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Tumor-draining lymph nodes (TDLNs) are usually the first station of tumor metastasis in lung cancer. TDLNs+ have distinct pathomorphologic and tumor microenvironment (TME)-compositional patterns, which still need to be thoroughly investigated in lung adenocarcinoma (LUAD). Here, we enrolled 312 LUAD patients with TDLNs+ from our institution between 2015 and 2019. 3DHISTECH was used to scan all of the TDLNs+. Based on morphologic features, TDLNs+ patterns were classified as polarized-type or scattered-type, and TME-compositional patterns were classified as colloid-type, necrosis-type, specific-type, and common-type. Multivariate analysis revealed an increased risk of early recurrence associated with scattered-type (HR 2.37, 95% CI: 1.06-5.28), colloid-type (HR 1.95, 95% CI: 1.03-3.67), and necrosis-type (HR 2.21, 95% CI: 1.13-4.89). NanoString transcriptional analysis revealed an immunosuppression and vascular invasion hallmark in scattered and necrosis patterns and an immunoactivated hallmark in polarized and common patterns. According to imaging mass cytometry (IMC), the scattered and necrosis patterns revealed that germinal centers (GC) were compromised, GCB cell and T cell proliferation were deficient, tumor cells had the potential for proliferation, and the immune attack may be weaker. In this study, we present evidence that LUAD patients have distinct patterns and immune hallmarks of TDLNs+ related to their prognosis.
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An enantioselective Pd-catalyzed intramolecular desymmetrizing cycloisomerization of N-(cyclopent-3-en-1-yl)propiolamides has been developed by employing a new chiral phosphoramidite ligand. A series of structurally unique bridged azabicycles are achieved in moderate to excellent yields with good E/Z selectivity and high enantioselectivity. Synthetic transformations are conducted to demonstrate the practical utility of this reaction.
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BACKGROUND: Circular RNAs (circRNAs) are an intriguing family of RNA molecules due to their crucial roles in the pathogenesis of oral squamous cell carcinoma (OSCC). Here, we sought to define the action of human circ_0004674 in OSCC progression. METHODS: The functional role of circ_0004674 was validated by determining its effect on cell growth, apoptosis, and tube formation ability of OSCC cells. For protein quantification, a western blot or immunohistochemistry method was applied. The interaction between miR-139-5p and circ_0004674 or zinc finger and BTB domain containing 2 (ZBTB2) was predicted by online algorithms, and their relationships were confirmed by dual-luciferase reporter and RIP assays. Xenograft models were established to uncover circ_0004674's role in tumor growth. RESULTS: Circ_0004674 expression was upregulated in OSCC. Functionally, knocking down circ_0004674 led to suppressed OSCC cell progression in vitro and delayed tumor growth in vivo. Mechanistically, circ_0004674 post-transcriptionally controlled ZBTB2 expression by competitively pairing to miR-139-5p. Furthermore, the deficiency of miR-139-5p abated circ_0004674 silencing-mediated OSCC cell progression repression, and augmentation of ZBTB2 reversed the anticancer effect of miR-139-5p on OSCC. CONCLUSION: Our findings uncover a novel regulatory cascade, the circ_0004674/miR-139-5p/ZBTB2 axis, with the ability to affect OSCC development in vitro and in vivo, providing a potential opportunity for development of OSCC therapy.
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Carcinoma de Células Escamosas , MicroARNs , Neoplasias de la Boca , ARN Circular , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Neoplasias de la Boca/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Ratones , Animales , Línea Celular Tumoral , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Regulación Neoplásica de la Expresión Génica , Proliferación Celular/genética , Apoptosis/genética , Femenino , Masculino , Ratones DesnudosRESUMEN
At present, preoperative chemotherapy is the standard of care for the neoadjuvant treatment of potentially resectable gastric cancer (GC). However, because the efficacy and prognosis are not ideal, curative effects for this population are unsatisfactory. With the development of immune checkpoint inhibitors, the results of a few encouraging early trials of immunotherapeutic agents as neoadjuvant therapies for resectable GC have been reported. However, markers of the efficacy of immune checkpoint inhibitors remain unclear. This prospective single-center, single-arm observational study was designed to evaluate the efficacy of sintilimab plus the fluorouracil, leucovorin, oxaliplatin and docetaxel regimen as a neoadjuvant treatment for localized GC. More importantly, this work assesses multiple dimensions and include ctDNA, the immune microenvironment and intestinal microbiome to explore correlations between biomarkers and neoadjuvant therapeutic efficacy. Clinical trial registration: ChiCTR2200061629 (www.chictr.org.cn/index.aspx).
