This case report describes a patient initially diagnosed with Gaucher disease (GD) with type I with homozygous mutation c.1448T > C p. (Leu483Pro) at age of 2, presenting with hepatosplenomegaly and cytopenia. Imiglucerase replacement therapy was initiated. At age 17, bilateral hearing loss developed, with subsequent Cranial MRI revealing thalamic damage, leading to a reclassification as type 3 GD. By age of 20, the patient presented with a range of symptoms, including abdominal pain, diarrhea, hypoproteinemia, multiple lymphadenopathy, edema, and Gaucher cell infiltration in the lymph nodes. Comprehensive diagnosis identifies Gaucher tumor and protein-losing enteropathy. Imiglucerase therapy at 90-120 U/kg every 2 weeks significantly improved clinical symptoms, emphasizing the importance of tailored interventions for managing GD manifestations.
Background: Esophageal cancer (EC) is an aggressive malignant tumor with poor prognosis and high incidence. It is the sixth leading cause of cancer-related death in the world, and the 5-year overall survival (OS) rate is only 12-20%. The rapid development of next-generation sequencing (NGS) has provided powerful help for the treatment and management of EC patients. Methods: Tumor tissue and blood samples of 43 Chinese patients with nonsurgical esophageal squamous cell carcinoma (ESCC) were sequenced using a 425 gene-panel. Genomic profiling was explored and and the Cox proportional hazards model was used to analyze the correlations between gene or signaling pathway alterations and prognosis. Results: In this study, the most common mutated genes were TP53 (90.5%), CCND1 (45.2%), FGF19 (38.1%), NOTCH1 (26.2%), PI3KCA (21.4%) and CDKN2A (19%). Among these mutations, PI3KCA and NOTCH1 showed mutual exclusion to some extent. In the univariate model, mutations in NOTCH1, CBLB and TSC2 genes and tumor mutation burden (TMB) ≥7 were independent biomarkers of OS. NOTCH1 (P=0.007, HR =2.87), CBLB (P=0.011, HR =4.68) and TSC2 (P=0.024, HR =3.7) were significantly associated with poorer OS, and patients with TMB ≥7 had longer OS (P=0.151, HR =0.31). In addition, patients who carried alteration in NOTCH signaling pathway had reduced OS (P=0.014, HR =2.54). Conclusions: NOTCH1, CBLB and TSC2 alterations were found to be potential indicators of poor prognosis in patients with ESCC. TMB was also positively correlated with the OS of ESCC patients, providing valuable insights for their treatment strategies.
BACKGROUND: Patients with peritoneal metastasis (PM) from gastric cancer (GC) exhibit poor prognosis. Chemoimmunotherapy offers promising clinical benefits; however, its efficacy and predictive biomarkers in a conversion therapy setting remain unclear. The authors aimed to retrospectively evaluate chemoimmunotherapy efficacy in a conversion therapy setting for GC patients with PM and establish a prediction model for assessing clinical benefits. MATERIALS AND METHODS: A retrospective evaluation of clinical outcomes encompassed 55 GC patients with PM who underwent chemoimmunotherapy in a conversion therapy setting. Baseline PM specimens were collected for genomic and transcriptomic profiling. Clinicopathological factors, gene signatures, and tumor immune microenvironment were evaluated to identify predictive markers and develop a prediction model. RESULTS: Chemoimmunotherapy achieved a 41.8% objective response rate and 72.4% R0 resection rate in GC patients with PM. Patients with conversion surgery showed better overall survival (OS) than those without the surgery (median OS: not reached vs 7.82 m, P<0.0001). Responders to chemoimmunotherapy showed higher ERBB2 and ERBB3 mutation frequencies, CTLA4 and HLA-DQB1 expression, and CD8+ T cell infiltration, but lower CDH1 mutation and naïve CD4+ T cell infiltration, compared to nonresponders. A prediction model was established integrating CDH1 and ERBB3 mutations, HLA-DQB1 expression, and naïve CD4+ T cell infiltration (AUC=0.918), which were further tested using an independent external cohort (AUC=0.785). CONCLUSION: This exploratory study comprehensively evaluated clinicopathological, genomic, and immune features and developed a novel prediction model, providing a rational basis for the selection of GC patients with PM for chemoimmunotherapy-involved conversion therapy.
