Background Neuroendocrine carcinomas (NECs) comprise a highly heterogeneous group of lethal malignancies arising from diverse anatomical sites. Objective We aimed to provide a functional blueprint for bridging the translational gap between fundamental discovery and clinical application in NEC. Design Building on our previously established cross-tissue transcriptional framework, we here performed comprehensive proteomic and phosphoproteomic profiling of 267 NECs spanning 26 anatomical sites. Result This integrated analysis recapitulated the five ANHPY transcriptional subtypes driven by master transcription factors (ASCL1, NEUROD1, HNF4A, POU2F3 and YAP1). These subtypes hijacked distinct lineage developmental programmes, which converged with specific RB1 status to dictate their molecular identities. Synergistic profiling of tissue and plasma proteomes, alongside cell secretomes, nominated subtype-specific diagnostic and therapeutic biomarkers. Specifically, we uncovered NAD + dependency as a metabolic vulnerability unique to subtype H, which is primarily distributed across gastroenteropancreatic NEC. Pharmacological inhibition of the NAD + salvage enzyme NAMPT achieved complete tumour regression in vivo by triggering synthetic lethality in the context of an inherent deficiency in NAD + biosynthesis. We also defined four tumour microenvironment (TME) subtypes that capture the extrinsic diversity of NEC. Notably, the ‘inflamed’ TME subtype was associated with superior immunotherapy responses, yielding an inflammatory signature that robustly stratified patients across diverse tissue origins. Conclusions This study delineated conserved molecular identities, multidimensional biomarkers, the immune landscape and subtype H-specific therapeutic strategies, paving the way for precision medicine in NEC.

Abstract Background Loss-of-function mutations in KEAP1 frequently occur in lung adenocarcinoma and are associated with poor prognosis and limited benefit from immunotherapy. However, the mechanisms linking KEAP1 deficiency to immune evasion remain elusive. Methods We combined patient data analysis, in vivo tumor models, and in vitro co-culture systems to investigate how KEAP1 deficiency shapes dendritic cell (DC) biology and response to PD-1 blockade. Ferroptosis induction assays, damage-associated molecular patterns (DAMPs) quantification, cytokine profiling, and mechanistic interrogation of the FSP1-CoQ10 axis were performed to delineate underlying pathways. Results Clinically, KEAP1 mutations correlated with poor response to PD-1 blockade and reduced DC infiltration. In murine models, KEAP1-deficient tumors exhibited marked resistance to anti-PD-1 therapy. Mechanistically, KEAP1 loss impaired DC function in vitro, as evidenced by reduced maturation, phagocytosis, and naïve CD8+ T-cell priming capacity. This defect was linked to two complementary mechanisms. First, KEAP1-deficient tumor cells resisted ferroptosis and failed to release immunogenic DAMPs, including extracellular ATP, HMGB1, and calreticulin. Second, KEAP1 deficiency reprogrammed the cytokine secretion profile, with downregulation of CCL2, IL-6, CXCL1, and CXCL2, thereby diminishing DC recruitment and inflammatory signaling. Notably, inhibition of the FSP1-CoQ10 antioxidant axis restored ferroptosis-associated immunogenic cell death. Conclusions Our study identifies KEAP1 deficiency as a driver of immune-cold tumor microenvironments and resistance to PD-1 blockade, acting through impaired ferroptosis-induced immunogenic cell death and disrupted DC function. Targeting the FSP1-CoQ10 pathway may restore DC function and sensitize KEAP1-mutant lung cancers to immunotherapy. Citation Format: Xinfeng Wang, Yuxin Yao, Tomi Jun, Kuan-lin Huang, Nan Sun, Jie He. KEAP1 loss-of-function suppresses immunogenic ferroptosis and limits PD-1 blockade efficacy through an NRF2-FSP1 pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 171.