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Neoplasias Gástricas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores , Docetaxel/uso terapéutico , Fluorouracilo/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Leucovorina/uso terapéutico , Terapia Neoadyuvante/métodos , Oxaliplatino/uso terapéutico , Estudios Prospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/tratamiento farmacológico , Microambiente TumoralRESUMEN
Two novel bacterial strains, designated as SYSU D00344T and SYSU D00433T, were isolated from soil of Gurbantunggut Desert in Xinjiang, north-west PR China. Cells of both strains were Gram-stain-negative, aerobic, short-rod-shaped, catalase-positive and non-motile. Oxidase activities of SYSU D00344T and SYSU D00433T were negative and positive, respectively. Optimal growth occurred at 30 °C, with 0-0.5â% (w/v) NaCl and at pH 7.0. The results of phylogenetic analysis of 16S rRNA gene sequences indicated that they represented members of the genus Rufibacter and were closely related to Rufibacter hautae NBS58-1T. The results of phylogenomic analysis indicated that the two strains formed two independent and robust branches distinct from all reference type strains. The analyses of average nucleotide identity (ANI), digital DNA-DNA hybridisation (dDDH) values and 16S rRNA gene similarities between the two strains and their relatives further demonstrated that SYSU D00344T and SYSU D00433T represented two different novel genospecies. The polar lipids consisted of phosphatidylethanolamine, one unidentified glycolipid, two unidentified aminophospholipids, and two or four unidentified lipids. MK-7 was the only respiratory quinone. The major fatty acids (>10â%) for both strains were identified as iso-C15â:â0, anteiso-C15â:â0 and summed feature 3 (C16â:â1ω7c and/or C16â:â1ω6c), as well as summed feature 4 (anteiso-C17â:â1B and/or iso-C17â:â1I) for SYSU D00344T and C16â:â1ω5c for SYSU D00433T. On the basis of the phylogenetic, phenotypic, chemotaxonomic and genotypic characteristics, we propose Rufibacter roseolus sp. nov. and Rufibacter aurantiacus sp. nov. as two novel species in the genus Rufibacter. The type strains are SYSU D00344T (=CGMCC 1.8625T=MCCC 1K04971T=KCTC 82274T) and SYSU D00433T (=CGMCC 1.8617T=MCCC 1K04982T=KCTC 82277T), respectively.
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Ácidos Grasos , Fosfolípidos , Ácidos Grasos/química , Filogenia , ARN Ribosómico 16S/genética , Composición de Base , Técnicas de Tipificación Bacteriana , ADN Bacteriano/genética , Análisis de Secuencia de ADN , Bacteroidetes , ChinaRESUMEN
Globally, gastrointestinal cancer is the most widespread neoplastic disease and the primary contributor to cancer-associated fatalities. Gastrointestinal signet ring cell carcinoma (SRCC) exhibits unique distinguishing features in several aspects when compared to adenocarcinomas (ACs). The scarcity of signet ring cell carcinoma has resulted in a heightened significance of related clinical and molecular investigations. However, a comprehensive and systematic review of the clinical, molecular, therapeutic, and research aspects of this disease is currently absent. This review provides an overview of the latest developments in our understanding of the clinical and molecular features of gastrointestinal signet ring cell carcinoma (SRCC). Additionally, we have compiled a list of potential therapeutic targets or biomarkers, as well as an examination of the current treatment options and the possible mechanisms of formation.
