Association between monocyte-lymphocyte ratio and all-cause and cardiovascular mortality in patients with chronic kidney diseases: A data analysis from national health and nutrition examination survey (NHANES) 2003-2010.

BACKGROUND: The relationship between monocyte-to-lymphocyte ratio (MLR) and prognosis in patients with chronic kidney disease (CKD) remains unclear. The aim of this study was to investigate the association between MLR and both all-cause mortality and cardiovascular disease (CVD) mortality in patients with CKD. METHODS: This study analyzed data from National Health and Nutrition Examination Survey 2003-2010. This study included 11262 eligible subjects, and 3015 of them were with CKD. We first compared the differences in clinical characteristics between individuals with and without CKD, and then grouped the CKD population based on quartiles of MLR. The partial correlation analysis was conducted to assess the relationships between MLR and some important clinical features. Cox proportional hazards models were used to investigate the associations between MLR and mortality from all-cause and cardiovascular disease. Restricted cubic spline (RCS) was used to investigate the dose-response relationship between MLR and mortality, the receiver operating characteristic (ROC) curves is used to compare the efficacy of MLR with different clinical biological indicators in assessing the risk of death. RESULTS: During a median follow-up of 10.3 years in CKD population, 1398 (43%) all-cause deaths and 526 (16%) CVD deaths occurred. It has been found that individuals with CKD have higher MLR level. The partial correlation analysis results showed that even after adjusting for age, sex, and race, MLR is still correlated with blood glucose, lipid levels, and kidney function indicators. The results of the cox proportional hazards regression model and Kaplan-Meier curve shown after adjusting for covariates, higher MLR was significantly associated with an increased risk of mortality. Consistent results were also observed when MLR was examined as categorical variable (quartiles). The RCS demonstrated a positive association between MLR and the risk of all-cause mortality and cardiovascular mortality. The ROC results indicate that the predictive efficacy of MLR for all-cause mortality risk is comparable to eGFR, higher than NLR and CRP. The predictive efficacy of MLR for cardiovascular mortality risk is higher than these three indicators. CONCLUSION: Compared to non-CKD population, the CKD population has higher levels of MLR. In the CKD population, MLR is positively correlated with the risk of death. Furthermore, the predictive efficacy of MLR for mortality risk is higher than other clinical indicators. This suggests that MLR can serve as a simple and effective clinical indicator for predicting mortality risk in CKD patients.

Fufang Luohanguo Qingfei granules reduces influenza virus susceptibility via MAVS-dependent type I interferon antiviral signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Luohanguo Qingfei granules (LQG) is a Chinese patent medicine, clinically used to treat flu-like symptoms including cough with yellow phlegm, impeded phlegm, dry throat and tongue. However, the protective activity of LQG against influenza infection is indeterminate. AIM OF THE STUDY: This study is to investigate the therapeutic effect of LQG on influenza infection and elucidate its underlying mechanism. MATERIALS AND METHODS: In vivo: A viral susceptible mouse model induced by restraint stress was established to investigate LQG's beneficial effects on influenza susceptibility. MAVS knockout (Mavs-/-) mice were used to verify the potential mechanism of LQG. In vitro: Corticosteroid (CORT)-treated A549 cells were employed to identify the active ingredients in LQG. Mice morbidity and mortality were monitored daily for 21 days. Histopathologic changes and inflammatory cytokines in lung tissues were examined by H&E staining and ELISA. RNA-seq was used to explore the signaling pathway influenced by LQG and further confirmed by qPCR. Immunoblotting and immunohistochemistry (IHC) were used to determine the protein levels. CO-IP and DARTS were applied to detect protein-protein interaction and compound-protein interaction, respectively. RESULTS: LQG effectively attenuated the susceptibility of restrained mice to H1N1 infection. LQG significantly boosted the production of IFN-ß transduced by mitochondrial antiviral-signaling protein (MAVS), while MAVS deficiency abrogated its protective effects on restrained mice infected with H1N1. Moreover, in vitro studies further revealed that mogroside Ⅱ B, amygdalin, and luteolin are potentially active components of LQG. CONCLUSION: These results suggested that LQG inhibited the mitofusin 2 (Mfn2)-mediated ubiquitination of MAVS by impeding the E3 ligase synoviolin 1 (SYVN1) recruitment, thereby enhancing IFN-ß antiviral response. Overall, our work elaborates a potential regimen for influenza treatment through reduction of stress-induced susceptibility.