Germline pathogenic variants in BRCA1 and BRCA2 confer disproportionately elevated cancer risks in breast and ovarian tissues, yet the basis for this tissue specificity remains incompletely understood. Here, we integrate bulk-tumor aneuploidy analysis across 340,824 cancer cases from three independent cohorts (TCGA, ICGC PCAWG, and FoundationCore) with single-cell whole-genome sequencing from two independent studies to investigate whether tissue-specific patterns of chromosomal deletion contribute to this phenomenon. We find that breast and ovarian cancers are consistently enriched for deletions of chromosome arms 17q and 13q-harboring the BRCA1 and BRCA2 genes, respectively-relative to other solid tumor types, and that mutational timing analysis independently places these deletions among the earliest somatic events in these cancers. Phylogenetic reconstruction of single-cell data reveals that in pre-malignant breast tissue from germline BRCA1/2 carriers, chr17q and chr13q deletions appear as localized subclonal events within small clades against a largely diploid background. In established malignancies, these same deletions are found within dominant clonal lineages accompanied by widespread genomic instability-consistent with clonal sweeps originating from early deletion events. These findings suggest that breast and ovarian cellular environments confer a selective advantage for chr17q and chr13q deletions, providing a mechanism that may contribute to the tissue-specific cancer risk observed in gBRCA1/2 carriers.

ABSTRACT Adenosine‐to‐inosine (A‐to‐I) RNA editing, predominantly catalyzed by the enzyme adenosine deaminase acting on RNA 1 (ADAR1), has attracted interest due to its essential functions in regulating immune response and cancer progression. This research investigates ADAR1 inhibition as a promising strategy aimed at improving immunotherapy efficacy in lung adenocarcinoma (LUAD) and explores the underlying mechanisms. Findings from murine models demonstrate that ADAR1 suppression within tumors notably improves the immune microenvironment, marked by increased PD‐L1 expression and enhanced CD8+ T‐cell infiltration, as well as elevated levels of CXCL9, CXCL10, and CXCL11. These changes promote antitumor T‐cell immune responses and amplify the effects of immunotherapy. Mechanistic investigations further reveal that deficiency in ADAR1 leads to an increase in double‐stranded RNA (dsRNA), which serves as a substrate for A‐to‐I editing. This activates downstream signaling via dsRNA receptors, including RIG‐I and MAVS, thereby inducing the IFN‐β pathway. Significantly, IFN‐β contributes to the ADAR1‐dependent modulation of the tumor immune microenvironment and carcinogenesis in LUAD. Clinical validation in LUAD patients further confirms that reduced ADAR1 expression is associated with improved immunotherapy responses. These findings suggest inhibiting ADAR1‐mediated A‐to‐I RNA editing is a promising approach to enhance the efficacy of immunotherapy in LUAD.

BACKGROUND:LKB1 (STK11)-deficient tumors exhibit an immunosuppressive microenvironment that limits the efficacy of immunotherapies such as anti-programmed cell death protein 1 (PD-1) antibodies. However, the underlying mechanisms driving immune evasion remain unclear. Dendritic cells (DCs), especially conventional DC 1 (cDC1), play a crucial role in antigen presentation and CD8+ T-cell activation, yet their dysfunction in LKB1-deficient tumors has not been well characterized. METHODS:Tumor-intrinsic LKB1 deficiency was modeled by subcutaneous inoculation of CRISPR/Cas9-engineered Stk11-knockout tumor cell lines into syngeneic mice. DC infiltration and function were assessed through a series of flow cytometry-based in vivo and in vitro assays, including analyses of infiltration, migration, antigen uptake, maturation, and CD8+ T-cell priming. Naïve CD8+ T-cell activation by cDC1s was evaluated via adoptive transfer of CD45.1+ OT-I T cells. Secretome proteomics and functional rescue experiments identified anterior gradient 2 (AGR2) as a key immunosuppressive mediator, and arginase 1 (ARG1) was validated as its functional interactor through liquid chromatography-tandem mass spectrometry (LC-MS/MS), co-immunoprecipitation, and imaging flow cytometry. Upstream regulation of AGR2 was investigated by AMPKα/FOXA1 silencing and chromatin immunoprecipitation (ChIP) quantitative PCR, revealing a tumor-intrinsic AMPKα-FOXA1-AGR2 axis driving DC dysfunction. RESULTS:LKB1-deficient tumors exhibited significantly reduced cDC1 infiltration, and cDC1s were functionally impaired in antigen uptake, migration, and naïve CD8+ T-cell priming. AGR2, a secreted protein transcriptionally upregulated via the tumor-intrinsic AMPKα-FOXA1 pathway, was identified as a key mediator of DC dysfunction. Mechanistically, AGR2 interacted with ARG1, stabilizing its expression and promoting ARG1 accumulation in DCs. Restoring DC infiltration and activity through FLT3L-driven expansion and tumor-antigen-specific DC supplementation significantly enhanced the efficacy of anti-PD-1 treatment in LKB1-deficient lung adenocarcinoma models. CONCLUSION:Our study identifies profound DC dysfunction-characterized by impaired antigen uptake, migration, and naïve CD8+ T-cell priming-as a key mechanism of immune evasion in LKB1-deficient tumors. This dysfunction is driven by tumor-secreted AGR2, which stabilizes ARG1 in DCs and suppresses CD8+ T-cell activation. Targeting the AMPKα-FOXA1-AGR2-ARG1 axis or restoring DC competence offers a promising strategy to enhance immunotherapy efficacy in LKB1-deficient subtype.