Anti-programmed cell death 1 immuno-monotherapy has become the second-line standard treatment for advanced esophageal squamous cell carcinoma (ESCC) after the failure of first-line chemotherapy. However, new biomarkers are still needed to identify patients at risk of tumor progression and to select patients with advanced ESCC who are likely to benefit from immunotherapy. A total of 12 patients with advanced ESCC treated with tislelizumab were prospectively enrolled and endoscopic biopsy samples were collected. Plasma was obtained prior to and after every 2-3 treatment cycles with tislelizumab and when disease progression occurred. Targeted sequencing of 425 genes from plasma cell-free DNA, DNA from leukocytes and fixed esophageal tumor biopsies was performed. The patients underwent imaging analyses every 6-8 weeks until disease progression. The association between status of circulating tumor DNA (ctDNA) or changes in ctDNA following tislelizumab immunotherapy and response, tumor progression and survival was determined. All patients had evaluable next-generation sequencing results at the time of analysis. The results showed that patients with ESCC with liver metastasis had a significantly shorter median progression-free survival (mPFS: 1.4 vs. 11.7 months; P=0.037). TSC complex subunit 2 [11.7 months vs. not reached (NR); P=0.004] and zinc finger protein 217 (11.7 months vs. NR; P=0.022) gene mutations were the independent and negative prognostic factors for median overall survival (OS), respectively. Of note, ctDNA dynamic changes expressed as ∆ mutant molecules per milliliter of plasma (∆MMPM; MMPM detected at the first monitoring time-point after the first infusion of tislelizumab as baseline MMPM) predicted progression-free survival (PFS) and OS more accurately compared to the ctDNA change of an individual gene. ∆MMPM <20% was an independent predictor of PFS (2.8 vs. 14.6 months; P=0.029), although there was no significant difference for OS (16.7 vs. 17.6 months; P=0.830). In conclusion, changes in ctDNA levels were associated with anti-tumor effects, progression and disease-specific survival. ctDNA sequencing is promising for predicting response and progression after tislelizumab immunotherapy as second-line monotherapy for advanced ESCC [the present study was part of the RATIONALE-302 study (ClinicalTrials.gov identifier no. NCT03430843; 29.01.2018)].
PURPOSE: The effect of genomic factors on the response of patients with esophageal squamous cell carcinoma (ESCC) to neoadjuvant chemoradiotherapy (nCRT), as well as how nCRT influences the genome and transcriptome of ESCC, remain largely unknown. METHODS AND MATERIALS: In total, 137 samples from 57 patients with ESCC undergoing nCRT were collected and subjected to whole-exome sequencing and RNA sequencing analysis. Genetic and clinicopathologic factors were compared between the patients achieving pathologic complete response and patients not achieving pathologic complete response. Genomic and transcriptomic profiles before and after nCRT were analyzed. RESULTS: Codeficiency of the DNA damage repair and HIPPO pathways synergistically sensitized ESCC to nCRT. nCRT induced small INDELs and focal chromosomal loss concurrently. Acquired INDEL% exhibited a decreasing trend with the increase of tumor regression grade (P = .06, Jonckheere's test). Multivariable Cox analysis indicated that higher acquired INDEL% was associated with better survival (adjusted hazard ratio [aHR], 0.93; 95% CI, 0.86-1.01; P = .067 for recurrence-free survival [RFS]; aHR, 0.86; 95% CI, 0.76-0.98; P = .028 for overall survival [OS], with 1% of acquired INDEL% as unit). The prognostic value of acquired INDEL% was confirmed by the Glioma Longitudinal AnalySiS data set (aHR, 0.95; 95% CI, 0.902-0.997; P = .037 for RFS; aHR, 0.96; 95% CI, 0.917-1.004; P = .076 for OS). Additionally, clonal expansion degree was negatively associated with patient survival (aHR, 5.87; 95% CI, 1.10-31.39; P = .038 for RFS; aHR, 9.09; 95% CI, 1.10-75.36; P = .041 for OS, with low clonal expression group as reference) and also negatively correlated with acquired INDEL% (Spearman ρ = -0.45; P = .02). The expression profile was changed after nCRT. The DNA replication gene set was downregulated, while the cell adhesion gene set was upregulated after nCRT. Acquired INDEL% was negatively correlated with the enrichment of the DNA replication gene set (Spearman ρ = -0.56; P = .003) but was positively correlated with the enrichment of the cell adhesion gene set (Spearman ρ = 0.40; P = .05) in posttreatment samples. CONCLUSIONS: nCRT remodels the genome and transcriptome of ESCC. Acquired INDEL% is a potential biomarker to indicate the effectiveness of nCRT and radiation sensitivity.