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Adenocarcinoma , Carcinoma de Células en Anillo de Sello , Neoplasias Gastrointestinales , Humanos , Neoplasias Gastrointestinales/terapia , Carcinoma de Células en Anillo de Sello/diagnóstico , Carcinoma de Células en Anillo de Sello/patología , BiomarcadoresAsunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Biomarcadores , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Inmunoterapia , Mutación , Biomarcadores de Tumor/genéticaRESUMEN
Hepatocellular carcinoma ranks fourth in cancer-related causes of death worldwide and second in China. Patients with hepatocellular carcinoma (HCC) at the early stage have a better prognosis compared to HCC patients at the late stage. Therefore, early screening for HCC is critical for clinical treatment decisions and improving the prognosis of patients. Ultrasound (US), computed tomography (CT), and serum alpha fetoprotein (AFP) have been used to screen HCC, but HCC is still difficult to be diagnosed in the early stage due to the low sensitivity of the above methods. It is urgent to find a method with high sensitivity and specificity for the early diagnosis of HCC. Liquid biopsy is a noninvasive detection method using blood or other bodily fluids. Cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) are important biomarkers for liquid biopsy. Recently, HCC screening methods using the application of cfDNA and ctDNA have become the hot spot of early HCC diagnostics. In this mini review, we summarize the latest research progress of liquid biopsy based on blood cfDNA in early screening of HCC.
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Carcinoma Hepatocelular , Ácidos Nucleicos Libres de Células , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Ácidos Nucleicos Libres de Células/genética , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Biomarcadores de Tumor/genética , Detección Precoz del Cáncer/métodos , Biopsia Líquida/métodosRESUMEN
This is a phase II study of PD-1 blockade plus chemoradiotherapy as preoperative therapy for patients with locally advanced or borderline resectable pancreatic cancer (LAPC or BRPC, respectively). Twenty-nine patients are enrolled in the study. The objective response rate (ORR) is 60%, and the R0 resection rate is 90% (9/10). The 12-month progression-free survival (PFS) rate and 12-month overall survival (OS) rate are 64% and 72%, respectively. Grade 3 or higher adverse events are anemia (8%), thrombocytopenia (8%), and jaundice (8%). Circulating tumor DNA analysis reveals that patients with a >50% decline in maximal somatic variant allelic frequency (maxVAF) between the first clinical evaluation and baseline have a longer survival outcome and a higher response rate and surgical rate than those who are not. PD-1 blockade plus chemoradiotherapy as preoperative therapy displays promising antitumor activity, and multiomics potential predictive biomarkers are identified and warrant further verification.
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Neoplasias Pancreáticas , Receptor de Muerte Celular Programada 1 , Humanos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/tratamiento farmacológico , Terapia Neoadyuvante , Quimioradioterapia , Supervivencia sin ProgresiónRESUMEN
BACKGROUND: Colorectal cancer (CRC) is the second most common cause of cancer-related death (9.4% of the 9.9 million cancer deaths). However, CRC develops slowly, and early detection and intervention can effectively improve the survival rate and quality of life. Although colonoscopy can detect and diagnose CRC, it is unsuitable for CRC screening in average-risk populations. Some commercial kits based on DNA mutation or methylation are approved for screening, but the low sensitivity for advanced adenoma or early-stage CRC would limit the applications. MAIN RESULTS: Recently, researchers have focused on developing noninvasive or minimally invasive, easily accessible biomarkers with higher sensitivity and accuracy for CRC screening. Numerous reports describe advances in biomarkers, including DNA mutations and methylation, mRNA and miRNA, gut microbes, and metabolites, as well as low-throughput multiomics panels. In small cohorts, the specificity and sensitivity improved when fecal immunochemical testing combined with other biomarkers; further verification in large cohorts is expected. In addition, the continuous improvement of laboratory technology has also improved the sensitivity of detection technology, such as PCR, and the application of CRISPR/Cas technology. Besides, artificial intelligence has extensively promoted the mining of biomarkers. Machine learning was performed to construct a diagnosis model for CRC screening based on the cfDNA fragment features from whole-genome sequencing data. In another study, multiomics markers, including cfDNA, epigenetic, and protein signals, were also discovered by machine learning. Finally, advancements in sensor technology promote the applicability of volatile organic compounds in CRC early detection. CONCLUSION: Here, the authors review advances in early detection and screening of CRC based on different biomarker types. Most studies reported optimistic findings based on preliminary research, and prospective clinical studies are ongoing. These promising biomarkers are expected to more accurately identify early-stage patients with CRC and be applied in the future.
