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BACKGROUND: Acral melanoma (AM) is the most common subtype in Chinese melanoma patients with a very poor prognosis. However, our understanding of the disease pathogenesis and molecular landscape is limited by the few studies that have been conducted. Here, we profiled the clinical characteristics, mutational landscapes and tumor immune microenvironment of AM patients to gain insights into disease characteristics and potential treatment strategies. METHODS: A total of 90 AM patients were enrolled and their tissue samples were subjected to next-generation sequencing and multiplexed immunohistochemistry tests. Kaplan-Meier curves and log-rank tests were used to analyze the prognostic potential of various genetic aberrations and immune cell compositions in AM. RESULTS: The median disease-free survival was 21.3 months and estimated median overall survival (OS) was 60 months. More advanced stages, older ages and thickness of greater than 4 mm were associated with worse prognosis in AM patients (HR = 2.57, 95% CI 1.25-5.29, p = 0.01; HR = 2.77, 95% CI 1.22-6.28, p = 0.02; HR = 3.43, 95% CI 1.51-7.82, p < 0.01, respectively), while patients who received post-surgical treatments had better survival (HR = 0.36, 95% CI 0.17-0.76, p = 0.01). The most frequently altered genes included BRAF (14.5%), KIT (16.9%), NRAS (12%), NF1 (10.8%), APC (7.2%), and ARID2 (6%). Copy number variations (CNV) were commonly found in CCND1 (19.3%), CDK4 (19.3%), MDM2 (14.5%) and FGF19 (12%). CDK4 amplifications was independently associated with shorter OS in AM patients (HR = 3.61, 95% CI 1.38-9.46, p = 0.01). CD8 + T cells (p < 0.001) and M1 macrophages (p = 0.05) were more highly enriched in the invasive margin than in the tumor center. Patients with higher levels of M1 macrophage infiltration in the invasive margin derived markedly longer OS (HR = 0.43, 95% CI 0.20-0.95, p = 0.03). Interestingly, in CDK4-amplified patients, there tended to be a low level of M1 macrophage infiltration in the invasive margin (p = 0.06), which likely explains the poor prognosis in such patients. CONCLUSIONS: Our study provided a comprehensive portrait of the clinicopathological features, genetic aberrations and tumor microenvironment profiles in AM patients and identified candidate prognostic factors, which may facilitate development of additional therapeutic options and better inform clinical management of AM patients. Based on these prognostic factors, further studies should focus on enhancing the infiltration of M1 macrophages, especially in CDK4-amplified AM patients.
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Melanoma , Neoplasias Cutâneas , Humanos , Prognóstico , Variações do Número de Cópias de DNA/genética , Microambiente Tumoral/genética , Melanoma/patologia , Neoplasias Cutâneas/genética , Melanoma Maligno CutâneoRESUMO
The conventional treatment strategies for patients with metastatic colorectal cancer (mCRC) are predominantly guided by the status of RAS and BRAF mutations. Although patients may exhibit analogous pathological characteristics and undergo similar treatment regimens, notable disparities in their prognostic outcomes can be observed. Therefore, tissue and plasma samples from 40 mCRC patients underwent next-generation sequencing targeting 425 cancer-relevant genes. Genomic variations and canonical oncogenic pathways were investigated for their prognostic effects in association with progression-free survival (PFS) of these patients. We found that patients with BRCA2 and KMT2A mutations exhibited worse prognostic outcomes after chemotherapy-based treatment (univariate, P < 0.01). Further pathway analysis indicated that alterations in the homologous recombination pathway and in the KMT2A signaling network were also significantly associated with shortened PFS (univariate, P < 0.01). Additionally, mutation signature analysis showed that patients with higher proportions of defective mismatch repair (dMMR)-related mutational signatures. Had a worse prognosis (univariate, P = 0.02). KMT2A mutations (hazard ratio [HR], 4.47; 95% confidence interval [CI], 1-19.93; P =0.050) and dMMR signature proportions (HR, 3.57; 95% CI, 1.42-8.96; P = 0.007) remained independently associated with PFS after multivariate analysis and the results were further externally validated. These findings may enhance our understanding of this disease and may potentially facilitate the optimization of its treatment approaches.
