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BACKGROUND: We evaluated the efficacy of adjuvant durvalumab after neoadjuvant concurrent chemoradiotherapy (CCRT) in patients with esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: This randomized, double-blind, phase II study included patients with ESCC who underwent curative surgery after neoadjuvant CCRT. Patients were randomized to receive either durvalumab (20 mg/kg/i.v. every 4 weeks for 12 months) or placebo in a 1:1 ratio and were stratified by age and pathologic tumor stage. The primary endpoint was disease-free survival (DFS). RESULTS: Between March 2016 and June 2018, 86 patients were randomized to the durvalumab (n = 45) or placebo (n = 41) arm. The median follow-up duration was 38.7 months. There was no difference in DFS [hazard ratio (HR) 1.18, 95% confidence interval (CI) 0.62-2.27, P = 0.61] or overall survival (HR 1.08, 95% CI 0.52-2.24, P = 0.85) between the two arms. Subgroup analysis was performed for patients for whom the post-CCRT programmed death-ligand 1 (PD-L1) expression profile could be assessed (n = 54). In the PD-L1-positive group, based on tumor proportion score ≥1%, durvalumab was associated with longer overall survival compared with the placebo (36-month survival rate: 94% versus 64%; HR 0.42, 95% CI 0.10-1.76), while in the PD-L1-negative group, it was associated with shorter overall survival (42% versus 55%; HR 1.53, 95% CI 0.48-4.83), showing the tendency of interaction between post-CCRT PD-L1 status and adjuvant durvalumab therapy for overall survival (interaction P = 0.18). CONCLUSIONS: We failed to demonstrate that adjuvant durvalumab improved survival after neoadjuvant CCRT in patients with ESCC. However, post-CCRT PD-L1 expression could predict the survival of patients who receive adjuvant durvalumab after neoadjuvant CCRT, which needs to be validated.
Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Esophageal Neoplasms/drug therapy , Esophageal Squamous Cell Carcinoma/chemically induced , Esophageal Squamous Cell Carcinoma/drug therapy , Humans , Neoadjuvant TherapyABSTRACT
BACKGROUND: Immune checkpoint inhibitors (ICIs) have been shown to be beneficial for some patients with advanced non-small-cell lung cancer (NSCLC). However, the underlying mechanisms mediating the limited response to ICIs remain unclear. PATIENTS AND METHODS: We carried out whole-exome sequencing on 198 advanced NSCLC tumors that had been sampled before anti-programmed cell death 1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) therapy. Detailed clinical characteristics were collected on these patients. We designed a new method to estimate human leukocyte antigen (HLA)-corrected tumor mutation burden (TMB), a modification which considers the loss of heterozygosity of HLA from conventional TMB. We carried out external validation of our findings utilizing 89 NSCLC samples and 110 melanoma samples from two independent cohorts of immunotherapy-treated patients. RESULTS: Homology-dependent recombination deficiency was identified in 37 patients (18.7%) and was associated with longer progression-free survival (PFS; P = 0.049). Using the HLA-corrected TMB, non-responders to ICIs were identified, despite having a high TMB (top 25%). Ten patients (21.3% of the high TMB group) were reclassified from the high TMB group into the low TMB group. The objective response rate (ORR), PFS, and overall survival (OS) were all lower in these patients compared with those of the high TMB group (ORR: 20% versus 59%, P = 0.0363; PFS: hazard ratio = 2.91, P = 0.007; OS: hazard ratio = 3.43, P = 0.004). Multivariate analyses showed that high HLA-corrected TMB was associated with a significant survival advantage (hazard ratio = 0.44, P = 0.015), whereas high conventional TMB was not associated with a survival advantage (hazard ratio = 0.63, P = 0.118). Applying this approach to the independent cohorts of 89 NSCLC patients and 110 melanoma patients, TMB-based survival prediction was significantly improved. CONCLUSION: HLA-corrected TMB can reconcile the observed disparity in relationships between TMB and ICI responses, and is of predictive and prognostic value for ICI therapies.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , B7-H1 Antigen/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , HLA Antigens , Homologous Recombination , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation , Programmed Cell Death 1 Receptor/geneticsABSTRACT
Since publication of the original article, the authors have noticed that there were errors in the labelling of Figures 6D and 6E. The correct figure and its legend are reproduced here. The authors wish to apologise for any inconvenience caused.