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Ácidos Nucleicos Libres de Células , Neoplasias Colorrectales , Humanos , Estudios Prospectivos , Inteligencia Artificial , Calidad de Vida , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Detección Precoz del Cáncer , ADN , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genéticaRESUMEN
The prognosis of biliary tract cancer (BTC) remains unsatisfactory. This single-arm, phase II clinical trial (ChiCTR2000036652) investigated the efficacy, safety, and predictive biomarkers of sintilimab plus gemcitabine and cisplatin as the first-line treatment for patients with advanced BTCs. The primary endpoint was overall survival (OS). Secondary endpoints included toxicities, progression-free survival (PFS), and objective response rate (ORR); multi-omics biomarkers were assessed as exploratory objective. Thirty patients were enrolled and received treatment, the median OS and PFS were 15.9 months and 5.1 months, the ORR was 36.7%. The most common grade 3 or 4 treatment-related adverse events were thrombocytopenia (33.3%), with no reported deaths nor unexpected safety events. Predefined biomarker analysis indicated that patients with homologous recombination repair pathway gene alterations or loss-of-function mutations in chromatin remodeling genes presented better tumor response and survival outcomes. Furthermore, transcriptome analysis revealed a markedly longer PFS and tumor response were associated with higher expression of a 3-gene effector T cell signature or an 18-gene inflamed T cell signature. Sintilimab plus gemcitabine and cisplatin meets pre-specified endpoints and displays acceptable safety profile, multiomics potential predictive biomarkers are identified and warrant further verification.
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Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/patología , Cisplatino/uso terapéutico , Desoxicitidina/uso terapéutico , GemcitabinaRESUMEN
BACKGROUND: The incidence of lung cancer tends to be younger, and adenocarcinoma is the main histological type. Even patients with the same tumor type may have significant differences in clinical features, tumor microenvironment and genomic background at different ages. Immune checkpoint inhibitors (ICIs) have been shown to improve clinical outcomes in patients with lung adenocarcinoma (LUAD). However, differences in ICI efficacy between older and younger patients are unknown. Our study aimed to explore the relationship between age and immunotherapy in LUAD. METHODS: In our study, 1313 resected LUAD patients in our hospital were divided into young (age ≤ 50) and old groups (age > 50), and the clinical characteristic differences between them were analyzed. Of these, next-generation sequencing (NGS) was performed on the 311 cases. In addition, immune-related signatures of 508 LUAD patients were analyzed by TCGA RNA expression data. Then, we validated genomic and clinical information of 270 LUAD samples in the MSKCC cohort. RESULTS: ERBB2 and EGFR gene mutations were significantly different between the two groups, and the gene mutation number in the old group was significantly higher than that in the young group. In addition, immune-related signatures of LUAD patients were analyzed by TCGA RNA expression data, which indicated that the patients in the old group might have a better immune microenvironment. Then, we validated the MSKCC cohort and found that the TMB of the old group was significantly higher than that of the young group, and the OS of immunotherapy was longer in the old group. CONCLUSION: Our study was the first to analyze the differences in the genomic landscape and immune-related biomarkers between the young and old groups of LUAD patients and found that the old group had a better efficacy of immunotherapy, providing a reference for the study design and treatment of patients with LUAD.