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BACKGROUND: A minority of patients with extensive-stage small cell lung cancer (ES-SCLC) exhibit prolonged survival following first-line chemoimmunotherapy, which warrants the use of reliable biomarkers. Here, we investigated the disparities in genomics and immune cell spatial distribution between long- and short-term survival of patients with ES-SCLC. METHODS: We retrospectively recruited 11 long-term (>2 years) and 13 short-term (<9 months) ES-SCLC survivors receiving first-line chemoimmunotherapy. The samples were processed using targeted next-generation sequencing (tNGS), programmed death ligand-1 staining, multiplex immunohistochemical staining for immune cells (mIHC), tumor mutation burden (TMB), and chromosomal instability score measurements. The expression of putative genes in SCLC at the bulk and single-cell RNA-sequencing levels, as well as the role of putative genes in pan-cancer immunotherapy cohorts, were analyzed. RESULTS: At the genomic level, a greater proportion of the smoking signature and higher TMB (>3.1) were associated with favorable survival. At the single-gene and pathway levels, tNGS revealed that MCL1 and STMN1 amplification and alterations in the apoptosis pathway were more common in short-term survivors, whereas alterations in the DLL3, KMT2B, HGF, EPHA3, ADGRB3, lysine deprivation, and HGF-cMET pathways were observed more frequently in long-term survivors. mIHC analysis of immune cells with different spatial distributions revealed that long-term survivors presented increased numbers of M1-like macrophages in all locations and decreased numbers of CD8+ T cells in the tumor stroma. Bulk transcriptomic analysis demonstrated that high levels of STMN1 and DLL3 represented an immune-suppressive tumor immune microenvironment (TIME), whereas HGF indicated an immune-responsive TIME. The expression levels of our putative genes were comparative in both TP53/RB1 mutant-type and TP53/RB1 wild-type. At the single-cell level, STMN1, MCL1, and DLL3 were highly expressed among all molecular subtypes (SCLC-A, SCLC-N, and SCLC-P), with STMN1 being enriched in cell division and G2M checkpoint pathways. CONCLUSIONS: For ES-SCLC patients receiving first-line chemoimmunotherapy, alterations in DLL3, KMT2B, HGF, EPHA3, and ADGRB3 and a greater proportion of M1-like macrophages infiltration in all locations were predictors of favorable survival, while MCL1 and STMN1 amplification, as well as a greater proportion of CD8+ T cells infiltrating the tumor stroma, predicted worse survival.
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BACKGROUND: Early-onset colorectal cancer (EOCRC) is associated with a poorer prognosis relative to late-onset colorectal cancer (LOCRC), and its incidence has witnessed a gradual escalation in recent years. This necessitates a comprehensive examination of the underlying pathogenesis and the identification of therapeutic targets specific to EOCRC patients. The present study aimed to delineate the distinct molecular landscape of EOCRC by juxtaposing it with that of LOCRC. METHODS: A total of 11 344 colorectal cancer patients, diagnosed between 2003 and 2022, were enrolled in this study, comprising 578 EOCRC cases and 10 766 LOCRC cases. Next-generation sequencing technology was employed to assess the tumor-related mutation and tumor mutation burden (TMB) in these patients. PD-L1 expression was quantified using immunohistochemistry. Microsatellite instability (MSI) was determined via capillary electrophoresis (2B3D NCI Panel). RESULTS: Upon comparing LOCRC with EOCRC patients, the latter group demonstrated a tendency towards advanced TNM stage, lower tumor differentiation, and less favorable histological types. Among LOCRC patients, those with MSI-H status were found to have an earlier TNM stage compared to those with MSI-L/MSS status. Significantly, the incidence of MSI-H was notably higher in EOCRC (10.2%) compared to LOCRC (2.2%). Mutations in the 7-gene panel (ARID1A, FANCI, CASP8, DGFRA, DPYD, TSHR, and PRKCI) were more prevalent in LOCRC. Within the EOCRC cohort, patients with the MSI-H subtype displayed an earlier TNM stage but concurrently exhibited poorer tissue differentiation and a higher frequency of mucinous adenocarcinoma. Among EOCRC patients, FBXW7, FAT1, ATM, ARID1A, and KMT2B mutations were significantly enriched in the MSI-H subgroup. A comparative analysis of MSI-H patients revealed heightened mutation frequencies of FGFBR2, PBRM1, RNF43, LRP1B, FBXW7, ATM, and ARID1A in the EOCRC group. Furthermore, EOCRC patients demonstrated a higher overall TMB, particularly in the MSI-H subtype. PD-L1 expression was elevated in EOCRC and positively associated with MSI status. CONCLUSIONS: This study revealed a significantly higher MSI-H distribution rate in EOCRC, and EOCRC exhibits a distinct mutational signature coupled with higher PD-L1 expression. These findings hold promise in guiding personalized therapeutic strategies for improved disease management in EOCRC patients.