Background: The circulating predictive factors for the outcomes of advanced non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs) remain elusive. We aimed to assess the predictive value of circulating cytokines for outcomes. Methods: Serum samples of 102 advanced-stage NSCLC patients who underwent immunotherapy were collected at baseline. The relative levels of 37 cytokines were detected. PD-L1 expression was also analyzed. Results: Higher serum CXCL12 levels (top 33%) were a poor predictive biomarker for durable clinical benefit (DCB) (23.5% vs. 72.1%, p<0.001), progression-free survival (PFS) (3.76 vs. 14.40 months; p<0.001) and overall survival (OS) (12.20 vs. 44.84 months; p=0.008). Compared with PD-L1-negative patients, PD-L1-positive patients had a significantly higher objective response rate (ORR) (70.0% vs. 28.8%, p<0.001) and a prolonged mPFS (25.35 vs. 4.64 months, p=0.003) and tended to have an increased mOS (44.84 vs. 20.42 months, p=0.087). A signature comprising PD-L1<1% and the top 33% CXCL12 level was associated with the lowest ORR (27.3% vs. 73.7%, p<0.001) and DCB (27.3% vs. 73.7%, p<0.001) and the worst mPFS (2.44 vs. 25.35 months, p<0.001) and mOS (11.97 vs. 44.84 months, p=0.007). Area under the curve (AUC) analyses of PD-L1 expression, CXCL12 level and PD-L1 expression plus CXCL12 level to predict DCB or no durable benefit (NDB) showed AUC values of 0.680, 0.719 and 0.794, respectively. Conclusion: Our findings suggest that serum cytokine CXCL12 levels can predict the outcomes of patients with NSCLC receiving ICI. Moreover, the combination of CXCL12 levels and PD-L1 status can predict outcomes with a significantly improved discriminatory power.
Antineoplastic Agents, Immunological , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Immune Checkpoint Inhibitors/therapeutic use , B7-H1 Antigen/metabolism , Cytokines/therapeutic use , Antineoplastic Agents, Immunological/pharmacology , Biomarkers, Tumor , Chemokine CXCL12
HER2-positive gastric cancer (GC) makes up 15-20% of all GC incidences, and targeted therapy with trastuzumab is the standard of treatment. However, the mechanisms of resistance to trastuzumab are still not fully understood and presents a significant challenge in clinical practice. In this study, whole exome sequencing (WES) was performed on paired tumor tissues before trastuzumab treatment (at baseline) and at progressive disease (PD) in 23 GC patients. Clinicopathological and molecular features that may be associated with primary and/or acquired resistance to trastuzumab were identified. Lauren classification of intestinal type was associated with a more prolonged progression-free survival (PFS) than diffuse type (HR = 0.29, P = 0.019). Patients with low tumor mutation burden (TMB) showed significantly worse PFS, while high chromosome instability (CIN) was correlated with prolonged OS (HR = 0.27; P = 0.044). Patients who responded to treatment had a higher CIN than nonresponders, and a positive trend towards increasing CIN was observed as response improved (P = 0.019). In our cohort, the most common genes to acquire mutations are AURKA, MYC, STK11, and LRP6 with four patients each. We also discovered an association between clonal branching pattern and survival, with an extensive clonal branching pattern being more closely related to a shorter PFS than other branching patterns (HR = 4.71; P = 0.008). We identified potential molecular and clinical factors that provide insight regarding potential association to trastuzumab resistance in advanced HER2-positive GC patients.
