AIs in high-grade serous ovarian cancer (HGSC). We used machine learning and statistics to generate improved criteria to identify HRD in HGSC (ovaHRDscar). ovaHRDscar significantly predicted clinical outcomes in three independent patient cohorts with higher precision than previous methods. Characterization of 98 spatiotemporally distinct metastatic samples revealed low intra-patient variation and indicated the primary tumor as the preferred site for clinical sampling in HGSC. Further, our approach improved the prediction of clinical outcomes in triple-negative breast cancer (tnbcHRDscar), validated in two independent patient cohorts. In conclusion, our tumor-specific, systematic approach has the potential to improve patient selection for HR-targeted therapies.

CBL0137 impairs homologous recombination repair and sensitizes high-grade serous ovarian carcinoma to PARP inhibitors

BackgroundHigh-grade serous ovarian carcinomas (HGSCs) are a heterogeneous subtype of epithelial ovarian cancers and include serous cancers arising in the fallopian tube and peritoneum. These cancers are now subdivided into homologous recombination repair (HR)-deficient and proficient subgroups as this classification impacts on management and prognosis. PARP inhibitors (PARPi) have shown significant clinical efficacy, particularly as maintenance therapy following response to platinum-based chemotherapy in BRCA-mutant or homologous recombination (HR)-deficient HGSCs in both the 1st and 2nd line settings. However, PARPi have limited clinical benefit in HR-proficient HGSCs which make up almost 50% of HGSC and improving outcomes in these patients is now a high priority due to the poor prognosis with ineffectiveness of the current standard of care. There are a number of potential lines of investigation including efforts in sensitizing HR-proficient tumors to PARPi. Herein, we aimed to develop a novel combination therapy by targeting SSRP1 using a small molecule inhibitor CBL0137 with PARPi in HR-proficient HGSCs.Experimental designWe tested anti-cancer activity of CBL0137 monotherapy using a panel of HGSC cell lines and patient-derived tumor cells in vitro. RNA sequencing was used to map global transcriptomic changes in CBL0137-treated patient-derived HR-proficient HGSC cells. We tested efficacy of CBL0137 in combination with PARPi using HGSC cell lines and patient-derived tumor cells in vitro and in vivo.ResultsWe show that SSRP1 inhibition using a small molecule, CBL0137, that traps SSRP1 onto chromatin, exerts a significant anti-growth activity in vitro against HGSC cell lines and patient-derived tumor cells, and also reduces tumor burden in vivo. CBL0137 induced DNA repair deficiency via inhibition of the HR repair pathway and sensitized SSRP1-high HR-proficient HGSC cell lines and patient-derived tumor cells/xenografts to the PARPi, Olaparib in vitro and in vivo. CBL0137 also enhanced the efficacy of DNA damaging platinum-based chemotherapy in HGSC patient-derived xenografts.ConclusionOur findings strongly suggest that combination of CBL0137 and PARP inhibition represents a novel therapeutic strategy for HR-proficient HGSCs that express high levels of SSRP1 and should be investigated in the clinic.

ENDOGENOUS DNA DAMAGE AS A DRIVER OF AGING AND TISSUE DYSFUNCTION

Abstract Aging is a complex multifactorial process that enhances stress or impairs the ability to cope with it, whereby increasing the risk of morbidity and mortality. Many factors can contribute to aging, such as macromolecular damage (including DNA damage) that accumulates in a time-dependent manner. DNA damage is also known to induce cellular senescence, a cell fate that is known to play a causal role in aging. To investigate the effects of DNA damage and cellular senescence on aging, animal models lacking Ercc1, an important DNA repair gene, were utilized. Ercc1-deficient mice age faster than wild-type littermates and exhibit the senescent cell burdens that are comparable to that of a naturally aged mouse. To investigate cell autonomous and non-autonomous effects of DNA repair deficiency on senescence and aging, Ercc1 was deleted in mice in a tissue-specific manner. Increased senescent cell burden and dysfunction were present in tissues specifically targeted for Ercc1 deletion. However, enhanced senescence was also present in some non-targeted tissues, suggesting that these occur through cell non-autonomous mechanisms.

Replication stress drives chromosomal instability in fibroblasts of childhood cancer survivors with second primary neoplasms

New development and optimization of oncologic strategies are steadily increasing the number of long-term cancer survivors being at risk of developing second primary neoplasms (SPNs) as a late consequence of genotoxic cancer therapies with the highest risk among former childhood cancer patients. Since risk factors and predictive biomarkers for therapy-associated SPN remain unknown, we examined the sensitivity to mild replication stress as a driver of genomic instability and carcinogenesis in fibroblasts from 23 long-term survivors of a pediatric first primary neoplasm (FPN), 22 patients with the same FPN and a subsequent SPN, and 22 controls with no neoplasm (NN) using the cytokinesis-block micronucleus (CBMN) assay. Mild replication stress was induced with the DNA-polymerase inhibitor aphidicolin (APH). Fibroblasts from patients with the DNA repair deficiency syndromes Bloom, Seckel, and Fanconi anemia served as positive controls and for validation of the CBMN assay supplemented by analysis of chromosomal aberrations, DNA repair foci (γH2AX/53BP1), and cell cycle regulation. APH treatment resulted in G2/M arrest and underestimation of cytogenetic damage beyond G2, which could be overcome by inhibition of Chk1. Basal micronuclei were significantly increased in DNA repair deficiency syndromes but comparable between NN, FPN, and SPN donors. After APH-induced replication stress, the average yield of micronuclei was significantly elevated in SPN donors compared to FPN (p = 0.013) as well as NN (p = 0.03) donors but substantially lower than for DNA repair deficiency syndromes. Our findings suggest that mild impairment of the response to replication stress induced by genotoxic impacts of DNA-damaging cancer therapies promotes genomic instability in a subset of long-term cancer survivors and may drive the development of an SPN. Our study provides a basis for detailed mechanistic studies as well as predictive bioassays for clinical surveillance, to identify cancer patients at high risk for SPNs at first diagnosis.

