RESUMEN

Background: Esophageal cancer (EC) is an aggressive malignant tumor with poor prognosis and high incidence. It is the sixth leading cause of cancer-related death in the world, and the 5-year overall survival (OS) rate is only 12-20%. The rapid development of next-generation sequencing (NGS) has provided powerful help for the treatment and management of EC patients. Methods: Tumor tissue and blood samples of 43 Chinese patients with nonsurgical esophageal squamous cell carcinoma (ESCC) were sequenced using a 425 gene-panel. Genomic profiling was explored and and the Cox proportional hazards model was used to analyze the correlations between gene or signaling pathway alterations and prognosis. Results: In this study, the most common mutated genes were TP53 (90.5%), CCND1 (45.2%), FGF19 (38.1%), NOTCH1 (26.2%), PI3KCA (21.4%) and CDKN2A (19%). Among these mutations, PI3KCA and NOTCH1 showed mutual exclusion to some extent. In the univariate model, mutations in NOTCH1, CBLB and TSC2 genes and tumor mutation burden (TMB) ≥7 were independent biomarkers of OS. NOTCH1 (P=0.007, HR =2.87), CBLB (P=0.011, HR =4.68) and TSC2 (P=0.024, HR =3.7) were significantly associated with poorer OS, and patients with TMB ≥7 had longer OS (P=0.151, HR =0.31). In addition, patients who carried alteration in NOTCH signaling pathway had reduced OS (P=0.014, HR =2.54). Conclusions: NOTCH1, CBLB and TSC2 alterations were found to be potential indicators of poor prognosis in patients with ESCC. TMB was also positively correlated with the OS of ESCC patients, providing valuable insights for their treatment strategies.

RESUMEN

While DNA-encoded macrocyclic libraries have gained substantial attention and several hit compounds have been identified from DNA-encoded library technology, efficient on-DNA macrocyclic methods are also required to construct DNA-linked libraries with a high degree of cyclization and DNA integrity. In this paper, we reported a set of on-DNA methodologies, including the use of an OPA-mediated three-component cyclization with native handles of amino acids and photoredox chemistries. These chemistries proceed smoothly under mild conditions in good to excellent conversions, successfully generating novel isoindole, isoindoline, indazolone, and bicyclic scaffolds.

Asunto(s)

RESUMEN

Programmed cell death 1 ligand 1 (PD-L1) has been approved as predictive biomarker for non-small-cell lung cancer (NSCLC) patients treated with PD-(L)1 blockade therapy. The clinical/genomic features associated with PD-L1 are not well studied. Genomic profiling of tumor biopsies from 883 Chinese NSCLC patients was performed by targeted next-generation sequencing. Immunohistochemical analysis was conducted to evaluate PD-L1 expression levels using antibodies Dako 22C3 and 28-8, respectively. Our study showed distinct correlation between PD-L1 expression and clinical/genomic characteristics when using different PD-L1 antibodies and in different histological subtypes including adenocarcinoma (ADC) and squamous cell carcinoma (SCC), respectively. PD-L1 high expression (22C3) was associated with male and lymph node metastasis only in ADC patients. Furthermore, mutations of TP53 and KRAS, KIF5B-RET fusion, copy number gains of PD-L1 and PD-L2, and arm-level amplifications of chr.12p were significantly associated with PD-L1 positive status in ADC patients. For SCC patients, the gain of EGFR and MDM2 and loss of PTPRD were negatively associated with PD-L1 expression. We also compared our results with other studies and found conflicting results presumably because of the multiplicity of antibody clones and platforms, the difference of cutoffs for assigning PD-L1 expression levels, and the variation in study populations. Our study can help to understand the utility and validity of PD-L1 as biomarker of response to immune checkpoint inhibitors.

RESUMEN

Different from the widely used constant discrimination factor Δ15N = 3.4‰ between two adjacent trophic positions (TPs), a scaled Δ15N framework for evaluating the TP of species was developed in 2014, that is, the Δ15N between two adjacent TPs decreases as the TP increases which is considered to be in closer conformity to the trophic cascade in the natural food web. In this study, we compared the two TP calculation methods and then reconsidered the evaluation of the trophic magnification factors (TMFs). Our results show that the TPscaled value is higher and the TMFs value is lower under the scaled Δ15N framework, indicating that the TMFs value under the constant Δ15N framework is often overestimated. We further constructed a diet proportion food web model, which shows that species with lower TP has higher contribution rate as food sources. In Xingkai Lake, the enrichment process of mercury in the food web is not strictly consistent with the diet proportion of the food web. Based on the diet proportion food web model and the mercury enrichment model, it can be found that the White shrimp (Exopalaemon modestus) is not only an important food source, but also the main source of mercury transmission in the food web. Overall, our findings have quantified the food web construction and thus facilitated a better understanding of the interaction between the diet proportion and the bio-concentration in the food web.