ABSTRACT
This corrects the article DOI: 10.1038/oncsis.2017.87.
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Epithelial splicing regulatory protein 1 (ESRP1) and 2 (ESRP2), epithelial cell-specific regulators of alternative splicing, are downregulated during the epithelial-mesenchymal transition (EMT). These factors have roles in tumor progression and metastasis in some cancers; however, their expression and function in ovarian cancer (OC) remain unclear. We found that ESRP1 and ESRP2 mRNAs were expressed at higher levels in OC cells than in immortalized ovarian surface epithelial (IOSE) cells, and confirmed their overexpression in OC tissues at the protein level. The Cancer Genome Atlas (TCGA) data analysis revealed frequent gene amplification of ESRP1 in OC tissues; however, we detected no significant correlation between ESRP1 gene copy number and gene expression in OC cells. Importantly, expression of ESRP1 and ESRP2 was inversely correlated with DNA methylation in OC cells, and ESRP2 overexpression in OC tissues was significantly associated with DNA hypomethylation. Notably, survival analysis using TCGA data from 541 OC tissues revealed that high ESRP1 expression was significantly associated with shorter 5-year survival of patients. Ectopic ESRP1 expression in mesenchymal OC cells promoted cell proliferation but suppressed cell migration. Furthermore, we found that ESRP1 drives a switch from mesenchymal to epithelial phenotype characterized by reduced cell migration in association with induction of epithelial cell-specific variant of CD44 and ENAH. Taken together, our findings suggest that an epigenetic mechanism is involved in ESRP1 overexpression, and that ESRP1 has a role in OC progression.
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AIM: To compare the abilities of conventional magnetic resonance imaging (MRI) and apparent diffusion coefficient (ADC) in differentiating between benign and malignant soft-tissue tumours (STT). MATERIAL AND METHODS: A total of 123 patients with STT who underwent 3 T MRI, including diffusion-weighted imaging (DWI), were retrospectively analysed using variate conventional MRI parameters, ADCmean and ADCmin. RESULTS: For the all-STT group, the correlation between the malignant STT conventional MRI parameters, except deep compartment involvement, compared to those of benign STT were statistically significant with univariate analysis. Maximum diameter of the tumour (p=0.001; odds ratio [OR], 8.97) and ADCmean (p=0.020; OR, 4.30) were independent factors with multivariate analysis. For the non-myxoid non-haemosiderin STT group, signal heterogeneity on axial T1-weighted imaging (T1WI; p=0.017), ADCmean, and ADCmin (p=0.001, p=0.001), showed significant differences with univariate analysis between malignancy and benignity. Signal heterogeneity in axial T1WI (p=0.025; OR, 12.64) and ADCmean (p=0.004; OR, 33.15) were independent factors with multivariate analysis. CONCLUSION: ADC values as well as conventional MRI parameters were useful in differentiating between benign and malignant STT. The ADCmean was the most powerful diagnostic parameter in non-myxoid non-haemosiderin STT.