Purpose:This study aims to evaluate the feasibility of using immune checkpoint-related gene polymorphisms and serum levels of PD-1, PD-L1 and CTLA4 in predicting chemotherapy resistance in patients with cervical cancer. Methods:Seven candidate SNPs in PDCD1, CD274 and CTLA4 were genotyped in 1032 cervical cancer patients (537 non-responders and 495 responders based on their responses to chemotherapy), and the serum level of PD-1, PD-L1 and CTLA4 was detected by ELISA. Results:The frequencies of minor allele A of PDCD1- rs2227982, CD274-rs2890658 and CTLA4-rs3087243 were significantly higher in non-responders than that in responders (p ≤ 0.0001). Moreover, the genotype AA of the three SNPs was associated with a 2.24, 3.78 and 2.71-fold increase in susceptibility to platinum resistance, respectively (p ≤ 0.0001). In addition, all of the three SNPs were associated with the risk of cisplatin resistance in both patients with squamous cell carcinoma and adenocarcinoma under different genetic models (p <0.05). The serum concentrations of PD-L1 and CTLA4 in the non-responder group were significantly higher than those in the responder group (p < 0.0001). Moreover, the PD-L1 and CTLA4 levels of carriers with mutant genotypes of CD274-rs2890658 and CTLA4-rs3087243 were significantly higher than those of with wild-type, and the serum levels of homozygous mutant carriers were even higher (p < 0.0001). Conclusion:The PDCD1- rs2227982, CD274-rs2890658 and CTLA4- rs3087243 polymorphisms and high serum levels of PD-L1 and CTLA4 may predict chemotherapy resistance in cervical cancer patients.

BackgroundCervical cancer is the fourth most common cancer in women globally, and the main cause of the disease has been found to be ongoing HPV infection. Cervical cancer remains the primary cause of cancer-related death despite major improvements in screening and treatment approaches, especially in low- and middle-income nations. Therefore, it is crucial to investigate the tumor microenvironment in advanced cervical cancer in order to identify possible treatment targets.Materials and methodsIn order to better understand malignant cervical cancer epithelial cells (EPCs), this study used bulk RNA-seq data from UCSC in conjunction with single-cell RNA sequencing data from the ArrayExpress database. After putting quality control procedures into place, cell type identification and clustering analysis using the Seurat software were carried out. To clarify functional pathways, enrichment analysis and differential gene expression were carried out. The CIBERSORT and ESTIMATE R packages were used to evaluate the immune microenvironment characteristics, and univariate and multivariate Cox regression analyses were used to extract prognostic features. Furthermore, assessments of drug sensitivity and functional enrichment were carried out.ResultsEight cell types were identified, with EPCs showing high proliferative and stemness features. Five EPC subpopulations were defined, with C1 NNMT+ CAEPCs driving tumor differentiation. A NNMT CAEPCs Risk Score (NCRS) model was developed, revealing a correlation between elevated NCRS scores and adverse patient outcomes characterized by immune evasion. In vitro experiments validated that the prognostic gene PLOD2 significantly enhances proliferation, migration, and invasion of cervical cancer cells.ConclusionThis investigation delineated eight cell types and five subpopulations of malignant EPCs in cervical cancer, establishing the C1 NNMT+ CAEPCs as a crucial therapeutic target. The NCRS model demonstrated its prognostic capability, indicating that higher scores are associated with poorer clinical outcomes. The validation of PLOD2 as a prognostic gene highlights its therapeutic potential, underscoring the critical need for integrating immunotherapy and targeted treatment strategies to enhance diagnostic and therapeutic approaches in cervical cancer.