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Idade de Início , Neoplasias Colorretais , Instabilidade de Microssatélites , Mutação , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Estudos de Casos e Controles , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Estadiamento de Neoplasias , Prognóstico , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
In this study, we develop a stacked ensemble model that utilizes cell-free DNA (cfDNA) fragmentomics for the early detection of esophageal squamous cell carcinoma (ESCC). This model incorporates four distinct fragmentomics features derived from whole-genome sequencing (WGS) and advanced machine learning algorithms for robust analysis. It is validated across both an independent validation cohort and an external cohort to ensure its generalizability and effectiveness. Notably, the model maintains its robustness in low-coverage sequencing environments, demonstrating its potentials in clinical settings with limited sequencing resources. With its remarkable sensitivity and specificity, this approach promises to significantly improve the early diagnosis and management of ESCC. This study represents a substantial step forward in the application of cfDNA fragmentomics in cancer diagnostics, emphasizing the need for further research to fully establish its clinical efficacy.
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BACKGROUND: Previous studies have suggested the potential synergistic antitumor activity when combining immune checkpoint inhibitors with anti-angiogenic agents in various solid tumors. We aimed to assess the efficacy and safety of camrelizumab (a humanized programmed cell death-1 antibody) plus apatinib (a vascular endothelial growth factor receptor tyrosine kinase inhibitor) for patients with advanced mucosal melanoma (MM), and explore-related biomarkers. METHODS: We conducted a single-center, open-label, single-arm, phase II study. Patients with unresectable or recurrent/metastatic MM received camrelizumab and apatinib. The primary endpoint was the confirmed objective response rate (ORR). RESULTS: Between April 2019 and June 2022, 32 patients were enrolled, with 50.0% previously received systemic therapy. Among 28 patients with evaluable response, the confirmed ORR was 42.9%, the disease control rate was 82.1%, and the median progression-free survival (PFS) was 8.05 months. The confirmed ORR was 42.9% (6/14) in both treatment-naïve and previously treated patients. Notably, treatment-naïve patients had a median PFS of 11.89 months, and those with prior treatment had a median PFS of 6.47 months. Grade 3 treatment-related adverse events were transaminase elevation, rash, hyperbilirubinemia, proteinuria, hypertension, thrombocytopenia, hand-foot syndrome and diarrhea. No treatment-related deaths were observed. Higher tumor mutation burden (TMB), increased T-cell receptor (TCR) diversity, and altered receptor tyrosine kinase (RTK)/RAS pathway correlated with better tumor response. CONCLUSION: Camrelizumab plus apatinib provided promising antitumor activity with acceptable toxicity in patients with advanced MM. TMB, TCR diversity and RTK/RAS pathway genes were identified as potential predictive biomarkers and warrant further validation. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry, ChiCTR1900023277.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Melanoma , Piridinas , Humanos , Masculino , Feminino , Melanoma/tratamento farmacológico , Melanoma/patologia , Piridinas/uso terapêutico , Piridinas/administração & dosagem , Piridinas/farmacologia , Piridinas/efeitos adversos , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Idoso , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Mucosa/efeitos dos fármacos , Mucosa/patologiaRESUMO
Colorectal cancer (CRC) is frequently diagnosed in advanced stages, highlighting the need for developing approaches for early detection. Liquid biopsy using cell-free DNA (cfDNA) fragmentomics is a promising approach, but the clinical application is hindered by complexity and cost. This study aimed to develop an integrated model using cfDNA fragmentomics for accurate, cost-effective early-stage CRC detection. Plasma cfDNA was extracted and sequenced from a training cohort of 360 participants, including 176 CRC patients and 184 healthy controls. An ensemble stacked model comprising five machine learning models was employed to distinguish CRC patients from healthy controls using five cfDNA fragmentomic features. The model was validated in an independent cohort of 236 participants (117 CRC patients and 119 controls) and a prospective cohort of 242 participants (129 CRC patients and 113 controls). The ensemble stacked model showed remarkable discriminatory power between CRC patients and controls, outperforming all base models and achieving a high area under the ROC curve (AUC) of 0.986 in the validation cohort. It reached 94.88% sensitivity and 98% specificity for detecting CRC in the validation cohort, with sensitivity increasing as cancer progressed. The model also demonstrated consistently high accuracy in within-run and between-run tests and across various conditions in healthy individuals. In the prospective cohort, it achieved 91.47% sensitivity and 95.58% specificity. This integrated model capitalizes on the multiplex nature of cfDNA fragmentomics to achieve high sensitivity and robustness, offering significant promise for early CRC detection and broad patient benefit.
