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Infection with Helicobacter pylori is known to confer a risk of gastric cancer. In this study, persons who carried certain genetic variants and were infected with H. pylori had an excess risk of gastric cancer.

ARID1A (the AT-rich interaction domain 1A, also known as BAF250a ) is one of the most commonly mutated genes in cancer 1 , 2 . The majority of ARID1A mutations are inactivating mutations and lead to loss of ARID1A expression 3 , which makes ARID1A a poor therapeutic target. Therefore, it is of clinical importance to identify molecular consequences of ARID1A deficiency that create therapeutic vulnerabilities in ARID1A -mutant tumors. In a proteomic screen, we found that ARID1A interacts with mismatch repair (MMR) protein MSH2. ARID1A recruited MSH2 to chromatin during DNA replication and promoted MMR. Conversely, ARID1A inactivation compromised MMR and increased mutagenesis. ARID1A deficiency correlated with microsatellite instability genomic signature and a predominant C>T mutation pattern and increased mutation load across multiple human cancer types. Tumors formed by an ARID1A-deficient ovarian cancer cell line in syngeneic mice displayed increased mutation load, elevated numbers of tumor-infiltrating lymphocytes, and PD-L1 expression. Notably, treatment with anti-PD-L1 antibody reduced tumor burden and prolonged survival of mice bearing ARID1A -deficient but not ARID1A -wild-type ovarian tumors. Together, these results suggest ARID1A deficiency contributes to impaired MMR and mutator phenotype in cancer, and may cooperate with immune checkpoint blockade therapy. Loss of mismatch-repair protein ARID1A in cancer correlates with high mutation load & checkpoint blockade response, complementing MSI-based prognosis.

BackgroundMost patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival.Objective and designThis observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age.Results3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer.ConclusionCarriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient’s age, gender and path_MMR variant. We have updated our open-access website www.lscarisk.org to facilitate this.

Prime editing (PE) is a powerful genome engineering approach that enables the introduction of base substitutions, insertions and deletions into any given genomic locus. However, the efficiency of PE varies widely and depends not only on the genomic region targeted, but also on the genetic background of the edited cell. Here, to determine which cellular factors affect PE efficiency, we carry out a focused genetic screen targeting 32 DNA repair factors, spanning all reported repair pathways. We show that, depending on cell line and type of edit, ablation of mismatch repair (MMR) affords a 2–17 fold increase in PE efficiency, across several human cell lines, types of edits and genomic loci. The accumulation of the key MMR factors MLH1 and MSH2 at PE sites argues for direct involvement of MMR in PE control. Our results shed new light on the mechanism of PE and suggest how its efficiency might be optimised. Prime Editing is a versatile genome engineering tool. Here, the authors identify the DNA repair pathway known as mismatch repair as inhibitory for Prime Editing, thus, loss of mismatch repair enhances the efficiency of Prime Editing.

The tumour suppressor TP53 is a master regulator of several cellular processes that collectively suppress tumorigenesis. The TP53 gene is mutated in ~50% of human cancers and these defects usually confer poor responses to therapy. The TP53 protein functions as a homo-tetrameric transcription factor, directly regulating the expression of ~500 target genes, some of them involved in cell death, cell cycling, cell senescence, DNA repair and metabolism. Originally, it was thought that the induction of apoptotic cell death was the principal mechanism by which TP53 prevents the development of tumours. However, gene targeted mice lacking the critical effectors of TP53-induced apoptosis (PUMA and NOXA) do not spontaneously develop tumours. Indeed, even mice lacking the critical mediators for TP53-induced apoptosis, G1/S cell cycle arrest and cell senescence, namely PUMA, NOXA and p21, do not spontaneously develop tumours. This suggests that TP53 must activate additional cellular responses to mediate tumour suppression. In this review, we will discuss the processes by which TP53 regulates cell death, cell cycling/cell senescence, DNA damage repair and metabolic adaptation, and place this in context of current understanding of TP53-mediated tumour suppression.Activation of TP53 can stimulate diverse cellular responses. In unstressed cells, the TP53 protein is bound and ubiquitinated by its negative regulator, the E3 ubiquitin ligase MDM2 (called HDM2 in humans). This targets the TP53 protein for ubiquitin-dependent proteasomal degradation. When cells are exposed to stress, such as DNA damage, MDM2 is phosphorylated and is then no longer able to ubiquitinate TP53, allowing for TP53 stabilisation and functional activation. Of note, TP53 can be phosphorylated at the N-terminus, and this also interferes with MDM2 binding and its ability to ubiquitinate TP53, and thereby prime it for proteasomal degradation. Once activated, TP53 can transcriptionally induce ~500 direct target genes, with some of them known to be critical for the induction of diverse cellular responses, including apoptotic cell death via induction of PUMA and NOXA, as well as genes involved in cell cycle arrest and cell senescence, (e.g., p21), DNA repair (e.g., MLH1, MSH2) and metabolism (e.g., TIGAR), to implement tumour suppression.