Metabolic disturbance and transcriptomic changes induced by methyl triclosan in human hepatocyte L02 cells.

PURPOSE: Methyl triclosan (MTCS) is one of the biomethylated by-products of triclosan (TCS). With the increasing use of TCS, the adverse effects of MTCS have attracted extensive attention in recent years. The purpose of this study was to investigate the cytotoxicity of MTCS and to explore the underlining mechanism using human hepatocyte L02 cells as in vitro model. RESULTS: The cytotoxicity results revealed that MTCS could inhibit cell viability, disturb the ratio of reduced glutathione (GSH) and oxidized glutathione (GSSG), and reduce the mitochondrial membrane potential (MMP) in a dose-dependent manner. In addition, MTCS exposure significantly promoted the cellular metabolic process, including enhanced conversion of glucose to lactic acid, and elevated content of intracellular triglyceride (TG) and total cholesterol (TC). RNA-sequencing and bioinformatics analysis indicated disorder of glucose and lipid metabolism was significantly induced after MTCS exposure. Protein-protein interaction network analysis and node identification suggested that Serine hydroxy methyltransferase 2 (SHMT2), Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), Asparagine synthetase (ASNS) and Phosphoglycerate dehydrogenase (PHGDH) are potential molecular markers of metabolism imbalance induced by MTCS. CONCLUSION: These results demonstrated that oxidative stress and metabolism dysregulation might be involved in the cytotoxicity of MTCS in L02 cells.

Dephosphorylation of CatC at Ser-18 improves salt and oxidative tolerance via promoting its tetramerization in rice.

Catalase (CAT) is a vital antioxidant enzyme, while phosphorylation pivotally regulates its function. Many phosphosites have been identified in CAT, but their functions remained largely elusive. We functionally studied five phosphoserines (Ser-9, -10, -11, -18, and -205) of CatC in rice (Oryza sativa L.). Phospho-Ser-9 and - 11 and dephospho-Ser-18 promoted the enzymatic activity of CatC and enhanced oxidative and salt tolerance in yeast. Phosphorylation status of Ser-18 did not affect CatC peroxisomal targeting and stability, but dephospho-Ser-18 promoted CatC tetramerization to enhance its activity. Moreover, overexpression of dephospho-mimic form CatCS18A in rice significantly improved the tolerance to salt and oxidative stresses by inhibiting the H2O2 accumulation. Together, these results elucidate the mechanism underlying dephosphorylation at Ser-18 promotes CatC activity and salt tolerance in rice. Ser-18 is a promising candidate phosphosite of CatC for breeding highly salt-tolerant rice.

An EGFR L858R mutation identified in 1862 Chinese NSCLC patients can be a promising neoantigen vaccine therapeutic strategy.

Background: This study aimed to develop a vaccine that targets mutation-derived neoantigen in Chinese non-small-cell lung cancer (NSCLC). Methods: A cohort of 1862 Chinese NSCLC patients who underwent targeted sequencing with a 1021-gene panel was investigated. HLA typing was done using OptiType v1.0 and neoantigens were predicted by netMHCpan v4.0. HLA LOH was inferred using the lohhla algorithm and TMB were quantified by counting the total number of non-synonymous ones based on our panel data. CIBERSORT was utilized to estimate the TME in different EGFR mutant subtype by using TCGA data. Results: HLA-A*11:01(42.59%) was the top one allele and HLA-A*33:03(12.94%) ranked 12th. EGFR L858R (22.61%) was the most prevalent gene variant. The binding affinity (IC50 MT = 22.9 nM) and shared frequency (2.93%) of EGFR L858R in combination with HLA-A*33:03 were optimal. In a subsequent further analysis on immunological features of EGFR mutant subtypes, 63.1% HLA loss of heterozygosity LOH (HLA LOH) and 0.37% (7 of 1862) B2M aberrations were found in our population, both had no significant association with EGFR mutant subtypes suggesting that the process of antigen presentation involved HLA LOH and B2M mechanisms in EGFR L858R is working. Tumor mutation burden (TMB) was investigated by utilizing our panel and showed that EGFR L858R had the lowest TMB compared with other EGFR mutant subtypes. In addition, analysis of 22 immune cell types from The Cancer Genome Atlas (TCGA) data showed EGFR L858R was correlated with low level of CD8 T cells, activated CD4 memory T cells and elevated level of macrophage M2 suggesting an inhibited tumor microenvironment (TME). Conclusion: Our study identified that EGFR L858R neoantigen had the potential to generate cancer vaccines in NSCLC patients with HLA A*33:03. The neoantigen-based vaccines may become an effective salvage regimen for EGFR L858R subgroup after targeted therapy or immune checkpoint inhibitors (ICIs) failure.