Neuroendocrine carcinomas (NECs) are extremely lethal malignancies that can arise at almost any anatomic site. Characterization of NECs is hindered by their rarity and significant inter- and intra-tissue heterogeneity. Herein, through an integrative analysis of over 1,000 NECs originating from 31 various tissues, we reveal their tissue-independent convergence and further unveil molecular divergence driven by distinct transcriptional regulators. Pan-tissue NECs are therefore categorized into five intrinsic subtypes defined by ASCL1, NEUROD1, HNF4A, POU2F3, and YAP1. A comprehensive portrait of these subtypes is depicted, highlighting subtype-specific transcriptional programs, genomic alterations, evolution trajectories, therapeutic vulnerabilities, and clinicopathological presentations. Notably, the newly discovered HNF4A-dominated subtype-H exhibits a gastrointestinal-like signature, wild-type RB1, unique neuroendocrine differentiation, poor chemotherapeutic response, and prevalent large-cell morphology. The proposal of uniform classification paradigm illuminates transcriptional basis of NEC heterogeneity and bridges the gap across different lineages and cytomorphological variants, in which context-dependent prevalence of subtypes underlies their phenotypic disparities.

BackgroundLung cancer is the leading cause of cancer deaths globally, with lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) being major subtypes. Immunotherapy has emerged as a promising approach for the treatment of lung cancer, but understanding the underlying mechanisms of immune dysregulation is crucial for the development of effective therapies. This study aimed to investigate the distinctive cellular features of LUAD and LUSC and identify potential biomarkers associated with the pathogenesis and clinical outcomes of each subtype.MethodsWe used digital cytometry techniques to analyze the RNA-Seq data of 1128 lung cancer patients from The Cancer Genome Atlas (TCGA) database. The abundance of cell subtypes and ecotypes in LUAD and LUSC patients was quantified. Univariate survival analysis was used to investigate their associations with patient overall survival (OS). Differential gene expression analysis and gene co-expression network construction were carried out to explore the gene expression patterns of LUSC patients with distinct survival outcomes. Scratch wound-healing assay, colony formation assay, and transwell assay were used to validate the candidate drugs for LUSC treatment.ResultsWe found differential expression of cell subtypes between LUAD and LUSC, with certain cell subtypes being prognostic for survival in both subtypes. We also identified differential gene expression and gene co-expression modules associated with macrophages.3/PCs.2 ratio in LUSC patients with distinct survival outcomes. Furthermore, ecotype ratios were found to be prognostic in both subtypes and machine learning models showed that certain cell subtypes, such as epithelial.cells.1, epithelial.cells.5, and endothelial.cells.2 are important for predicting LUSC. Ginkgolide B and triamterene can inhibit the proliferation, invasion, and migration of LUSC cell lines.ConclusionWe provide insight into the distinctive cellular features of LUAD and LUSC, and identify potential biomarkers associated with the pathogenesis and clinical outcomes of each subtype. Ginkgolide B and triamterene could be promising drugs for LUSC treatment.

Ferroptosis is a new type of programmed cell death different from other cell death pathways such as apoptosis,autophagy,necrosis,and pyroptosis in terms of initiation,mechanisms,and molecular characteristics.As the accumulation of phospholipid hydroperoxides is the hallmark of ferroptosis,the balance between oxidative damage and antioxidant defense is critical to the regulatory mechanism of ferroptosis.In cancer,the upregulation of antioxidant defense pathways can inhibit ferroptosis,thereby promoting cancer cells to survive the oxidative stress and develop drug resistance.This review systematically introduces the main features and regulatory mechanisms of ferroptosis.In addition,we summarize the role of ferroptosis in the progression and drug resistance of malignant tumors,providing novel implications for further research on the pathogenesis of malignant tumors and discovery of new targets for anti-cancer therapy.