Background: KMT2D mutation (KMT2DMT) was found to play an important role in cancer immunity and response to immune checkpoint inhibitors (ICIs). The present study aims to investigate the association between KMT2D exon 39 mutation (K-ex39MT) and molecular and clinical characteristics in colorectal adenocarcinoma (CRAD). Methods: We performed profiling of KMT2DMT and K-ex39MT via Kaplan-Meier analysis, cBioportal, Immune-related functional analysis and correlation analysis with TCGA and MSK cohorts to explore their effects on the prognosis, immune landscape, molecular characteristics and drug sensitivity in CRAD. Panel gene sequencing of 30 in-house CRAD tissues and multiple immunofluorescences (mIF) were also used. Results: In multi-cancer, patients with KMT2DMT have a worse overall survival (OS), and CRAD with K-ex39MT exhibited a greater degree of immune cellular infiltration. For CRAD, compared with KMT2D exon39 wild type (K-ex39WT), K-ex39MT patients had higher tumor mutational burden (TMB) and lower copy number alteration (CNA), and were accompanied by more immune cell infiltration including activated T cells, NK cells, Treg cells and exhausted T cells and enrichment of immune-related genes and pathways. In drug sensitivity prediction, K-ex39MT patients have a lower CTX-S score and IC50 of 5-Fluorouracil and irinotecan, and higher Tumor Immune Dysfunction and Rejection (TIDE) dysfunction score. Conclusions: CRAD patients with K-ex39MT have more abundant immune cell infiltration and enrichment of immune-related pathways and signatures. And they may be more sensitive to some chemotherapies but less to cetuximab.
Background: Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like (LFL) syndrome are rare hereditary diseases characterized by predisposition to a diverse spectrum of cancer types, primarily sarcoma. The pathogenic variants underlying the majority of LFL cases remain to be explored. Methods: We performed whole-exome sequencing (WES) on 13 core members of a large LFL family with highly aggregated incidences of cancers, including cases with sarcoma, non-small cell lung cancer and cardiac angiosarcoma, and conducted a comprehensive literature review of candidate gene associations in LFS/LFL syndromes or sarcoma to identify potential pathogenic germline variants. Results: No germline variants in the best-known LFL/LFS-associated gene TP53 were detected. Of all the genes associated with LFS/LFL or sarcoma that we have surveyed, we identified a novel p.P35L germline variant in POT1 (protection of telomeres 1). Germline and somatic alterations in POT1 have been implicated in a series of familial cancers, including angiosarcoma, glioma, melanoma and colorectal cancer. This particular variant is located in the telomere-binding OB1 domain, which is important in maintaining the proper telomere length, and showed high conservation across different POT1 orthologues. No record of the variant was found in any of the 1000 genomes, ExAC, gnomAD, dpSNP and COSMIC databases. Prediction algorithms and in silico structural analysis suggested completely disrupted protein structure and function of POT1 in the presence of this mutation. Conclusions: Leveraging WES, we identified a novel germline risk allele, p.P35L in POT1, that likely predisposes to LFL syndrome. Our results support the routine testing of POT1 and other LFL/LFS-associated genes in the risk populations to enable early cancer diagnosis, prevention and intervention.