Maximum Somatic Allele Frequency-Adjusted Blood-Based Tumor Mutational Burden Predicts the Efficacy of Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Recent studies exhibited the unstable prediction ability of blood-based tumor mutational burden (bTMB) when predicting the response of immune checkpoint inhibitors (ICIs) therapy in patients with non-small cell lung cancer (NSCLC). Circulating tumor DNA (ctDNA) abundance, usually represented by maximum somatic allele frequency (MSAF), was one possible confounding factor influencing bTMB ability in ICIs response prediction. METHODS: MSAF-adjusted bTMB (Ma-bTMB) was established and validated in patients with advanced NSCLC among Geneplus Cancer Genome Database (GCGD, n = 1679), Zhuo (n = 35), Wang (n = 45), POPLAR (NCT01903993, n = 211) and OAK (NCT02008227, n = 642) cohorts. RESULTS: MSAF demonstrated a modest positive correlation with bTMB and a negative one with survival benefit. Improved survival outcomes of ICIs therapy have been observed among patients with high-Ma-bTMB compared to those with low-Ma-bTMB in Zhuo and Wang cohorts. In addition, compared to low-Ma-bTMB, high-Ma-bTMB was associated with more positive clinical benefits from ICIs therapy than chemotherapy both in POPLAR and OAK cohorts. Further exploration suggested that Ma-bTMB could precisely identify more potential ICIs beneficiaries compared to bTMB and LAF-bTMB, complementary to PD-L1 expression. CONCLUSIONS: We developed Ma-bTMB, a convenient, readily available, non-invasive predictive biomarker effectively differentiates beneficiaries of ICIs therapy in advanced NSCLC, warranting future clinical trials.

Circulating Tumor DNA: Less Invasive, More Representative Method to Unveil the Genomic Landscape of Newly Diagnosed Multiple Myeloma Than Bone Marrow Aspirates.

Multiple myeloma (MM) is highly heterogenous and dynamic in its genomic abnormalities. Capturing a representative image of these alterations is essential in understanding the molecular pathogenesis and progression of the disease but was limited by single-site invasive bone marrow (BM) biopsy-based genomics studies. We compared the mutational landscapes of circulating tumor DNA (ctDNA) and BM in 82 patients with newly diagnosed MM. A 413-gene panel was used in the sequencing. Our results showed that more than 70% of MM patients showed one or more genes with somatic mutations and at least half of the mutated genes were shared between ctDNA and BM samples. Compared to the BM samples, ctDNA exhibited more types of driver mutations in the shared driver genes, higher numbers of uniquely mutated genes and subclonal clusters, more translocation-associated mutations, and higher frequencies of mutated genes enriched in the transcriptional regulation pathway. Multivariate Cox analysis showed that age, ctDNA mutations in the transcriptional regulation pathway and DNA repair pathway were independent predictors of progression-free survival (PFS). Our results demonstrated sequencing of ctDNA provides more thorough information on the genomic instability and is a potential representative biomarker for risk stratification and in newly diagnosed MM than bone marrow.

Generation of Allogeneic CAR T Cells through Specific Degradation of the T Cell Antigen Receptor by E3 Ubiquitin Ligase Fusion Proteins.