Recently, a novel oral, irreversible pan-HER tyrosine kinase inhibitor, pyrotinib, has shown anticancer effects on HER2-mutant non-small cell lung cancer (NSCLC) patients, but the explicit responses of lung cancer cells towards pyrotinib treatment are barely investigated. In our current study, we employed single-cell RNA sequencing to profile the longitudinal transcriptomic dynamics of lung cancer cells during the pyrotinib treatment, unraveling the potential resistance mechanisms. We treated a lung adenocarcinoma cell line, H358, with pyrotinib at doses of 100nM, 200nM, 500nM, and 1000nM every four days, respectively. Then, the untreated cells (P0) as well as longitudinal samples after each administration (P4, P8, P12, P16) were harvested for further analysis. After quality control, a total of 41,804 cells were sequenced and included for further analysis. The differentially expressed genes were determined using MAST and the differentially enriched cancer hallmark signatures based on single-sample Gene Set Variation Analysis (ssGSVA) were identified. The single-cell data revealed that the untreated cells (Sample P0) and persistent cells (Sample P16) had stable and distinct gene expression patterns, while cells during the course of treatment shared similar expression features at a transitional state. Several cancer driver genes were found to be aberrantly regulated during the administration, like EPHA2, CDKN2A, CDK4, PTEN, and MYC. Also, some pathways related to immune response were suppressed after pyrotinib treatment, including interferon alpha response, interferon gamma response, TNFA signaling via NF-κB, and inflammatory response. Intriguingly, CD274 (the gene encoding PD-L1) and LGALS9 were found to significantly decrease after pyrotinib treatment, suggesting that pyrotinib may be associated with outcomes of immunotherapy. With the large cell numbers analyzed, we distinguished an isolated, small subpopulation of cells characterized by the enriched expression of MGP, COL1A1, COL1A2, SPARC, and COL3A1 along with the elevated EMT and angiogenesis scores, suggesting its critical role in pyrotinib resistance. Collectively, our study for the first time reveals the transcriptomic evolution of NSCLC cells in response to pyrotinib administration at the single-cell resolution, providing new insights into potential mechanisms of resistance to this novel regimen in NSCLC. Citation Format: Xinfeng Wang, Yuan Li, Runsen Jin, Nan Sun, Jie He. Single-cell analysis sheds light on the resistance mechanisms of a novel pan-HER inhibitor, pyrotinib, in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5349.

BackgroundThe early-stage lung adenocarcinoma (LUAD) incidence has increased with heightened public awareness and lung cancer screening implementation. Lipid metabolism abnormalities are associated with lung cancer initiation and progression. However, the comprehensive features and clinical significance of the immunometabolism landscape and lipid metabolism-related genes (LMRGs) in cancer recurrence for early-stage LUAD remain obscure. MethodsLMRGs were extracted from Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Samples from The Cancer Genome Atlas (TCGA) were used as training cohort, and samples from four Gene Expression Omnibus (GEO) datasets were used as validation cohorts. The LUAD recurrence-associated LMRG molecular pattern and signature was constructed through unsupervised consensus clustering, time-dependent receiver operating characteristic (ROC), and least absolute shrinkage and selection operator (LASSO) analyses. Kaplan-Meier, ROC, and multivariate Cox regression analyses and prognostic meta-analysis were used to test the suitability and stability of the signature. We used Gene Ontology (GO), KEGG pathway, immune cell infiltration, chemotherapy response analyses, gene set variation analysis (GSVA), and GSEA to explore molecular mechanisms and immune landscapes related to the signature and the potential of the signature to predict immunotherapy or chemotherapy response. ResultsFirst, two LMRG molecular patterns were established, which showed diverse prognoses and immune infiltration statuses. Then, a 12-gene signature was identified, and a risk model was built. The signature remained an independent prognostic parameter in multivariate Cox regression and prognostic meta-analysis. In addition, this signature stratified patients into high- and low-risk groups with significantly different recurrence rates and was well validated in different clinical subgroups and several independent validation cohorts. The results of GO and KEGG analyses and GSEA showed that there were differences in multiple lipid metabolism, immune response, and drug metabolism pathways between the high- and low-risk groups. Further analyses revealed that the signature-based risk model was related to distinct immune cell proportions, immune checkpoint parameters, and immunotherapy and chemotherapy response, consistent with the GO, KEGG, and GSEA results. ConclusionsThis is the first lipid metabolism-based signature for predicting recurrence, and it could provide vital guidance to achieve optimized antitumor for immunotherapy or chemotherapy for early-stage LUAD.