Glutamine synthetase (GS) catalyzes de novo synthesis of glutamine that facilitates cancer cell growth. In the liver, GS functions next to the urea cycle to remove ammonia waste. As a dysregulated urea cycle is implicated in cancer development, the impact of GS's ammonia clearance function has not been explored in cancer. Here, we show that oncogenic activation of ß-catenin (encoded by CTNNB1) led to a decreased urea cycle and elevated ammonia waste burden. While ß-catenin induced the expression of GS, which is thought to be cancer promoting, surprisingly, genetic ablation of hepatic GS accelerated the onset of liver tumors in several mouse models that involved ß-catenin activation. Mechanistically, GS ablation exacerbated hyperammonemia and facilitated the production of glutamate-derived nonessential amino acids, which subsequently stimulated mechanistic target of rapamycin complex 1 (mTORC1). Pharmacological and genetic inhibition of mTORC1 and glutamic transaminases suppressed tumorigenesis facilitated by GS ablation. While patients with hepatocellular carcinoma, especially those with CTNNB1 mutations, have an overall defective urea cycle and increased expression of GS, there exists a subset of patients with low GS expression that is associated with mTORC1 hyperactivation. Therefore, GS-mediated ammonia clearance serves as a tumor-suppressing mechanism in livers that harbor ß-catenin activation mutations and a compromised urea cycle.
Glutamate-Ammonia Ligase , Liver Neoplasms , Animals , Mice , Glutamate-Ammonia Ligase/genetics , Glutamate-Ammonia Ligase/metabolism , beta Catenin/genetics , beta Catenin/metabolism , Mechanistic Target of Rapamycin Complex 1/genetics , Mechanistic Target of Rapamycin Complex 1/metabolism , Ammonia/metabolism , Nitrogen/metabolism , Liver Neoplasms/metabolism , Liver/metabolism , Glutamine/metabolism , Homeostasis , Urea/metabolism
Objective: The aim of this study is to determine the clinical efficacy of bile-derived liquid biopsy compared with plasma and tumor tissue biopsy in patients with biliary tract carcinoma (BTC). Methods: A total of 13 patients with BTC were enrolled in this cohort. Tumor tissue, bile, and plasma samples were obtained and analyzed using next-generation sequencing for genomic profiling. Results: Bile and plasma samples were collected from all 13 patients, and 11 patients also had matched tumor tissues available. The cell-free DNA (cfDNA) concentration was significantly higher in the bile supernatant than in plasma (median: 1918 vs. 63.1 ng/ml, p = 0.0017). The bile supernatant and pellet had a significantly higher mean mutation allele frequency (MF) than plasma (median: 3.84% vs. 4.22% vs. 0.16%; p < 0.001). Genomic alterations were predominantly missense. Both bile supernatant and pellet had significantly more genomic alterations than plasma (average: 9.3 vs. 7.2 vs. 2.3 alterations per sample; p < 0.01). Among the top 10 most frequent genomic alterations, the consistency between bile supernatant and tumor tissue was 90.00% (18/20), that between bile pellet and tumor tissue was 85.00% (17/20), and that between the plasma and tissue was only 35.00% (7/20). MAF of both bile supernatant and pellet was positively correlated with that in tissue samples (ρ < 0.0001, spearman r = 0.777, and ρ < 0.0001, spearman r = 0.787, respectively), but no significant correlation with tissue was found in the plasma (ρ = 0.966, spearman r = 0.008). Furthermore, additional genomic alterations could be detected in bile supernatant and pellet than in tissue. Potential targets for targeted therapy were identified in bile supernatant and pellet. Regarding copy number variation (CNV) and chromosomal instability (CIN) detection, four additional CNVs from two patients were detected in the bile supernatant that was not detected in tissues (i.e., amplification of TERC, IL7R, RICTOR, and TERT). CIN was significantly higher in tumor tissue than in plasma. The CIN of the bile was also significantly higher than that of plasma. There was no significant difference in CIN between the tissue and the bile supernatant. Conclusion: The consistency of all genomic alterations and tumor tissue-determined genomic alteration in the bile supernatant/pellet was significantly higher than in plasma. Bile supernatants/pellets are better for genetic sequencing and may also have potential clinical value to guide targeted therapy and evaluate prognosis. Bile cfDNA may be a feasible substitute for tumor tissue in the genetic testing of patients with BTC.