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Adenocarcinoma del Pulmón , Adenocarcinoma , Neoplasias Pulmonares , Humanos , Genómica , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/terapia , Inmunoterapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Adenocarcinoma/genética , Adenocarcinoma/terapia , ARN , Microambiente Tumoral/genéticaRESUMEN
BACKGROUND: Leptomeningeal metastases (LMs) are highly invasive which leads to poor prognosis, but the accurate diagnosis of LM is challenging. It is necessary to investigate more advanced diagnostic methods to realize precision medicine. The main purpose of this study was to select a more effective method for the auxiliary diagnosis of LM by comparing various detection methods. The secondary purpose was to explore the value of cerebrospinal fluid (CSF) tumor markers (TMs) and circulating tumor DNA (ctDNA) testing in guiding clinical treatment. METHODS: TMs in serum and CSF of patients were detected by chemiluminescence. The ctDNA of CSF and plasma were detected by the next-generation sequencing (NGS) technology. RESULTS: In total, 54 tumor patients participated in this study, in which 39 with LM and 15 without LM (8 with parenchymal tumor and 7 without brain metastasis). The results showed that the sensitivity and accuracy of CSF cytology isolated during the first lumbar puncture were 0.31 (95% CI 0.17-0.48) and 0.50 (95% CI 0.36-0.64), respectively. The sensitivity and accuracy of CSF_CEA were 0.71 (95% CI 0.54-0.85) and 0.78 (95% CI 0.64-0.89), which were better than those of CSF_NSE and CSF_CFRA-211. The sensitivity and accuracy of CSF_ctDNA were 0.92 (95% CI 0.79-0.98) and 0.91 (95% CI 0.80-0.97), significantly higher than that of CSF cytology (P < 0.01). The sensitivity and accuracy of CSF_CEA combined with CSF_ctDNA were 0.97 (95% CI, 0.87-1.00) and 0.94 (95% CI 0.85-0.99), which were significantly higher than the traditional methods CSF cytology (P < 0.01). For LM patients with hydrocephalus, the sensitivity of CSF ctDNA even achieved 100% (14/14). CONCLUSION: CSF_CEA combined with CSF_ctDNA could be used to accurately distinguish patients with LM from those with no brain metastasis and from those with parenchymal tumors. CSF_ctDNA testing reveals a unique mutation profile for patients with LM. Dynamic detection of CSF TM and ctDNA can better predict the efficacy and reveal the cause of drug resistance to guide subsequent treatment. CLINICAL TRIAL REGISTRATION: Clinical trial registration number: NCT03029065.
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Neoplasias Encefálicas , ADN Tumoral Circulante , Neoplasias Pulmonares , Carcinomatosis Meníngea , Humanos , Mutación , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Biomarcadores de Tumor/genética , Neoplasias Pulmonares/patologíaRESUMEN
ERBB2 amplification is one of the most important and mature targets for HER2-targeted drug therapy. Somatic mutations of ERBB2 in the tyrosine kinase domain have been studied extensively, and play a role in response to anti-HER2 therapy among different cancer types. However, ERBB2 fusion has not been got attention and its relevance to HER2-targeted therapy is unclear. We comprehensively characterized ERBB2 fusions from next-generation sequencing (NGS) data between May 2018 and October 2021 in 32,131 various solid tumors. Among the tumors, 0.28% harbored ERBB2 fusions, which occurred more commonly in gastroesophageal junction cancer (3.12%; 3/96), breast cancer (1.89%; 8/422), urothelial carcinoma (1.72%; 1/58), and gastric cancer (1.60%; 23/1,437). Our population presented with a median age of 65 years (range 28 to 88 years), a high proportion of men (55 men vs 34 women; 61.80%). Among the patients with ERBB2 fusions, TP53 (82%), APC (18%), and CDK4 (15%) were the top3 co-mutant genes. What's more, most patients with ERBB2 fusion also had ERBB2 amplification (75.28%; 67/89), which was similar to the data in the TCGA database (88.00%; 44/50). Furthermore, TCGA database shows that patients with ERBB2 fusions in pan-cancer had a worse prognosis than those without ERBB2 fusions, as well as in breast cancer. Besides, ERBB2 amplification combined with ERBB2 fusion had worse prognosis than those with only ERBB2 amplification. ERBB2 fusion may interfere the effect of anti-HER2-targeted antibody drugs and influence the prognosis of patients with ERBB2 amplification. Prospective clinical trials are warranted to confirm the results in the future.
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Background: NRAS wildtype melanoma accounts for approximately 80% of melanomas. Previous studies have shown that NRAS wildtype melanoma had higher response rates and better prognoses than NRAS-mutant patients following immunotherapy, while as major actors in tumor cells and tumor microenvironment (TME), the association between NOTCH family genes and response to immunotherapy in NRAS wildtype melanoma remains indistinct. Objective: We aim to explore whether NOTCH family gene variation is associated with genomic factors in immune checkpoint inhibitor (ICI) response in NRAS wildtype melanoma and with clinical results in these patients. Method: This research used genomic data of 265 NRAS wildtype ICI-pretreatment samples from five ICI-treated melanoma cohorts to analyze the relationship between NOTCH family gene mutation and the efficacy of ICI therapy. Results: NRAS wildtype melanomas with NOTCH4-Mut were identified to be associated with prolonged overall survival (OS) in both the discovery (HR: 0.30, 95% CI: 0.11-0.83, P = 0.01) and validation cohorts(HR: 0.21, 95% CI: 0.07-0.68, P = 0.003). Moreover, NOTCH4-Mut melanoma had a superior clinical response in the discovery cohort (ORR, 40.0% vs 13.11%, P = 0.057) and validation cohort (ORR, 68.75% vs 30.07%, P = 0.004). Further exploration found that NOTCH4-Mut tumors had higher tumor mutation burden (TMB) and tumor neoantigen burden (TNB) (P <0.05). NOTCH4-Mut tumors had a significantly increased mutation in the DNA damage response (DDR) pathway. Gene set enrichment analysis revealed NOTCH4-Mut tumor enhanced anti-tumor immunity. Conclusion: NOTCH4 mutation may promote tumor immunity and serve as a biomarker to predict good immune response in NRAS wildtype melanoma and guide immunotherapeutic responsiveness.