BACKGROUND:Although immune checkpoint inhibitors (ICIs) against programmed cell death protein 1 (PD-1) and its ligand PD-L1 have demonstrated potency towards treating patients with non-small cell lung carcinoma (NSCLC), the potential association between Kirsten rat sarcoma viral oncogene homolog (KRAS) oncogene substitutions and the efficacy of ICIs remains unclear. In this study, we aimed to find point mutations in the KRAS gene resistant to ICIs and elucidate resistance mechanism. METHODS:The association between KRAS variant status and the efficacy of ICIs was explored with a clinical cohort (n = 74), and confirmed with a mouse model. In addition, the tumor immune microenvironment (TIME) of KRAS-mutant NSCLC, such as CD8+ tumor-infiltrating lymphocytes (TILs) and PD-L1 level, was investigated. Cell lines expressing classic KRAS substitutions were used to explore signaling pathway activation involved in the formation of TIME. Furthermore, interventions that improved TIME were developed to increase responsiveness to ICIs. RESULTS:We observed the inferior efficacy of ICIs in KRAS-G12D-mutant NSCLC. Based upon transcriptome data and immunostaining results from KRAS-mutant NSCLC, KRAS-G12D point mutation negatively correlated with PD-L1 level and secretion of chemokines CXCL10/CXCL11 that led to a decrease in CD8+ TILs, which in turn yielded an immunosuppressive TIME. The analysis of cell lines overexpressing classic KRAS substitutions further revealed that KRAS-G12D mutation suppressed PD-L1 level via the P70S6K/PI3K/AKT axis and reduced CXCL10/CXCL11 levels by down-regulating high mobility group protein A2 (HMGA2) level. Notably, paclitaxel, a chemotherapeutic agent, upregulated HMGA2 level, and in turn, stimulated the secretion of CXCL10/CXCL11. Moreover, PD-L1 blockade combined with paclitaxel significantly suppressed tumor growth compared with PD-L1 inhibitor monotherapy in a mouse model with KRAS-G12D-mutant lung adenocarcinoma. Further analyses revealed that the combined treatment significantly enhanced the recruitment of CD8+ TILs via the up-regulation of CXCL10/CXCL11 levels. Results of clinical study also revealed the superior efficacy of chemo-immunotherapy in patients with KRAS-G12D-mutant NSCLC compared with ICI monotherapy. CONCLUSIONS:Our study elucidated the molecular mechanism by which KRAS-G12D mutation drives immunosuppression and enhances resistance of ICIs in NSCLC. Importantly, our findings demonstrate that ICIs in combination with chemotherapy may be more effective in patients with KRAS-G12D-mutant NSCLC.