BACKGROUND: Although with the impressive efficacy, several patients showed intrinsic resistance or an unsatisfactory response to Osimertinib. We aim to explore the impact of clinical and molecular features on efficacy and outcome of patients with EGFR T790M-mutation non-small cell lung cancer (NSCLC) receiving second-line Osimertinib. METHODS: Patients with EGFR T790M-mutant NSCLC who had acquired resistance to the first-generation EGFR TKI and then received Osimertinib as second-line treatment were included. Patients' demographic and clinical information, as well as molecular data were extracted from electronic medical records. The impact of clinical and molecular features on treatment response and patients' outcome were assessed. RESULTS: Among the 99 patients, 60 patients were tissue/pleural effusion T790M positive and 69 patients were plasma positive with a median PFS of 12.1 m and 9.9 m (P = 0.25), respectively. In addition, median PFS were similar between patients of plasma T790M + and patients of plasma T790M- (P = 0.94). The Pearson correlation test showed no significant relationship between plasma T790M abundance and PFS (r = 0.074, P = 0.546). In subgroup analyses, PFS was significantly improved in elder patients (P = 0.009) and patients with longer PFS to the first-generation EGFR TKI (P = 0.0008), while smokers tended to have worse PFS compared with non-smokers (P = 0.064). PARP1 mutant-type patients had a worse PFS compared with wild-type group (P = 0.0003). Patients with MYC amplification also had a worse PFS than MYC wild-type patients (P = 0.016). A significant PFS shrinkage was observed in TMB-High group as 6.77 m, compared with 19.10 m in TMB-Low group. The multivariate Cox analysis revealed that years ≥ 65 was an independent positive feature for PFS, while PARP1 mutation and TMB-H were negative features for PFS. CONCLUSION: In conclusion, our findings in this study demonstrated that clinical and molecular features can be served as predictive biomarkers to stratify patients with EGFR T790M-mutant NSCLC receiving second-line Osimertinib.
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Acrylamides , Aged , Aniline Compounds , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , ErbB Receptors/therapeutic use , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation , Protein Kinase Inhibitors/therapeutic use
The histological transformation from adenocarcinoma (ADC) to squamous cell carcinoma (SCC) is rare but recurrently occurs post TKI treatment in EGFR-mutated non-small cell lung cancer patients with a very limited number of clinical cases published. The outcome of patients after SCC onset is poor as no established treatment guidelines were available. Here we report a case who was initially diagnosed with lung ADC with EGFR L858R driver mutation and demonstrated a partial response (PR) to gefitinib for 27 months before disease progression. The rapidly progressive lung metastatic lesions were determined as an SCC histology with positive PD-L1 expression. Besides EGFR L858R, the metastatic SCC harbored the amplification of CD274 and PDCD1LG2 detected by targeted next-generation sequencing (NGS), which encode PD-L1 and PD-L2, respectively. The disease remained stable on the combination therapy of pembrolizumab plus chemotherapy for eight months until the primary ADC lesion progressed. After the failure of progressed primary ADC lesion with radiotherapy and immunotherapy, systemic ADC metastases were developed in multiple locations including kidney, liver, and chest wall with EGFR L858R mutation but negative PD-L1 expression. The patient then received the combination therapy of bevacizumab plus chemotherapy and the disease remained stable for five months. Since August 2021, afatinib has been administrated which led to a PR and the disease has remained stable up till present. This study demonstrated a primary lung ADC who developed systemic ADC metastases and local SCC transformation with distinct molecular features. The patient has achieved long-term clinical benefit upon multiple lines of chemotherapy and immunotherapy, which provided valuable insight into the treatment of advanced SCC-transformed lung ADC patients.