Receptor downregulation is instrumental for many therapeutic interventions. Receptor knockout through gene-editing technologies is efficient but can introduce off-target mutations and chromothripsis. Regulation of gene expression at the protein level is a promising alternative. Here, we present results showing the targeted T cell antigen receptor (TCR) degradation using chimeric E3 fusion proteins that we call Receptor Targeting Chimeras (ReceptorTAC). We show that TCR degradation is dependent on enzymatically active, membrane-anchored E3 ligase variants. TCR specificity was achieved by direct fusion of an E3 domain to the CD3ζ transmembrane sequence. Jurkat and primary T cells stably expressing the ReceptorTAC constructs showed significantly reduced responses to TCR stimulation. We also used our ReceptorTAC technology to generate TCR-deficient, claudin18.2-specific CAR T cells, where the activity of the CAR was unaffected by the expression of the ReceptorTAC. These data indicate that our ReceptorTAC molecule can be used to generate allogeneic CAR T cells.

Next-generation Sequencing Reveals Age-dependent Genetic Underpinnings in Lung adenocarcinoma.

Background: More than 40% of lung cancer patients are diagnosed at ages over 70. However, the genomic and clinical characteristics among them remain elusive. Here, we performed targeted capture sequence to characterize the mutational spectrum of Chinese lung adenocarcinoma (LUAD) patients across ages. Patients and Methods: 2025 LUAD patients were divided into three groups: young (≤50 years old) (n=416, 20.54%), intermediate (51~69 years old) (n=1271, 62.77%), and aged (≥70 years old) (n=338, 16.69%). 1,021-gene panel and 59-gene panel were used for sequencing with tissue samples. Genetic alterations and tumor mutation burden (TMB) in LUAD patients were investigated. Results: The frequency of mutations affecting 20 genes were significantly higher in aged group than in young group, and fourteen of them were not reported before, including involved in cell cycle/apoptosis signaling (FAT1, FAT2), DNA damage repair (FANCA and FANCM), chromatin histone modification (KDM6A), RTK/RAS/PI3K signaling (FLT4 and MTOR), NOTCH signaling (NOTCH1, NOTCH2 and NOTCH4) and other signaling pathway or cellular regulatory factor (KEAP1, ASXL1, EPHB1 and ABCB1). Six previously reported mutated genes (RBM10, KRAS, LRP1B, CDKN2A and KMT2C/D) were also significantly more frequent in aged group. Among clinical actionable mutation sites, KRAS mutation was presented more common in aged group; both MET exon 14 skipping and MET amplification were significantly positively correlated with old age; the fusions of ALK, ROS1, RET and ERBB2 exon 20 insertion were less frequent in aged group. Furthermore, a higher level of TMB was found in aged group compared with young group. Conclusion: In this study, we revealed the differences of somatic genetic mutations and TMB between young and aged LUAD patients, which may provide directions of targeted therapy and advantages of immunotherapy for the elderly in the future.

Clinical and genomic features of Chinese lung cancer patients with germline mutations.

The germline mutation landscape in Chinese lung cancer patients has not been well defined. In this study, sequencing data of 1,021 cancer genes of 1,794 Chinese lung cancer patients was analyzed. A total of 111 pathogenic or likely pathogenic germline mutations were identified, significantly higher than non-cancer individuals (111/1794 vs. 84/10,588, p < 2.2e-16). BRCA1/2 germline mutations are associated with earlier onset age (median 52.5 vs 60 years-old, p = 0.008). Among 29 cancer disposition genes with germline mutations detected in Chinese cohort and/or TCGA lung cancer cohort, Only 11 from 29 genes are identified in both cohorts and BRCA2 mutations are significantly more common in Chinese cohort (p = 0.015). Chinese patients with germline mutations have different prevalence of somatic KRAS, MET exon 14 skipping and TP53 mutations compared to those without. Our findings suggest potential ethnic and etiologic differences between Western and Asian lung cancer patients.

Liquid biopsy in diffuse large B-cell lymphoma: utility in cell origin determination and survival prediction in Chinese patients.