Pathogenic germline variants of BRCA1 and BRCA2 disproportionally elevated the risk of specific cancer types (ex. breast [BRCA] and ovarian [OV] cancer) compared to tumors arising from other tissues. The reason underlying the strong tissue-specificity for BRCA-associated cancer risk remains largely unknown. Under the two-hit hypothesis, BRCA-mediated oncogenesis is thought to originate from a cell where the germline BRCA1/2 variant underwent loss of heterozygosity (LOH) of the wildtype BRCA allele, resulting in homologous recombination DNA repair deficiencies. Notably, tumor aneuploidy and loss of chromosome arms also show strong tissue specificity across cancer types. The apparent tissue specificities of BRCA-associated cancer risk and chromosome aneuploidy, together with deletion-induced LOH underlying the two-hit hypothesis, pose an intriguing possibility that they may be linked. Using genomic data from the TCGA PanCanAtlas and ICGC PCAWG projects, we calculated the frequencies of deletions of the chromosomal arms where the BRCA1/2 genes are located (17q for BRCA1; 13q for BRCA2) across different cancer types in tumors with no whole-genome doublings (WGD). Among TCGA cases, OV and BRCA showed significantly higher frequencies of 17q deletion (32.75% and 8.05%, respectively) than other cancer types (ranked 2/30 and 5/30, permutation p-value = 0.030 and 0.024), and relatively higher frequencies of 13q deletion (32.75% and 21.92%, respectively) compared to other cancers (ranked 5/32 and 8/32, p-value = 0.101 and 0.078). As expected, cancer types showing high fractions of BRCA1/2 deletions overlap with those showing 17q/13q deletions and often include BRCA and OV. Subsequently, we determined how often BRCA1/2 deletion co-occurred and thus may be caused by the corresponding 17q/13q deletions, showing that BRCA1 deletion carriers who also had chr17q deletion accounted for 40.76% in OV and 25.93% in BRCA patients, compared to 33.33% in all other cancer types while BRCA2 deletion carriers who also had chr13q deletion accounted for OV (53.97%) and BRCA (58.60%) patients, compared to 49.83% in all other cancer types. In addition, we validated our findings in non-overlapping cases of the ICGC PCAWG projects. Consistent with TCGA results, OV and BRCA showed higher frequencies of 17q and 13q deletion compared to other cancer types. To conclude, we identified a correlation between cross-cancer difference in arm-level and focal chromosome aneuploidy affecting BRCA1/2 and BRCA-associated cancer risk, and how chromosome aneuploid may give rise to tissue-specific risks of cancer remain to be investigated. Citation Format: Xinfeng Wang, Tomi Jun, Nan Sun, Jie He, Kuan-lin Huang. Tissue specificity of chromosome aneuploidy correlates with BRCA-associated cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5692.

Background: Octreotide long-acting release (LAR) is a common drug used for acromegaly that aims to normalize serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1). However, only a few studies have evaluated its efficacy and safety in Chinese patients. This retrospective study aimed to assess its efficacy and safety in a cohort of Chinese patients with acromegaly. Methods: A total of 163 patients with acromegaly, who received continuous and regular octreotide LAR treatment at least three times at Peking Union Medical College Hospital between 2010 and 2020, were enrolled. Clinical characteristics, acromegaly activity, and other laboratory tests before and after treatment were collected for analysis. Results: The study enrolled 163 patients, including 71 men (43.6%) with a mean age of 40.94 +/- 13.00 years. After octreotide LAR treatment, 34.4% of the patients achieved GH control (<2.5 ng/mL), while IGF-1 levels were normalized in 23.3% of the patients. Also, fasting GH levels were downregulated from 4.95 ng/mL [interquartile range (IQR) 2.225, 10.325 ng/mL] at baseline to 3.2 ng/mL (IQR 1.5, 6.6 ng/mL) (P<0.001), and IGF-1/upper limit of the normal (ULN) declined from 1.89 (IQR 1.22, 2.40) to 1.41 (IQR 0.97, 1.89) (P<0.001). In addition, 65 patients experienced moderate adverse events. During the follow-up, none of the patients discontinued octreotide LAR. Further logistic regression showed that comorbidity [odds ratio (OR), 3.19; 95% confidence interval (CI): 1.20-9.27; P=0.025] and previous surgery only (OR, 0.21; 95% CI: 0.08-0.58; P=0.003) were two risk factors for the development of adverse events. Conclusions: Our findings revealed that octreotide LAR treatment is effective in normalizing GH and IGF-1 levels in Chinese patients with acromegaly. In addition, adverse events related to octreotide LAR use were moderate and well tolerated by the patients.