Background Claudin-18 (CLDN18) is a highly specific tight junction protein of the gastric mucosa. An isoform of CLDN18, the Claudin 18.2, has recently emerged as an innovative drug target for metastatic gastric cancer. Methods We investigated the immunohistochemical profile of CLDN18, p53, p16, E-cadherin, MSH2, MSH6, MLH1, PSM2, HER2, and PDL-1 in a large series of 523 primary gastric carcinomas (GCs; n  = 408) and gastro-oesophageal carcinomas (GECs; n  = 115) and 135 matched and synchronous nodal metastases. The status of HER2 and EBER by means of chromogenic in situ hybridisation (CISH) was also evaluated. Results High membranous CLDN18 expression was present in 150/510 (29.4%) primary cases and in 45/132 (34.1%) metastases. An abnormal expression (i.e. nuclear and/or cytoplasmic) was observed in 115 (22.5%) primary cases and in 33 (25.0%) metastases. A 38.8% of the cases showed significant CLDN18 intratumoural variability among the different tissue microarray cores obtained from the same tumour. Positive membrane CLDN18 expression was statistically associated with non-antral GCs ( p  = 0.016), Lauren diffuse type ( p  = 0.009), and with EBV-associated cancers ( p  < 0.001). Conclusions CLDN18 is frequently expressed in gastric and gastro-oesophageal cancers; further studies should investigate the prognostic significance of CLDN18 heterogeneity in order to implement its test into clinical practice.

Brain region-specific degeneration and somatic expansions of the mutant Huntingtin ( mHTT ) CAG tract are key features of Huntington’s disease (HD). However, the relationships among CAG expansions, death of specific cell types and molecular events associated with these processes are not established. Here, we used fluorescence-activated nuclear sorting (FANS) and deep molecular profiling to gain insight into the properties of cell types of the human striatum and cerebellum in HD and control donors. CAG expansions arise at mHTT in striatal medium spiny neurons (MSNs), cholinergic interneurons and cerebellar Purkinje neurons, and at mutant ATXN3 in MSNs from SCA3 donors. CAG expansions in MSNs are associated with higher levels of MSH2 and MSH3 (forming MutSβ), which can inhibit nucleolytic excision of CAG slip-outs by FAN1. Our data support a model in which CAG expansions are necessary but may not be sufficient for cell death and identify transcriptional changes associated with somatic CAG expansions and striatal toxicity. Fluorescence-activated nuclear sorting combined with deep profiling shows that Huntington’s disease repeat expansions arise in specific cell types and are associated with elevated MSH2 and MSH3, which promote expansions in vitro by inhibiting excision of CAG slip-outs by FAN1.

The pathogenesis of DNA mismatch repair (MMR)-deficient endometrial carcinoma (EC) is driven by inactivating methylation or less frequently mutation of an MMR gene ( MLH1, PMS2, MSH2 , or MSH6 ). This study evaluated the prognostic and clinicopathologic differences between methylation-linked and nonmethylated MMR-deficient endometrioid ECs. We performed MMR immunohistochemistry and methylation-specific multiplex ligation-dependent probe amplification, and classified 682 unselected endometrioid ECs as MMR proficient (MMRp, n  = 438) and MMR deficient (MMRd, n  = 244), with the latter subcategorized as methylated (MMRd Met) and nonmethylated tumors. Loss of MMR protein expression was detected in 35.8% of the tumors as follows: MLH1 + PMS2 in 29.8%, PMS2 in 0.9%, MSH2 + MSH6 in 1.3%, MSH6 in 2.8%, and multiple abnormalities in 0.9%. Of the 244 MMRd cases, 76% were methylation-linked. MMR deficiency was associated with older age, high grade of differentiation (G3), advanced stage (II–IV), larger tumor size, abundant tumor-infiltrating lymphocytes, PD-L1 positivity in immune cells and combined positive score, wild-type p53, negative L1CAM, ARID1A loss, and type of adjuvant therapy. MMRd-Met phenotype correlated with older age and larger tumor size, and predicted diminished disease-specific survival in the whole cohort. In the MMRd subgroup, univariate analysis demonstrated an association between disease-specific survival and disease stage II–IV, high grade (G3), deep myometrial invasion, lymphovascular invasion, ER negativity, and L1CAM positivity. In conclusion, MMR methylation profile correlates with clinicopathologic characteristics of endometrioid EC, and MMRd-Met phenotype predicts lower disease-specific survival. MMR deficiency, but not MLH1 methylation status, correlates with T-cell inflammation and PD-L1 expression.