The utility of circulating tumor DNA (ctDNA) in classifying the cell origin of diffuse large B-cell lymphoma (DLBCL) has not been explored in the Chinese population. In this study, we aimed to investigate the genetic characteristics of DLBCL based on both tumor and ctDNA sequencing and to assess the predictive value of ctDNA in DLBCL. A targeted sequencing panel of 413 genes was applied to tumor biopsies and paired plasma samples obtained from 30 patients with DLBCL before therapeutic intervention (pretreatment). The concordance between plasma genotyping classification and traditional cell-of-origin classification using tumor tissue was 80.0% (20/25). Patients with higher baseline plasma ctDNA levels had poorer survival compared to those with lower ctDNA levels (2-year progression survival rate: 40.0% vs. 80.0%, p = 0.011; 5-year overall survival rate: 30.5% vs. 70.0%, p = 0.004). Collectively, our results demonstrated that pretreatment ctDNA analysis could assist origin determination and prognosis prediction clinically.

Comprehensive analysis of oncogenic fusions in mismatch repair deficient colorectal carcinomas by sequential DNA and RNA next generation sequencing.

BACKGROUND: Colorectal carcinoma (CRC) harboring oncogenic fusions has been reported to be highly enriched in mismatch repair deficient (dMMR) tumors with MLH1 hypermethylation (MLH1me+) and wild-type BRAF and RAS. In this study, dMMR CRCs were screened for oncogene fusions using sequential DNA and RNA next generation sequencing (NGS). RESULTS: Comprehensive analysis of fusion variants, genetic profiles and clinicopathological features in fusion-positive dMMR CRCs was performed. Among 193 consecutive dMMR CRCs, 39 cases were identified as MLH1me+ BRAF/RAS wild-type. Eighteen fusion-positive cases were detected by DNA NGS, all of which were MLH1me+ and BRAF/RAS wild-type. RNA NGS was sequentially conducted in the remaining 21 MLH1me+ BRAF/RAS wild-type cases lacking oncogenic fusions by DNA NGS, and revealed four additional fusions, increasing the proportion of fusion-positive tumors from 46% (18/39) to 56% (22/39) in MLH1me+ BRAF/RAS wild-type dMMR cases. All 22 fusions were found to involve RTK-RAS pathway. Most fusions affected targetable receptor tyrosine kinases, including NTRK1(9/22, 41%), NTRK3(5/22, 23%), ALK(3/22, 14%), RET(2/22, 9%) and MET(1/22, 5%), whilst only two fusions affected mitogen-activated protein kinase cascade components BRAF and MAPK1, respectively. RNF43 was identified as the most frequently mutated genes, followed by APC, TGFBR2, ATM, BRCA2 and FBXW7. The vast majority (19/22, 86%) displayed alterations in key WNT pathway components, whereas none harbored additional mutations in RTK-RAS pathway. In addition, fusion-positive tumors were typically diagnosed in elder patients and predominantly right-sided, and showed a significantly higher preponderance of hepatic flexure localization (P < 0.001) and poor differentiation (P = 0.019), compared to fusion-negative MLH1me+ CRCs. CONCLUSIONS: We proved that sequential DNA and RNA NGS was highly effective for fusion detection in dMMR CRCs, and proposed an optimized practical fusion screening strategy. We further revealed that dMMR CRCs harboring oncogenic fusion was a genetically and clinicopathologically distinctive subgroup, and justified more precise molecular subtyping for personalized therapy.

Construction and Validation of a Platinum Sensitivity Predictive Model With Multiple Genomic Variations for Epithelial Ovarian Cancer.

Platinum-based chemotherapy is still the standard of care after cytoreductive surgery in the first-line treatment for epithelial ovarian cancer. This study aims to integrate novel biomarkers for predicting platinum sensitivity in EOC after initial cytoreductive surgery precisely. To this end, 60 patients were recruited from September 2014 to October 2019. Based on the duration of progress-free survival, 44 and 16 patients were assigned to platinum-sensitive and platinum-resistant group, respectively. Next generation sequencing was performed to dissect the genomic features of ovarian tumors obtained from surgery. Multiple genomic variations were compared between two groups, including single-nucleotide variant, single base or indel signature, loss of heterozygosity (LOH), whole-genome duplication (WGD), and others. The results demonstrated that patients with characteristics including positive SBS10a signature (p < 0.05), or FAM175A LOH (p < 0.01), or negative WGD (p < 0.01) were significantly enriched in platinum-sensitive group. Consistently, patients with positive SBS10a signature (15.8 vs. 10.1 months, p < 0.05), or FAM175A LOH (16.5 vs. 9.2 months, p < 0.05), or negative WGD (16.5 vs. 9.1 months, p < 0.05) have significantly longer PFS than those without these genetic features. By integrating these three biomarkers, a lasso regression model was employed to train and test for all patients, with the AUC value 0.864 in platinum sensitivity prediction. Notably, 388 ovarian cancer patients from TCGA dataset were leveraged as independent validation cohort with AUC value 0.808, suggesting the favorable performance and reliability of this model.