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GTP Fosfohidrolasas , Melanoma , Proteínas de la Membrana , Receptor Notch4 , Biomarcadores , GTP Fosfohidrolasas/genética , Humanos , Factores Inmunológicos/uso terapéutico , Inmunoterapia/métodos , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/terapia , Proteínas de la Membrana/genética , Mutación , Receptor Notch4/genética , Microambiente Tumoral/genéticaRESUMEN
Background: Patients with early-stage laryngeal cancer, even stage T1-2N0, are at considerable risk of recurrence and death. The genetic and immunologic characteristics of recurrent laryngeal cancer remain unclear. Methods: A total of 52 T1-2N0 laryngeal cancer patients were enrolled. Of these, 42 tissue samples were performed by targeted DNA sequencing, and 21 cases were performed by NanoString immuno-oncology targeted RNA sequencing to identify the distinct molecular bases and immunologic features associated with relapse in patients with early laryngeal cancer, respectively. Results: To the best to our knowledge, we present for the first time an overview of the genomic mutation spectrum of early-stage laryngeal cancers. A total of 469 genomic alterations were detected in 211 distinct cancer-relevant genes, and the genes found to be mutated in more than five patients (>10%) included tumor protein p53 (TP53, 78.5%), FAT atypical cadherin 1 (FAT1, 26%), LDL receptor related protein 1B (LRP1B, 19%), cyclin dependent kinase inhibitor 2A (CDKN2A, 17%), tet methylcytosine dioxygenase 2 (TET2, 17%), notch receptor 1 (NOTCH1, 12%) and neuregulin 1 (NRG1, 12%). Recurrent laryngeal cancer demonstrated a higher tumor mutation burden (TMB), as well as higher LRP1B mutation and NOTCH1 mutation rates. Univariate and multivariate analyses revealed that high TMB (TMB-H) and NOTCH1 mutation are independent genetic factors that are significantly associated with shorter relapse-free survival (RFS). Simultaneously, the results of the transcriptome analysis presented recurrent tumors with NOTCH1 mutation displayed upregulation of the cell cycle pathway, along with decreased B cells score, T cells score, immune signature score and tumor-infiltrating lymphocytes (TILs) score. The Cancer Genome Atlas (TCGA)-laryngeal cancer dataset also revealed weakened immune response and impaired adhesion functions in NOTCH1-mutant patients. Conclusions: Genomic instability and impaired immune response are key features of the immunosurveillance escape and recurrence of early laryngeal cancer after surgery. These findings revealed immunophenotypic attenuation in recurrent tumors and provided valuable information for improving the management of these high-risk patients. Due to the small number of patients in this study, these differences need to be further validated in a larger cohort.