Esophageal squamous cell carcinoma (ESCC) is one of the most common and lethal malignant tumors. The incidence of malignant transformation of esophageal mucosa increases greatly due to long-term exposure to factors such as smoking, drinking, and poor eating habits. Furthermore, multiple primary tumors could occur synchronously or asynchronously in the upper aerodigestive tract, especially in the esophagus, adding difficulty to the treatment of ESCC. Genetic mutations are important during the malignant transformation from normal mucosa to esophageal cancer, but the underlying mechanism has not been fully elucidated. In this study, we used whole-exome sequencing (WES) to profile genetic variations in physiologically normal mucosa (PNM) and ESCC tumors, as well as PNM of non-ESCC subjects. We found significant differences in mutation frequencies of NOTCH1 and NOTCH2, copy number variations (CNVs) at both gene and chromosomal arm levels, and cancer-related HIPPO, WNT, and NRF2 signaling pathways between ESCC tumors and normal mucosa. Our analysis of both primary tumors and paired PNM in bifocal ESCC revealed three different primary tumor evolution modes, and the most common mode exhibited a complete genomic divergence in all the samples from the same patient. Furthermore, the mutation frequency of TP53 was significantly higher in ESCC cases than that in non-ESCC cases. Overall, our results provide important evidence for further elucidating the mechanisms of genetic mutations underlying the cause of ESCC.
Tumor-infiltrating lymphocytes (TILs) offer a key for morphological diagnosis of lymphoepithelioma-like carcinoma (LELC) and are the foundation of oncoimmunology. To date, no reports have found a specific risk stratification value of TILs and related it to genomic variation in LELC. Based on the stromal TILs (str-TILs) ratio, we classified 105 Epstein-Barr virus (EBV)-associated LELC cases into two subtypes: patients with ≥60% str-TILs area ratio in tumor were classified as subtype I, and otherwise as subtype II. Subtype I patients had significantly better progression-free survival (PFS) and overall survival (OS). We also explored the genomic characteristics of EBV-associated LELC within different involved organs. We performed whole-exome sequencing for 51 patients with enough tissue and analyzed the genomic characteristics of EBV-associated LELC. Overall, EBV-associated LELCs were characterized by a low somatic mutation rate and copy number variations; the enriched genetic lesions affected RTK-RAS, PI3K, and cell cycle pathways. Moreover, EBV-associated LELCs from different organs were more similar to each other genetically as compared with other traditional carcinomas of the same sites-as evidenced by unsupervised clustering based on the quantitative data from both mutation signature and chromosomal aneuploidies. Notably, EBV-associated LELC patients with oncogenic driver alterations showed a worse prognosis compared with patients without such alterations. © 2022 The Pathological Society of Great Britain and Ireland.
Carcinoma, Squamous Cell , Epstein-Barr Virus Infections , DNA Copy Number Variations , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/genetics , Genomics , Herpesvirus 4, Human/genetics , Humans , Lymphocytes, Tumor-Infiltrating
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of large lymphoid B cell malignancy with distinct clinical and genetic features. Recently, NOTCH1 mutations were identified in DLBCL cases by Next-generation sequencing (NGS), but the clinical features and prognostic impact were not systematically studied. Here, NOTCH1 genes in 161 DLBCL samples were sequenced by NGS. The prognostic value of NOTCH1 mutations was assessed in the context of clinical and laboratory factors, such as international prognostic index (IPI), cell-of-origin classification, double expression of BCL2 and c-MYC. The combined data from three Western cohorts were used to validate these results. As a result, NOTCH1 mutations were found in 17(10.6%) patients, and three patients had a hotspot mutation of c.7541_7542delCT. The presence of NOTCH1 mutations was significantly associated with poor complete response and progression free survival(PFS), which was independent of established clinical and laboratory parameters. In addition, 30 (1.92%) of 1562 patients treated with R-CHOP regimen in those combined Western cohorts had NOTCH1 mutations. Meta-analysis of the Western cohorts confirmed that NOTCH1 mutations were also associated with poor PFS and OS. In conclusion, DLBCL patients with the NOTCH1 mutations have worse PFS and OS, and the NOTCH1 mutations can be used as an independent predictor for patients with DLBCL.