The prevalence of HLA-I LOH in Chinese pan-cancer patients and genomic features of patients harboring HLA-I LOH.

HLA-I LOH may facilitate immune evasion. However, large population studies on the prevalence of HLA-I LOH across different cancer types and in relation to mutational profiles are lacking, in particular, in the Chinese population. In this study, analysis was performed in 1504 advanced pan-cancer patients and 134 early-stage non-small-cell lung cancer patients using a 1021-gene panel. The consistency between the 1021-gene panel and whole-exome sequencing was evaluated in 45 samples, where concordant results were obtained in 95.6% (43/45) of the samples. Analytical results revealed that the prevalence of HLA-I LOH in tumor tissue presents considerable differences across cancer types. HLA-I LOH was relevant to genomic instability, reflected in higher tumor mutation burden level. HLA-I LOH occurs more frequently in MSS samples than in MSI-H samples. The alteration frequencies of p53 pathway, RTK/RAS pathway, Notch pathway, Hippo pathway, and Nrf2 pathway in HLA-I LOH group were significantly higher than that in HLA-I stable group (p < .0001, p < .0001, p = .032, p = .013, p = .003, respectively). In DNA damage response pathways, alterations in the checkpoint factor pathway and Fanconi anemia pathway are enriched in HLA-I LOH group (p < .0001, p = .023, respectively). Besides, HLA-I LOH was accompanied by higher mutation rates of several tumor suppressors, including TP53 and LRP1B. These results may shed light on follow-up tumor immunology research.

Characteristics and Management of TP53-Mutated Diffuse Large B-Cell Lymphoma Patients.

BACKGROUND/AIM: TP53 mutation is recognized as a negative prognostic factor for patients with diffuse large B-cell lymphoma (DLBCL). Here, we present the characteristics of TP53 mut DLBCL patients following investigation of the effect of a treatment approach on survival of TP53 mut DLBCL patients. METHODS: A total of 44 DLBCL patients with TP53 mut and treated with an R-CHOP regimen were included for analysis. Patients who failed to achieve a complete response (CR) to initial treatment or relapsed in the first 6 months after initial CR were deemed to have primary refractory disease. RESULTS: Among 44 patients harboring TP53 mutations who underwent upfront R-CHOP or R-CHOP-like treatment, 21 (47.7%) had limited-stage and 23 (52.3%) presented advanced-stage disease. Apart from the seven patients receiving upfront surgical resection, 37 had measurable disease under the R-CHOP regimen, with 59.1% (n=26) developing primary refractory disease. Seven limited-stage patients after early complete resection and one with residue resection remained event-free at median follow-up of 37 months. Multivariate analysis revealed that elevated baseline lactate dehydrogenase (LDH), extranodal involvement (two or more), Ann Arbor stage, and locoregional treatment (surgery or radiation therapy) were independent indicators for progression-free survival (PFS). After adjustment for baseline LDH and extranodal involvement, adding locoregional treatment including surgery and radiation to the R-CHOP regimen significantly improved PFS (p=0.008) and overall survival (p=0.017) in limited-stage TP53 mut DLBCL patients compared to R-CHOP-only treatment. CONCLUSION: This study presents the characteristics of TP53-mutated DLBCL and implies a potential benefit of locoregional treatment in limited-stage DLBCL patients with TP53 mutations.

Next-generation sequencing reveals heterogeneous genetic alterations in key signaling pathways of mismatch repair deficient colorectal carcinomas.