Asunto(s)

RESUMEN

BACKGROUND: Defects in replication repair-associated DNA polymerases often manifest an ultra-high tumor mutational burden (TMB), which is associated with higher probabilities of response to immunotherapies. The functional and clinical implications of different polymerase variants remain unclear. METHODS: Targeted next-generation sequencing using a 425-cancer gene panel, which covers all exonic regions of three polymerase genes (POLE, POLD1, and POLH), was conducted in a cohort of 12,266 patients across 16 different tumor types from January 2017 to January 2019. Prognostication of POL variant-positive patients was performed using a cohort of 4679 patients from the The Cancer Genome Atlas (TCGA) datasets. RESULTS: The overall prevalence of somatic and germline polymerase variants was 4.2% (95% CI 3.8% to 4.5%) and 0.7% (95% CI 0.5% to 0.8%), respectively, with highest frequencies in endometrial, urinary, prostate, and colorectal cancers (CRCs). While most germline polymerase variants showed no clear functional consequences, we identified a candidate p.T466A affecting the exonuclease domain of POLE, which might be underlying the early onset in a case with childhood CRC. Low frequencies of known hot-spot somatic mutations in POLE were detected and were associated with younger age, the male sex, and microsatellite stability. In both the panel and TCGA cohorts, POLE drivers exhibited high frequencies of alterations in genes in the DNA damage and repair (DDR) pathways, including BRCA2, ATM, MSH6, and ATR. Variants of unknown significance (VUS) of different polymerase domains showed variable penetrance with those in the exonuclease domain of POLE and POLD1 displaying high TMB. VUS in POL genes exhibited an additive effect as carriers of multiple VUS had exponentially increased TMB and prolonged overall survival. Similar to cases with driver mutations, the TMB-high POL VUS samples showed DDR pathway involvement and polymerase hypermutation signatures. Combinatorial analysis of POL and DDR pathway status further supported the potential additive effects of POL VUS and DDR pathway genes and revealed distinct prognostic subclasses that were independent of cancer type and TMB. CONCLUSIONS: Our results demonstrate the pathogenicity and additive prognostic value of POL VUS and DDR pathway gene alterations and suggest that genetic testing may be warranted in patients with diverse solid tumors.

Asunto(s)

RESUMEN

PURPOSE: Large cell neuroendocrine carcinoma (LCNEC) and classic large cell carcinoma (LCC) are two distinct entities with different histological and biological characteristics. However, the mutational profiles and the clinical behavior of the two subtypes of lung cancer remain to be explored. PATIENTS AND METHODS: Pathological diagnoses of all screened patients were finally confirmed by three or four experienced pathologists. Patients with uncertain pathological diagnoses were excluded. Finally, we genetically profiled ten patients with LCNEC and seven with LCC. ALL patients were subjected to next-generation sequencing (NGS) test, which included nine patients sequenced with a 139-gene panel and eight patients with a 425-gene panel. Including only intersected mutations from these two panels, survival analysis was further conducted. RESULTS: Both LCNEC and LCC showed high prevalence in male patients, with no clear association with smoking history. Potential targetable mutations in KRAS and RET were detected in the study cohort. However, LCNEC and LCC showed distinct mutational profiles with an enrichment of RB1/TP53 co-mutations in a subset of LCNEC patients. SMARCA4 and KEAP1 mutations were exclusively found in LCC patients, and RICTOR, BRAF, ROS1 and TET2 mutations were only detected in LCNEC. LCC patients in the cohort had shorter survival compared to LCNEC patients (p=0.006). Survival analysis revealed an association between SMARCA4 mutations and poor outcome in the study cohort and in the LCC subset. Mutations in BRAF were associated with a trend of increased survival in the study cohort, as well as in the LCNEC subset. Finally, TET2 mutations were associated with poor outcome in the LCNEC cohort. CONCLUSION: LCC and LCNEC were both heterogeneous diseases with limited treatment options. Our study identified potential targetable mutations and prognostic biomarkers that might provide more therapeutic options and improve individualized patient care.