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Germline variations in the DNA polymerase genes, POLE and POLD1, can lead to a hereditary cancer syndrome that is characterized by frequent gastrointestinal polyposis and multiple primary malignant tumors. However, because of its rare occurrence, this disorder has not been extensively studied. In this report, we present the case of a 22-year-old female patient who had been diagnosed with gastrointestinal polyposis, breast fibroadenoma, multiple primary colorectal cancers, and glioblastoma (grade IV) within a span of 4 years. Next-generation sequencing analysis revealed a germline variant in POLD1 (c.1816C>A; p.L606M). In silico analysis using protein functional predicting software, including SIFT, Polyphen, GERP++, and CADD, further confirmed the pathogenicity of POLD1 p.L606M (classified as ACMG grade Class 4). In line with polymerase deficiency, both rectal cancer and glioblastoma tissues exhibited a high tumor mutation burden, with 16.9 muts/Mb and 347.1 muts/Mb, respectively. Interestingly, the patient has no family history of cancer, and gene examination of both parents confirms that this is a de novo germline variant. Therefore, molecular screening for POLD1 may be necessary for patients with such a cancer spectrum, regardless of their family history.
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Introduction: Immune checkpoint inhibitors (ICI) have changed the treatment of non-small cell lung cancer (NSCLC). Furthermore, compared with monotherapy, ICI combination therapy had better efficacy and partly different mechanism. Therefore, we aim to investigate and improve biomarkers specialized for ICI combination therapy. Methods: We enrolled 53 NSCLC patients treated with ICI combination therapy and collected their tissue and plasma samples to perform next-generation sequencing (NGS) with a 425-gene panel. Results: The line of treatment was the only clinical factor significantly affecting objective response rate (ORR) and progression-free survival (PFS). Surprisingly, classical markers PD-L1 and TMB only had limited predictive values in the ICI combination therapy. Instead, we found RB1 mutation was significantly associated with prognosis. Patients with mutated RB1 had shorter PFS than those with wild RB1 (134d vs 219d, p=0.018). Subsequent analysis showed the RB1 related mutated cell cycle and chromosomal instability were also deleterious to prognosis (103d vs 411d, p<0.001; 138d vs 505d, p=0.018). Additionally, patients with more circulating tumor DNA (ctDNA) had significantly shorter PFS (41d vs 194d, p=0.0043). Conclusion: This study identified that NSCLC patients with mutated RB1 were less sensitive to ICI combination therapy. RB1 mutations and following cell cycle abnormalities and chromosomal instability can potentially guide clinical management.
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Background: Lung cancer is the deadliest and most diagnosed type of cancer worldwide. The 5-year survival rate of lung adenocarcinoma (LUAD) dropped significantly when tumor stages advanced. Patients who received surgically resecting at the pre-invasive stage had a 5-year survival rate of nearly 100%. However, the study on the differences in gene expression profiles and immune microenvironment among pre-invasive LUAD patients is still lacking. Methods: In this study, the gene expression profiles of three pre-invasive LUAD stages were compared using the RNA-sequencing data of 10 adenocarcinoma in situ (AIS) samples, 12 minimally invasive adenocarcinoma (MIA) samples, and 10 invasive adenocarcinoma (IAC) samples. Results: The high expression levels of PTGFRN (Hazard Ratio [HR] = 1.45; 95% Confidence Interval [CI]: 1.08-1.94; log-rank P = 0.013) and SPP1 (HR = 1.44; 95% CI: 1.07-1.93; log-rank P = 0.015) were identified to be associated with LUAD prognosis. Moreover, the early LUAD invasion was accompanied by the enhancement of antigen presentation ability, reflected by the increase of myeloid dendritic cells infiltration rate (Cuzick test P < 0.01) and the upregulation of seven important genes participating in the antigen presentation, including HLA-A (Cuzick test P = 0.03), MICA (Cuzick test P = 0.01), MICB (Cuzick test P = 0.01), HLA-DPA1 (Cuzick test P = 0.04), HLA-DQA2 (Cuzick test P < 0.01), HLA-DQB1 (Cuzick test P = 0.03), and HLA-DQB2 (Cuzick test P < 0.01). However, the tumor-killing ability of the immune system was inhibited during this process, as there were no rising cytotoxic T cell activity (Cuzick test P = 0.20) and no increasing expression in genes encoding cytotoxic proteins. Conclusion: In all, our research elucidated the changes in the immune microenvironment during early-stage LUAD evolution and may provide a theoretical basis for developing novel early-stage lung cancer therapeutic targets.