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Neoplasias Laríngeas , Receptor Notch1 , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Humanos , Inmunidad/genética , Neoplasias Laríngeas/complicaciones , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/cirugía , Mutación , Recurrencia Local de Neoplasia/patología , Receptor Notch1/genética , Receptor Notch1/inmunologíaRESUMEN
BACKGROUND: Pappalysin 2 (PAPPA2) mutation, occurring most frequently in skin cutaneous melanoma (SKCM) and non-small cell lung cancer (NSCLC), is found to be related to anti-tumour immune response. However, the association between PAPPA2 and the efficacy of immune checkpoint inhibitors (ICIs) therapy remains unknown. METHODS: To analyse the performance of PAPPA2 mutation as an indicator stratifying beneficiaries of ICIs, seven public cohorts with whole-exome sequencing (WES) data were divided into the NSCLC set (n = 165) and the SKCM set (n = 210). For further validation, 41 NSCLC patients receiving anti-PD-(L)1 treatment were enrolled in China cohort (n = 41). The mechanism was explored based on The Cancer Genome Atlas database (n = 1467). RESULTS: In the NSCLC set, patients with PAPPA2 mutation (PAPPA2-Mut) demonstrated a significantly superior progress free survival (PFS, hazard ratio [HR], 0.28 [95% CI, 0.14-0.53]; p < 0.001) and objective response rate (ORR, 77.8% vs. 23.2%; p < 0.001) compared to those with wide-type PAPPA2 (PAPPA2-WT), consistent in the SKCM set (overall survival, HR, 0.49 [95% CI: 0.31-0.78], p < 0.001; ORR, 34.1% vs. 16.9%, p = 0.039) and China cohort. Similar results were observed in multivariable models. Accordingly, PAPPA2 mutation exhibited superior performance in predicting ICIs efficacy compared with other published ICIs-related gene mutations, such as EPHA family, MUC16, LRP1B and TTN, etc. In addition, combined utilization of PAPPA2 mutation and tumour mutational burden (TMB) could expand the identification of potential responders to ICIs therapy in both NSCLC set (HR, 0.36 [95% CI: 0.23-0.57], p < 0.001) and SKCM set (HR, 0.51 [95% CI: 0.34-0.76], p < 0.001). Moreover, PAPPA2 mutation was correlated with enhanced anti-tumour immunity including higher activated CD4 memory T cells level, lower Treg cells level, and upregulated DNA damage repair pathways. CONCLUSIONS: Our findings indicated that PAPPA2 mutation could serve as a novel indicator to stratify beneficiaries from ICIs therapy in NSCLC and SKCM, warranting further prospective studies.
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Antineoplásicos Inmunológicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Melanoma , Neoplasias Cutáneas , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/genética , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Melanoma/tratamiento farmacológico , Melanoma/genética , Mutación/genética , Proteína Plasmática A Asociada al Embarazo/genética , Estudios Prospectivos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Melanoma Cutáneo MalignoRESUMEN
Introduction: Chronic obstructive pulmonary disease (COPD) and lung cancer often coexist, but its pathophysiology and genomics features are still unclear. Methods: In this study, we retrospectively collected lung cancer concomitant COPD (COPD-LC) and non-COPD lung cancer (non-COPD-LC) patients, who performed next generation sequencing (NGS) and had clinicopathological information simultaneously. The COPD-LC data from the TCGA cohort were collected to conduct further analysis. Results: A total of 51 COPD-LC patients and 88 non-COPD-LC patients were included in the study. Clinicopathological analysis showed that proportion of male gender, older age, and smoking patients were all substantially higher in COPD-LC group than in non-COPD-LC group (all P<0.01). Comparing the genomic data of the two groups in our cohort, COPD-LC had higher mutation frequency of LRP1B (43% vs 9%, P = 0.001), EPHA5 (24% vs 1%, P = 0.002), PRKDC (14% vs 1%, P = 0.039), PREX2 (14% vs 0%, P = 0.012), and FAT1 (14% vs 0%, P = 0.012), which had a relationship with improved tumor immunity. Immunotherapy biomarker of PD-L1 positive expression (62.5% vs 52.0%, P = 0.397) and tumor mutation burden (TMB, median TMB: 7.09 vs 2.94, P = 0.004) also were higher in COPD-LC. In addition, RNA data from TCGA further indicated tumor immunity increased in COPD-LC. Whereas, COPD-LC had lower frequency of EGFR mutation (19% vs 50%, P = 0.013) and EGFR mutant COPD-LC treated with EGFR-TKI had worse progression-free survival (PFS) (HR = 3.52, 95% CI: 1.27-9.80, P = 0.01). Conclusion: In this retrospective study, we first explored molecular features of COPD-LC in a Chinese population. Although COPD-LC had lower EGFR mutant frequency and worse PFS with target treatment, high PD-L1 expression and TMB indicated these patients may benefit from immunotherapy.