IntroductionLynch syndrome (LS) is the commonest hereditary colorectal cancer syndrome, necessitating regular colonoscopy surveillance. Diagnostic outcomes are variably reported in LS and influenced by colonoscopy quality. We aimed to determine the incidence and risk factors for colorectal neoplasia in LS in a UK population undergoing high-quality colonoscopy.MethodsWe conducted a 5-year retrospective study of LS patients undergoing colonoscopy surveillance at St. Mark’s Hospital, London. Patient demographics, colonoscopy quality and clinicopathological data including adenoma (ADR) and CRC detection were analysed. Risk factors for neoplasia were evaluated by multivariate logistic regression with odds ratios (OR) and 95% confidence intervals (CI).ResultsWe analysed 992 colonoscopies in 473 LS patients (58.4% female; median age 48 years; 36.2% MLH1, 31.9% MSH2, 16.7% MSH6, 12.9% PMS2, 2.3% EPCAM) over a median follow-up of 30 months. Caecal intubation rate was 97.6%, with 96.3% achieving adequate preparation, and a median withdrawal time of 15 minutes. The median interval between procedures was 2.1 years; 15.9% were index procedures.ADR was 31.3% (index 26.6%; follow-up 32.1%), while CRC was detected in 28 (5.9%) patients (15 from index procedures). ADR was lowest in MLH1 carriers (24.5%). Proximal (68.4%), non-advanced (87.7%) adenomas predominated, with a high prevalence of flat adenomas (Paris Is 67.5%, Paris II 38.6%). Increasing age (50-65 years, OR 8.4 [95%CI:3.8-18.5], >65 years, OR 15.0 [95%CI:6.4-35.0]), body mass index ≥25kg/m2 (OR 1.4 [95%CI:1.0-2.0]) and buscopan (OR 1.8 [95%CI:1.2-2.6]) were associated with increased adenoma detection.In patients with normal or metaplastic polyps, 26.3% and 46.2% respectively, subsequently developed more advanced pathology (table 1). Conversely, those with advanced polyps on index colonoscopy were associated with non-advanced adenomas (23.1%) or advanced polyps (30.8%) on follow-up.Abstract P133 Table 1Worst colonoscopy outcomes during index and subsequent procedures (X2=37.96, p=0.002)Worst colonoscopy outcomes Surveillance, N (%) Normal Metaplastic polyps Non advanced adenoma Advanced polyps* Colorectal cancer Index Normal 24 (63.2) 4 (10.5) 9 (23.7) 0 (0) 1 (2.6) Metaplastic polyps 4 (30.8) 3 (23.1) 6 (46.2) 0 (0) 0 (0) Non-advanced adenoma 4 (33.3) 1 (8.3) 7 (58.3) 0 (0) 0 (0) Advanced polyps* 3 (23.1) 2 (15.4) 3 (23.1) 4 (30.8) 1 (7.7) Colorectal cancer 3 (30.0) 3 (30.0) 4 (40.0) 0 (0) 0 (0) *Advanced polyps: advanced adenomas (≥10mm, villous histology, high grade dysplasia or serrated adenomas) and advanced serrated polyps (≥10mm or dysplasia)ConclusionsThis is the largest UK evaluation on LS, demonstrating a high adenoma burden with distinct characteristics. Initial colonoscopy findings determine future outcomes, highlighting the importance of high-quality surveillance. This supports the LS bowel cancer screening programme to optimise surveillance strategies in LS.

Background Cisplatin (CDDP) has become a standard-of-care treatment for muscle-invasive bladder cancer (MIBC), while chemoresistance remains a major challenge. Accumulating evidence indicates that circular RNAs (circRNAs) are discrete functional entities. However, the regulatory functions as well as complexities of circRNAs in modulating CDDP-based chemotherapy in bladder cancer are yet to be well revealed. Methods Through analyzing the expression profile of circRNAs in bladder cancer tissues, RNA FISH, circRNA pull-down assay, mass spectrometry analysis and RIP, circLIFR was identified and its interaction with MSH2 was confirmed. The effects of circLIFR and MSH2 on CDDP-based chemotherapy were explored by flow cytometry and rescue experiments. Co-IP and Western blot were used to investigate the molecular mechanisms underlying the functions of circLIFR and MSH2. Biological implications of circLIFR and MSH2 in bladder cancer were implemented in tumor xenograft models and PDX models. Results CircLIFR was downregulated in bladder cancer and expression was positively correlated with favorable prognosis. Moreover, circLIFR synergizing with MSH2, which was a mediator of CDDP sensitivity in bladder cancer cells, positively modulated sensitivity to CDDP in vitro and in vivo. Mechanistically, circLIFR augmented the interaction between MutSα and ATM, ultimately contributing to stabilize p73, which triggered to apoptosis. Importantly, MIBC with high expression of circLIFR and MSH2 was more sensitive to CDDP-based chemotherapy in tumor xenograft models and PDX models. Conclusions CircLIFR could interact with MSH2 to positively modulate CDDP-sensitivity through MutSα/ATM-p73 axis in bladder cancer. CircLIFR and MSH2 might be act as promising therapeutic targets for CDDP-resistant bladder cancer.