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BACKGROUND: The standard neoadjuvant treatments in patients with esophageal squamous cell carcinoma (ESCC) still have either poor safety or efficacy. Better therapies are needed in China. METHODS: This was an open-label, single-arm, phase 2 trial. Patients with potentially resectable ESCC (cT1b-3, Nany, M0 or T4a, N0-1, or M0) received preoperative intravenous sintilimab plus triplet chemotherapy (liposomal paclitaxel, cisplatin, and S-1) every 3 weeks for two cycles. The primary endpoints were safety and surgical feasibility; the secondary endpoint was major pathological response (MPR) rate. Genomic biomarkers (genetic mutations, tumor mutational burden (TMB), circulating tumor DNA status and immune microenvironment) in baseline tumor samples were investigated. RESULTS: All 30 patients completed two cycles of neoadjuvant treatment and underwent surgical resection. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 36.7% (11/30) of patients. The most frequent TRAEs were decreased white cell count (76.7%), anemia (76.7%), and decreased neutrophil count (73.3%). All TRAEs were hematological toxicities; none caused ≥30 days surgical delay. The MPR and pathological complete response (pCR) rates were 50.0% (15/30; 95% CI 33.2 to 66.9) and 20.0% (6/30; 95% CI 9.5 to 37.3), respectively. Patients with higher TMB and more clonal mutations were more likely to respond. ERBB2 alterations and ctDNA high-releaser status have a negative correlation with neoadjuvant ICI response. No significant difference was observed between therapeutic response and tumor immune microenvironment. CONCLUSIONS: Neoadjuvant sintilimab plus platinum-based triplet chemotherapy appeared safe and feasible, did not delay surgery and induced a pCR rate of 20.0% in patients with potentially resectable ESCC. TRIAL REGISTRATION NUMBER: NCT03946969.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/terapia , Terapia Neoadjuvante/efeitos adversos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Microambiente TumoralRESUMO
To characterize the spectrum of mosaic RB1 pathogenic alleles and map the distribution of mutant cells in available tissues from mosaic patients. Next-generation sequencing was performed on blood samples from 263 retinoblastoma families to identify mosaic RB1 variant alleles. A variety of available tissues were sampled to determine tissue distribution and fraction of mutant cells in five mosaic patients who consented to participate in mosaic pathogenic allele research. Twelve identified mosaic RB1 variants were all "null" pathogenic alleles and displayed reduced expressivity. The use of next-generation deep sequencing increased the sensitivity of mosaicism detection to 0.03% in the case of tissue DNA. In the five mosaic participants, we observed coherent but uneven, bilateral asymmetrical distribution of mutant cells across various tissues. They all carried early-embryonic mosaic pathogenic alleles and had significantly higher variant fractions in blood than in other tissues. Variant fractions of ipsilateral tissue samples were not concordant higher or lower compared with the contralateral side. Only ipsilateral conjunctival and oral epithelial cells showed concordance in mosaicism levels. No associations were observed between the laterality of affected eyes and variant fractions of any tissue type. NGS allows the detection of low-level mosaicism. Mosaic RB1 pathogenic alleles are prone to occur at very early stages of human embryonic development. With respect to genetic counseling, risk prediction should take into account unrecognized mosaicism. The underlying tissue distribution patterns of mosaic RB1 variant alleles remain to be determined.