Colorectal carcinoma (CRC) with deficient mismatch repair (dMMR) is an etiologically heterogeneous molecular entity. We investigated the genetic profile, focusing on key signaling pathways and molecular diversity of dMMR CRCs. In this study, next-generation sequencing was applied to 156 consecutive dMMR CRCs and 225 randomly selected proficient MMR (pMMR) CRCs diagnosed between July 2015 and December 2019 at Peking Union Medical College Hospital. Genetic alterations and MLH1 promoter hypermethylation (MLH1me+) were analyzed. Among the most frequently mutated genes, RNF43, ARID1A, PIK3CA, ATM, and BRCA2 mutants were enriched in dMMR CRCs, whereas APC and TP53 mutations were enriched in pMMR CRCs. In dMMR group, RNF43, APC, ARID1A, and BRCA2 mutations were largely microsatellite instability events. WNT pathway was commonly altered regardless of MMR status. Compared to pMMR CRCs, dMMR CRCs had remarkably more prevalent PI3K, RTK-RAS, TGFß, and DNA damage repair pathway alterations and more multiple mutations in WNT and PI3K pathways. Within dMMR tumors, mutual exclusivity occurred between CTNNB1 mutation and APC or RNF43 mutation, while coexistence existed between BRAF and RNF43 mutation, as well as RAS and APC mutation. MLH1me+ dMMR CRCs had significantly more frequent RNF43 mutations but less frequent KRAS, APC, and CTNNB1 mutations comparing to MLH1-unmethylated dMMR CRCs. RNF43/BRAF comutations were detected in MLH1me+ dMMR CRCs, whereas RAS/APC comutations were largely detected in Lynch syndrome-associated cases. RNF43 mutation was independently associated with MLH1me+ rather than BRAF mutations. dMMR CRCs bearing receptor tyrosine kinase fusion demonstrated no additional RTK-RAS mutations, significantly fewer PI3K alterations and more TGFBR2 mutations than other dMMR tumors. Our study revealed that dMMR CRCs had distinctive gene mutation spectra and signaling pathway interaction patterns compared to proficient mismatch repair (pMMR) CRCs, and molecular heterogeneity was evident for these divergent oncogenic pathways. These findings justify the use of individualized therapy targeted to dMMR CRC subgroups.

Analysis of MET kinase domain rearrangement in NSCLC.

OBJECTIVES: Many MET rearrangements have been identified in various tumor types. However, the frequencies and characteristics of MET rearrangements are not well defined in non-small-cell lung cancer (NSCLC). We sought to illustrate the distribution of MET kinase domain rearrangements (KDREs) in NSCLC, and to uncover novel targets for further drug development in these patients. MATERIALS AND METHODS: Targeted sequencing using a 1021-gene panel or a 59-gene panel was performed in 5965 NSCLC cases. We sequenced all MET exons and used bioinformatics techniques to identify fusions. RESULTS: Fifteen MET KDREs were identified from all patients. The incidence of MET KDRE was 0.26% (15/5695) in the cohort; 60% (9/15) of the fused partners were the genes upstream or downstream of MET. All the fusions of the MET gene with upstream genes or specific regions within them were due to inversions, while the fusions with downstream genes or their encompassed regions were caused by duplications or intra-chromosomal translocations. In the MET KDRE-positive NSCLC cases who did not receive targeted therapies, 75% (6/8) harbored no actionable mutation referring to the NCCN guideline. CONCLUSION: Our study illustrated the MET KDRE in NSCLC cases among the Chinese population and unearthed novel targets to develop new effective therapies for patients with MET KDRE.