Background and Objective: Although anti-programmed cell death protein 1 (PD-1) antibodies have exerted remarkable anticancer activity in non-small cell lung cancer (NSCLC), it remains a challenge to identify patients who can benefit from these treatments. Immune-related adverse events (irAEs) may be associated with improved clinical outcomes after immune checkpoint inhibition. However, no conclusive evidence of this correlation has been summarized in patients with NSCLC receiving PD-1 inhibitors. We performed a systematic review and meta-analysis to evaluate the association between irAEs induced by anti-PD-1 antibodies and clinical outcomes in patients with NSCLC. Methods: Various databases were searched from their inception to January 9, 2021, followed by screening of eligible studies. Hazard ratios were used for the pooled analysis of overall survival (OS) and progression-free survival (PFS), while odds ratios (ORs) were utilized to pool objective response rates (ORRs) and disease control rates (DCRs). A random-effects model was applied to all analyses. Results: A total of 26 cohorts, including 8,452 patients with NSCLC receiving anti-PD-1 antibodies, were enrolled in the study. Significantly improved OS (HR: 0.51; 95% CI: 0.44-0.60; P < 0.01) and PFS (HR: 0.50; 95% CI: 0.43-0.58; P < 0.01) were found to be correlated with irAEs. In addition, patients with NSCLC who developed irAEs after PD-1 inhibition demonstrated better responses to therapies, confirmed by pooled ORs of ORRs (OR: 3.41; 95% CI: 2.66-4.35; P < 0.01) and DCRs (OR: 4.08; 95% CI: 2.30-7.24; P < 0.01). Furthermore, subgroup analysis suggested that both skin and endocrine irAEs are closely correlated with a reduced risk of death, whereas pulmonary irAEs showed no association with longer OS. Conclusions: In patients with NSCLC treated with anti-PD-1 therapies, the presence of irAEs was strongly correlated with better survival and response, suggesting its potential role as a predictive biomarker for outcomes after PD-1 inhibition.

The tumor mutational burden (TMB) is closely related to immunotherapy outcome. However, the cost of TMB detection is extremely high, which limits its use in clinical practice. A new indicator of genomic instability, the average copy number variation (CNVA), calculates the changes of 0.5‐Mb chromosomal fragments and requires extremely low sequencing depth.

食管癌(esophageal cancer,EC)是常见的癌症之一,组织病理类型分为食管鳞状细胞癌和食管腺癌.因确诊晚,并缺乏有效的治疗手段,EC成为世界范围的公共健康问题之一.与常规的肿瘤活检不同,液态活检因损伤性小,可作为传统活检的补充甚至替代方法.尤其是细胞游离DNA(cell-free DNA,cf DNA),在癌症临床管理中已表现出应用前景.cf DNA已成为非侵入性癌症诊断和监测的有效循环分子标志物.虽然很多研究报道了cf DNA在各种癌症中的临床应用,但对其在EC中的作用尚缺乏了解.因此,我们就这一主题进行了综述,并讨论了其在EC诊断和监测中的优势及局限性.

AbstractDysregulated expression of S100A7 is found in several cancers and plays an important role in tumor progression; however, its carcinogenic role in esophageal squamous carcinoma (ESCC) is still poorly understood. Here, we identified that the levels of S100A7 were remarkably upregulated in 341 tumor tissues (P < .001) and 274 serum samples (P < .001) of ESCC patients compared with normal control. It was an independent prognostic factor (P = .026). Furthermore, a new diagnostic model for ESCC based on serum S100A7, SCC, and crfra21‐1 was established with area under curve (AUC) up to 0.863 (95% CI: 0.802‐0.925). Mechanically, we found upregulated S100A7 could promote cell migration and proliferation through intracellular binding to JAB1 and paracrine interaction with RAGE receptors and then activates the downstream signaling pathways. In addition, exocrine S100A7 could promote M2 macrophage infiltration and polarization by up‐regulating M2 macrophage associated proteins, and tumor angiogenesis by enhancing the activation of p‐ErK and p‐FAK pathways. Further animal experiments confirmed the role of S100A7 in promoting M2 macrophage infiltration and angiogenesis in ESCC. In conclusion, these findings highlighted the potential diagnostic and prognostic value of S100A7 in patients with ESCC. Meanwhile, our results reveal that S100A7 promotes tumor progression by activating oncogenic pathways and remodeling tumor microenvironment, which paving the way for the progress of S100A7 as a therapeutic target for cancer treatment.