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Neoplasias da Retina , Retinoblastoma , Humanos , Alelos , Sequenciamento de Nucleotídeos em Larga Escala , Mosaicismo , Neoplasias da Retina/genética , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Proteínas de Ligação a Retinoblastoma/genética , Distribuição Tecidual , Ubiquitina-Proteína Ligases/genéticaRESUMO
Background: Neoadjuvant chemotherapy (NAC) has been expanded to hormone receptor (HR) positive breast cancer (BC) patients with operable disease, to increase the likelihood of breast-conserving surgery. Genomic profiling at baseline would reveal NAC response relevant genomic features and signaling pathways, guiding clinical NAC utilization based on patients' genomic characteristics. Methods: We prospectively studied stage II/III BC patients who were eligible for breast-conserving surgery. Patients received epirubicin and cyclophosphamide for 4 cycles, followed by another 4-cycle docetaxel, and human epidermal growth factor receptor (HER2) positive patients were additionally treated with herceptin when using docetaxel (EC-T(H)). NAC responses were evaluated as pathologic complete response (pCR) or non-pathologic complete response (non-pCR). Genomic features related to NAC responses were identified by profiling baseline tumor tissues sampled one day before NAC, using whole-exome sequencing. Differentially expressed genes and up-/down-regulated pathways were investigated by performing RNA-sequencing. Results: A total of 25 stage II/III BC patients were enrolled, including 5 patients ultimately evaluated as pCR and 20 patients evaluated as non-pCR. PIK3CA (48%) and TP53 (40%) mutations were enriched in patients not achieving pCR. Mutated phosphatidylinositol-3-kinase-AKT (PI3K-AKT) pathway and homologous recombinational repair pathway were also more frequently observed in patients evaluated as non-pCR. Significant arm-level amplifications (8q24.23 and 17q12) and deletions (1p32.2, 4p14, 7q11.23, 10q21.3, 11q23.3, etc.) were identified among patients not achieving pCR, while patients achieving pCR displayed no significant copy number alterations. Significantly up-regulated expression of PI3K-AKT pathway genes was also detected among patients failed to achieve pCR, compared to patients achieving pCR. Conclusion: Compared to BC patients achieving pCR to NAC, aberrant activation of PI3K-AKT pathway genes were more frequently observed in patients not achieving pCR, consistent with the significant up-regulation of PI3K-AKT pathway gene expression in the non-pCR subgroup. Together, these findings indicate that upregulated PI3K-AKT pathway serves as a potential indicator of lack of response to NAC in stage II/III BC patients, and other effective therapeutic options are urgently needed for those resistant patients.
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EGFR exon 20 insertions (EGFR e20ins) account for up to 10% of EGFR mutations in lung cancer; however, tumors with EGFR e20ins had poor response rates to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib, erlotinib, afatinib, and osimertinib, and the heterogeneity of EGFR e20ins further complicates the clinical studies. Here, we retrospectively screened next-generation sequencing (NGS) data from 24 468 lung cancer patients, and a total of 85 unique EGFR e20ins variants were identified in 547 cases (2.24%), with p.A767_V769dup (25.1%) and p.S768_D770dup (17.6%) being the most prevalent ones. Comprehensive genomic profiling revealed that TP53 mutations frequently coexisted with p.H773dup (77.8%, P = 0.0558) and p.A767_V769dup (62.8%, P = 0.0325), while RB1 mutations usually co-occurred with p.H773_V774insAH (33.3%, P = 0.0551), implying that different EGFR e20ins variants might require distinct genomic context for tumorigenesis and/or maintenance. Despite that treatment regimens were highly diverse for EGFR e20ins-positive patients, we observed an overall response rate of 14% and a disease control rate (DCR) of 38.4% in 65 patients who received at least one EGFR TKI. The progression-free survival (PFS) differs significantly in six representative EGFR e20ins variants (P = 0.017), and EGFR p.A763_Y764insFQEA was associated with better PFS than other EGFR e20ins when treating with various EGFR TKIs. Some EGFR e20ins variants showed at least partial response to first-generation EGFR TKIs, including p.A767_V769dup, p.S768_D770dup, p.N771_H773dup, p.A763_Y764insFQEA, and p.D770_N771insG. Poziotinib achieved higher DCR for p.S768_D770dup than for p.A767_V769dup, whereas osimertinib showed limited effects for these two insertions when used as the first-line treatment. Overall, our results demonstrated that EGFR e20ins were highly diversified in terms of insertion patterns and co-occurring mutations and these EGFR e20ins variants showed different clinical responses to various EGFR TKIs, suggesting the clinical importance of selecting proper EGFR TKI treatment based on the specific EGFR e20ins type.