Biomarker-driven drug repurposing on biologically similar cancers with DNA-repair deficiencies.

Similar molecular and genetic aberrations among diseases can lead to the discovery of jointly important treatment options across biologically similar diseases. Oncologists closely looked at several hormone-dependent cancers and identified remarkable pathological and molecular similarities in their DNA repair pathway abnormalities. Although deficiencies in Homologous Recombination (HR) pathway plays a significant role towards cancer progression, there could be other DNA-repair pathway deficiencies that requires careful investigation. In this paper, through a biomarker-driven drug repurposing model, we identified several potential drug candidates for breast and prostate cancer patients with DNA-repair deficiencies based on common specific biomarkers and irrespective of the organ the tumors originated from. Normalized discounted cumulative gain (NDCG) and sensitivity analysis were used to assess the performance of the drug repurposing model. Our results showed that Mitoxantrone and Genistein were among drugs with high therapeutic effects that significantly reverted the gene expression changes caused by the disease (FDR adjusted p-values for prostate cancer =1.225e-4 and 8.195e-8, respectively) for patients with deficiencies in their homologous recombination (HR) pathways. The proposed multi-cancer treatment framework, suitable for patients whose cancers had common specific biomarkers, has the potential to identify promising drug candidates by enriching the study population through the integration of multiple cancers and targeting patients who respond poorly to organ-specific treatments.

Complex Roles of NEIL1 and OGG1: Insights Gained from Murine Knockouts and Human Polymorphic Variants

DNA glycosylases promote genomic stability by initiating base excision repair (BER) in both the nuclear and mitochondrial genomes. Several of these enzymes have overlapping substrate recognition, through which a degree of redundancy in lesion recognition is achieved. For example, OGG1 and NEIL1 both recognize and release the imidazole-ring-fragmented guanine, FapyGua as part of a common overall pathway to cleanse the genome of damaged bases. However, these glycosylases have many differences, including their differential breadth of substrate specificity, the contrasting chemistries through which base release occurs, the subsequent steps required to complete the BER pathway, and the identity of specific protein-binding partners. Beyond these differences, the complexities and differences of their in vivo biological roles have been primarily elucidated in studies of murine models harboring a knockout of Neil1 or Ogg1, with the diversity of phenotypic manifestations exceeding what might have been anticipated for a DNA glycosylase deficiency. Pathologies associated with deficiencies in nuclear DNA repair include differential cancer susceptibilities, where Ogg1-deficient mice are generally refractory to carcinogenesis, while deficiencies in Neil1-deficient mice confer cancer susceptibility. In contrast to NEIL1, OGG1 functions as a key transcription factor in regulating inflammation and other complex gene cascades. With regard to phenotypes attributed to mitochondrial repair, knockout of either of these genes results in age- and diet-induced metabolic syndrome. The adverse health consequences associated with metabolic syndrome can be largely overcome by expression of a mitochondrial-targeted human OGG1 in both wild-type and Ogg1-deficient mice. The goal of this review is to compare the roles that NEIL1 and OGG1 play in maintaining genomic integrity, with emphasis on insights gained from not only the diverse phenotypes that are manifested in knockout and transgenic mice, but also human disease susceptibility associated with polymorphic variants.

Deep learning identifies morphological patterns of homologous recombination deficiency in luminal breast cancers from whole slide images

Homologous recombination DNA-repair deficiency (HRD) is becoming a well-recognized marker of platinum salt and polyADP-ribose polymerase inhibitor chemotherapies in ovarian and breast cancers. While large-scale screening for HRD using genomic markers is logistically and economically challenging, stained tissue slides are routinely acquired in clinical practice. With the objectives of providing a robust deep-learning method for HRD prediction from tissue slides and identifying related morphological phenotypes, we first show that digital pathology workflows are sensitive to potential biases in the training set, then we propose a method to overcome the influence of these biases, and we develop an interpretation method capable of identifying complex phenotypes. Application to our carefully curated in-house datasetallows us to predict HRD with high accuracy (area under the receiver-operator characteristics curve 0.86) and to identify morphological phenotypes related to HRD. In particular, the presence of laminated fibrosis and clear tumor cells associated with HRD open new hypotheses regarding its phenotypic impact.

Deficiencies in mismatch DNA repair: providing the soil for large-to-giant congenital melanocytic naevus development.

Deficiencies in mismatch DNA repair: providing the soil for large-to-giant congenital melanocytic naevus development.