Genomic Alterations and MYD88MUT Variant Mapping in Patients with Diffuse Large B-Cell Lymphoma and Response to Ibrutinib.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous malignancy. Following front-line immunochemotherapy, 30-40% of DLBCL patients develop relapsed or refractory (r/r) disease, which can be treated with ibrutinib. It has been previously reported that MYD88MUT affects the response to ibrutinib in patients with r/r DLBCL. OBJECTIVE: Here, we aimed to gather understanding of MYD88MUT in r/r DLBCL patients and to evaluate its influence on response to ibrutinib. PATIENTS AND METHODS: In this study, tissue samples from DLBCL patients (n = 212) were retrospectively collected and sequenced by target-capturing panels of either 413 or 112 genes that are frequently mutated in non-Hodgkin's lymphoma. Sixty patients with MYD88 mutations and available clinical information were included for further analysis. RESULTS: Seven MYD88MUT variants were identified, L265P (65.0%, n = 39), S219C (13.3%, n = 8), S243N (8.3%, n = 5), P258L (6.7%, n = 4), F283V (1.7%, n = 1), P141R (1.7%, n = 1), and V217F (1.7%, n = 1). One patient had MYD88 amplification. In addition, mutations in PIM1 (67%, n = 40), IGH fusion (48%, n = 29), CD79B (43%, n = 26), KMT2D (30%, n = 18), and TP53 (27%, n = 17) were identified. For patients with L265P, IRF4 (p = 0.011) was frequently mutated. Otherwise, TET2 (p = 0.016), NOTCH2 (p = 0.044), MET (p = 0.037), SOCS1 (p = 0.011), TNFRSF14 (p = 0.011), EZH2 (p = 0.037), and BCL6 (p < 0.001) mutations were associated with MYD88MUT non-L265P variants. The incidence rate of MYD88MUT L265P was significantly higher with central nervous system involvement (p = 0.034). Four out of nine MYD88MUT patients responded to ibrutinib containing treatment, and this included those with MYD88MUT/CD79BWT. CONCLUSIONS: This study adds clinical observations with MYD88MUT patients, further helping to understand the genetic features and possible correlation of MYD88MUT with response to ibrutinib.

Implications of driver genes associated with a high tumor mutation burden identified using next-generation sequencing on immunotherapy in hepatocellular carcinoma.

Immune checkpoint blockade (ICB) therapy is a treatment strategy for hepatocellular carcinoma (HCC); however, its clinical efficacy is limited to a select subset of patients. Next-generation sequencing has identified the value of tumor mutation burden (TMB) as a predictor for ICB efficacy in multiple types of tumor, including HCC. Specific driver gene mutations may be indicative of a high TMB (TMB-H) and analysis of such mutations may provide novel insights into the underlying mechanisms of TMB-H and potential therapeutic strategies. In the present study, a hybridization-capture method was used to target 1.45 Mb of the genomic sequence (coding sequence, 1 Mb), analyzing the somatic mutation landscape of 81 HCC tumor samples. Mutations in five genes were significantly associated with TMB-H, including mutations in tumor protein 53 (TP53), Catenin®1 (CTNNB1), AT-rich interactive domain-containing protein 1A (ARID1A), myeloid/lymphoid or mixed-lineage leukemia (MLL) and nuclear receptor co-repressor 1 (NCOR1). Further analysis using The Cancer Genome Atlas Liver Hepatocellular Carcinoma database showed that TP53, CTNNB1 and MLL mutations were positively correlated with TMB-H. Meanwhile, mutations in ARID1A, TP53 and MLL were associated with poor overall survival of patients with HCC. Overall, TMB-H and associated driver gene mutations may have potential as predictive biomarkers of ICB therapy efficacy for treatment of patients with HCC.

Does CSR affect the cost of equity capital: Empirical evidence from the targeted poverty alleviation of listed companies in China.

Social responsibility fulfillment helps modern enterprises achieve sustainable development. Based on empirical data on China's A-share listed companies in 2013-2016, this paper examines the impact of corporate social responsibility performance on a company's financing costs from the perspective of targeted poverty alleviation. Specifically, we find that enterprises' engagement in poverty alleviation social responsibility helps to reduce the cost of equity capital. The result is robust to using alternative indicators of the cost of equity capital, propensity score matching method, change model and sample removed financial sector. Furthermore, we find that the negative relationship between enterprises' engagement in poverty relief and the cost of equity capital is mainly concentrated in private enterprises and in the central and eastern regions of China. Moreover, the negative relationship mainly exists after China's listed companies were forced to disclose information on poverty alleviation. This paper also finds that institutional investors' shareholding plays a partial mediating role in this reduction effect and that enterprises' poverty alleviation efforts help companies improve their financial performance and firm value. This study enriches the relevant literature on corporate social responsibility and the cost of equity capital and has reference value for corporate sustainable development. It also provides a theoretical basis for corporate poverty alleviation work in developing countries and the economic results of CSR.