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Povo Asiático/genética , Éxons/genética , Variação Genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutagênese Insercional/genética , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/farmacologiaRESUMO
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.
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BACKGROUND: While there have been encouraging preliminary clinical results for immune checkpoint inhibitors (ICIs) in BTCs, it remains a challenge to identify the subset of patients who may benefit. In this study, we evaluated the efficacy of ICI treatment in patients with advanced BTCs, and explored potential biomarkers that are predictive of response. METHODS: The study enrolled 26 patients with advanced microsatellite stable BTCs (15 with gallbladder cancers [GCs] and 11 with intrahepatic cholangiocarcinoma [ICCs]) who received ICI treatment. Targeted next-generation sequencing (NGS) was performed on tumor tissue samples collected from 17 patients. Clinical and genomic characteristics were assessed for the correlation with clinical outcome. RESULTS: Analysis of the baseline clinical characteristics showed that performance score (PS) of 0 was associated with a better prognosis than PS of 1 (HR = 1.08 × 109 ; 95% CI, 0â¼Inf; P = .002). No significant correlations were found between clinical outcome and inflammation-related indicators. NGS profiling of the available tumor tissues, revealed largely non-overlapping somatic alterations between GCs and ICCs. Mutations in LRP1B (HR = 0.26; 95% CI, 0.06-1.21; P = .067), ERBB2 (HR = 0.15; 95% CI, 0.02-1.19; P = .04), or PKHD1 (HR < 0.01; 95% CI, 0-Inf; P = .04) showed strong association with increased progression-free survival (PFS) benefit. Subsequent analysis showed that alterations in the RTK-RAS pathway were associated with improved outcomes (HR = 0.12; 95% CI, 0.02-0.63; P = .003). Tumor mutation burden (TMB) was higher in patients with GC than those with ICC, and was associated with LRP1B mutations (P = .032). We found that patients with 19q amplification (19q Amp) and 9p deletion (9p Del) had poor PFS outcome (19q Amp, HR = 15.4; 95% CI, 2.7-88.5; P < .001; 9p Del; HR = 4.88 × 109 ; 95% CI, 0-Inf; P < .001), while those with chromosomal instability derived PFS benefit (HR = 0.24; 95% CI, 0.05-1.17; P = .057). CONCLUSION: Our study identified several potential clinical and genomic features that may serve as biomarkers of clinical response to ICIs in advanced BTCs patients. A larger sample size is required for further verification.
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PURPOSE: Immune checkpoint inhibitors (ICI) have revolutionized cancer management. However, molecular determinants of response to ICIs remain incompletely understood. EXPERIMENTAL DESIGN: We performed genomic profiling of 78 patients with non-small cell lung cancer (NSCLC) who underwent anti-PD-(L)1 therapies by both whole-exome and targeted next-generation sequencing (a 422-cancer-gene panel) to explore the predictive biomarkers of ICI response. Tumor mutation burden (TMB), and specific somatic mutations and copy-number alterations (CNA) were evaluated for their associations with immunotherapy response. RESULTS: We confirmed that high TMB was associated with improved clinical outcomes, and TMB quantified by gene panel strongly correlated with WES results (Spearman's ρ = 0.81). Compared with wild-type, patients with FAT1 mutations had higher durable clinical benefit (DCB, 71.4% vs. 22.7%, P = 0.01) and objective response rates (ORR, 57.1% vs. 15.2%, P = 0.02). On the other hand, patients with activating mutations in EGFR/ERBB2 had reduced median progression-free survival (mPFS) compared with others [51.0 vs. 70.5 days, P = 0.0037, HR, 2.47; 95% confidence interval (CI), 1.32-4.62]. In addition, copy-number loss in specific chromosome 3p segments containing the tumor-suppressor ITGA9 and several chemokine receptor pathway genes, were highly predictive of poor clinical outcome (survival rates at 6 months, 0% vs. 31%, P = 0.012, HR, 2.08; 95% CI, 1.09-4.00). Our findings were further validated in two independently published datasets comprising multiple cancer types. CONCLUSIONS: We identified novel genomic biomarkers that were predictive of response to anti-PD-(L)1 therapies. Our findings suggest that comprehensive profiling of TMB and the aforementioned molecular markers could result in greater predictive power of response to ICI therapies in NSCLC.