Anaplastic lymphoma kinase (ALK) fusion is a well-defined biomarker for ALK tyrosine kinase inhibitors (TKIs) treatment in non-small cell lung cancer (NSCLC). Alectinib, a second-generation ALK-TKI, has been shown to have significantly longer progression-free survival (PFS) than first-generation ALK inhibitors in untreated ALK-rearranged NSCLC patients. However, its clinical efficacy on rare ALK fusions remains unclear. Herein, two advanced NSCLC patients received first-line alectinib treatment, given their positive ALK fusion status as determined by immunohistochemistry (IHC) testing results. Patients showed limited clinical response (PFS: 4 months) and primary resistance to alectinib respectively. Molecular profiling using next-generation sequencing (NGS) further revealed a striatin (STRN)-ALK fusion in the first patient accompanied by MET amplification, and a LIM domain only protein 7 (LMO7)-ALK fusion in another patient without any other known oncogenic alterations. Both patients demonstrated improved survival after they switched to second-line crizotinib (PFS: 11 months) and ensartinib (PFS: 18 months), respectively, up till the last follow-up assessment. In conclusion, the clinical efficacy of ALK-TKIs including alectinib for lung cancer with uncommon ALK gene fusions is still under evaluation. This study and literature review results showed mixed responses to alectinib in NSCLC patients who harboured rare ALK fusions. Comprehensive molecular profiling of tumour is thus strongly warranted for precise treatment strategies.
Anaplastic Lymphoma Kinase/genetics , Carbazoles/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Oncogene Proteins, Fusion/genetics , Piperidines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Adult , Biomarkers, Tumor , Carbazoles/administration & dosage , Carbazoles/adverse effects , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/mortality , Disease Management , Female , Genetic Testing , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/mortality , Male , Middle Aged , Molecular Targeted Therapy , Neoplasm Staging , Piperidines/administration & dosage , Piperidines/adverse effects , Prognosis , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Tomography, X-Ray Computed , Treatment Outcome
BACKGROUND: Micropapillary adenocarcinoma is one of the most aggressive histologic subtypes of lung adenocarcinoma (LADC), and even a minor proportion of micropapillary component (MPC) within the LADC could contribute to poor prognosis. Comprehensive analysis of genetic and immunological features of LADC with different percentages of MPC would help better understand cancer biology of this LADC subtype and direct future treatments. METHODS: We performed next-generation sequencing (NGS) for a discovery cohort of 43 LADC patients whose tumors were micro-dissected to separate MPC and non-MPC lesions and a reference cohort of 113 LADC patients. MPC-enriched genetic alterations that were detected in the discovery cohort were then confirmed using a validation cohort of 183 LADC patients. Immunological staining was also conducted on the MPC-containing samples in the discovery cohort. RESULTS: Tumors with a higher percentage of MPC tended to harbor more tumor mutation burdens (TMBs) and chromosome instability (CIN). Some rare genetic events may serve as the genetic landscape to drive micropapillary tumor progression. Specifically, alterations in transcription termination factor 1 (TTF1), brain-specific angiogenesis inhibitor 3 (BAI3), mammalian target of rapamycin (MTOR), and cyclin-dependent kinase inhibitor 2A (CDKN2A) were cross-validated to be enriched in MPC-contained LADC. Additionally, tumors with a higher percentage of MPC were associated with a higher percentage of CD4+, CD8+, and PD-L1+ staining, and some genetic changes that were enriched in MPC, including MET amplification and MTOR mutation, were correlated with increased PD-L1 expression. CONCLUSION: We identified multiple novel MPC-enriched genetic changes that could help us understand the nature of this aggressive cancer subtype. High MPC tumors tended to have elevated levels of TMBs, T cell infiltration, and immunosuppression than low MPC tumors, implying the potential link between MPC content and sensitivity to immunotherapy.