RESUMEN

AIM: The aim of this study was to investigate the expression of platelet-derived growth factor-C in aqueous humor of patients with neovascular glaucoma and its correlation with vascular endothelial growth factor. METHODS: This study involved 62 eyes of 62 patients with advanced neovascular glaucoma requiring transscleral cyclophotocoagulation. Aqueous humor was collected through paracentesis. Samples from 11 eyes of 11 patients with age-related cataract were collected as control. Concentrations of platelet-derived growth factor-C and vascular endothelial growth factor in aqueous humor were quantified by enzyme-linked immunosorbent assay. Meanwhile, the correlations between the concentrations of platelet-derived growth factor-C and vascular endothelial growth factor were analyzed. The elements including retinal photocoagulation treatment, iris neovascularization grade, and primary fundus disease were also studied to find out their roles in the concentrations of the two factors. RESULTS: The vascular endothelial growth factor and platelet-derived growth factor-C concentrations in aqueous humor from controls were (679.54 ± 49.81) pg/mL and (18.60 ± 1.85) pg/mL, respectively. Both of them were significantly lower than neovascular glaucoma patients (p < 0.001). The vascular endothelial growth factor and platelet-derived growth factor-C concentrations of neovascular glaucoma patients treated with retinal photocoagulation were (1095.99 ± 52.71) pg/mL and (28.55 ± 0.94) pg/mL, respectively, which were both significantly lower than those of untreated neovascular glaucoma patients, (1146.28 ± 69.57) pg/mL and (30.04 ± 1.64) pg/mL (p = 0.008, p = 0.034). There was a weak correlation between the expression level of vascular endothelial growth factor and platelet-derived growth factor-C in aqueous humor with neovascular glaucoma (r = 0.346, p = 0.006). However, iris neovascularization grade and primary fundus disease were not significant elements in the expression level of vascular endothelial growth factor and platelet-derived growth factor-C. CONCLUSION: Higher concentrations of vascular endothelial growth factor and platelet-derived growth factor-C were found in aqueous humor of patients with neovascular glaucoma compared with control, which could be lowered by retinal photocoagulation to some extent. Platelet-derived growth factor-C inhibitors may be another potential target for ocular neovascular diseases.

Asunto(s)

RESUMEN

BACKGROUND: Invasive mucinous adenocarcinoma (IMA) of the lung is a distinct histological subtype with unique clinical and pathological features. Despite previous genomic studies on lung IMA, the genetic characteristics and the prognosis-related biomarkers in Chinese surgically resected lung IMA remain unclear. METHODS: We collected 76 surgically resected primary tumors of invasive lung adenocarcinoma, including 51 IMA and 25 non-mucinous adenocarcinomas (non-IMA). IMA was further divided into pure-IMA (mucinous features≥90%) and mixed-IMA subgroups. Comprehensive genomic profiling based on targeted next-generation sequencing (NGS) of 425 genes was explored and genomic characteristics were evaluated for the correlation with postoperative disease-free survival (DFS). RESULTS: IMA had a unique genetic profile, with more diverse driver mutations and more tumor drivers/suppressors co-occurrence than that of non-IMA. The frequency of EGFR (72.0% vs. 40.0% vs. 23.1%, p=0.002) and ALK (undetected vs. 20.0% vs. 26.9%, p=0.015) alterations showed a trend of gradual decrease and increase from non-IMA to mixed-IMA to pure-IMA, respectively. The frequency of KRAS mutations in pure-IMA was higher than that in mixed-IMA, albeit statistically insignificant (23.1% vs. 4.0%, p=0.10). TP53 mutation was significantly less in pure-IMA compared to mixed-IMA and non-IMA (23.1% vs. 52.0% vs. 56.0%, p=0.03). Besides, IMA exhibited less arm-level amplifications (p=0.04) and more arm-level deletions (p=0.004) than non-IMA, and the frequency of amplification and deletion also showed a trend of gradual decrease and increase from non-IMA to mixed-IMA to pure-IMA, respectively. Furthermore, prognosis analysis in stage III IMA patients showed that patients harboring alterations in EGFR (mDFS=30.3 vs. 16.0 months, HR=0.19, P=0.027) and PI3K pathway (mDFS=36.0 vs. 16.0 months, HR=0.12, P=0.023) achieved prolonged DFS, while patients with poorly differentiated tumors (mDFS=14.1 vs. 28.0 months, HR=3.75, p=0.037) or with KRAS mutations (mDFS=13.0 vs. 20.0 months, HR=6.95, p=0.027) had shorter DFS. Multivariate analysis showed that KRAS mutations, PI3K pathway alterations, and tumor differentiation status were independent factors that have statistically significant influences on clinical outcomes of IMA patients. CONCLUSION: Our study provided genomic insights into Chinese surgically resected lung IMA. We also identified several genomic features that may serve as potential biomarkers on postoperative recurrence in IMA patients with stage III disease.