Subject(s)
Magnetic Resonance Imaging , Soft Tissue Neoplasms/diagnostic imaging , Adolescent , Adult , Aged , Aged, 80 and over , Child , Diagnosis, Differential , Diffusion Magnetic Resonance Imaging , Female , Humans , Male , Middle Aged , Neoplasms/diagnostic imaging , Neoplasms/pathology , Retrospective Studies , Soft Tissue Neoplasms/pathology , Young AdultABSTRACT
Background: Chromosomal rearrangements involving RET, which are found in about 1% of non-small cell lung cancer (NSCLC), define a unique molecular subset. We performed this study to examine the efficacy and safety of vandetanib 300 mg daily in this patient population. Patients and methods: This study was a multi-center, open-label, phase II clinical trial. Patients were enrolled if they had metastatic or recurrent NSCLC with a RET rearrangement, which was confirmed by fluorescence in situ hybridization, had progressive disease against platinum-based doublet chemotherapy, and had a performance status of 0-2. The primary endpoint was the objective response rate. Results: A total of 18 patients were enrolled in this study between July 2013 and October 2015. Patients were aged 35-71 years; three had a performance status of 2, and the majority were a heavily pretreated population (≥ two different previous chemotherapy regimens in 72% of the patients). Among the 17 evaluable patients, three had a partial response (objective response rate = 18%) and eight had a stable disease (disease control rate = 65%). Among these patients, the partial response or disease stabilization was durable for more than 6 months in eight patients. Vandetanib also showed a progression-free survival of 4.5 months, and an overall survival of 11.6 months during a median follow-up duration of 14 months. The safety profile was comparable with previous studies of vandetanib. Most vandetanib-related adverse events were mild with prevalent hypertension and rash (in >70% of patients). Grade 3 toxicity included hypertension (n = 3), QT prolongation (2), and elevation of aminotransferases (1), and as a consequence the dose was reduced in four patients. There were no adverse events associated with grade 4 or 5 toxicity. Conclusion: Vandetanib is moderately active in pretreated patients with advanced NSCLC-harboring RET rearrangements.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Piperidines/therapeutic use , Proto-Oncogene Proteins c-ret/genetics , Quinazolines/therapeutic use , Adenocarcinoma/genetics , Adult , Aged , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Mutation , Treatment Outcome , Tumor BurdenABSTRACT
BACKGROUND: Programmed death-ligand 1 (PD-L1) expression has been suggested as a potential predictive biomarker of response to anti-PD-1/PD-L1 therapy. In this study, we investigated whether the expression of PD-L1 in tumour cells is affected by neoadjuvant concurrent chemoradiotherapy (CCRT) or chemotherapy in oesophageal squamous cell carcinoma. PATIENTS AND METHODS: Between 2004 and 2014, we collected the medical records of locally advanced oesophageal cancer patients consecutively diagnosed and treated with neoadjuvant CCRT or chemotherapy, followed by curative resection. PD-L1 expression in acquired tissue specimens was evaluated by immunohistochemistry using the H-score. The changes in PD-L1 expression between paired samples were evaluated and we also analysed PD-L1 expression in surgical tumour specimens to evaluate its prognostic role. RESULTS: Twenty-eight paired tumour tissues that were acquired before and after neoadjuvant therapy were available: 19 patients with CCRT and 9 with chemotherapy before complete oesophagectomy. The PD-L1 H-score increased significantly from baseline tumour tissues to surgical tumour tissues after neoadjuvant CCRT (P = 0.007, median H-score from 28 to 52), whereas it decreased significantly after neoadjuvant chemotherapy (P = 0.048, median H-score from 53 to 22). In a total of 73 patients, including 45 additional cases for the prognosis analysis, patients with higher PD-L1 H-scores (≥ 20) had poorer overall survival (median 16.7 versus 32.9 months, P = 0.02) than those with lower H-scores (<20). CONCLUSIONS: PD-L1 expression in tumour cells increased in oesophageal cancer patients who received neoadjuvant CCRT. Further studies with more cases are necessary to validate these findings.
Subject(s)
B7-H1 Antigen/metabolism , Biomarkers, Tumor/metabolism , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/therapy , Chemoradiotherapy, Adjuvant , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/therapy , Neoadjuvant Therapy , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Chemotherapy, Adjuvant , Esophageal Neoplasms/mortality , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma , Esophagectomy , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Male , Medical Records , Middle Aged , Retrospective Studies , Treatment Outcome , Up-RegulationABSTRACT
BACKGROUND: Once regarded as a smoker's disease, small-cell lung cancer (SCLC) has been occasionally detected in never-smokers as smoking rates decrease worldwide. We investigated the clinical and genetic characteristics of SCLC in never-smokers. PATIENTS AND METHODS: Patients diagnosed with SCLC were grouped into smokers and never-smokers. The clinical outcomes of the two groups were compared. For SCLC in never-smokers, somatic mutation profiling was carried out using the AmpliSeq™ Cancer Hotspot Panel v2 and semiconductor sequencing technology. Epidermal growth factor receptor (EGFR) mutation was confirmed by PNAClamp™. RESULTS: In total, 391 SCLC patients treated over a 5-year period were analyzed. Fifty patients (13%) were never-smokers. The median overall survival was 18.2 months in never-smokers and 13.1 months in smokers (P = 0.054). Never-smoking history was independently a good prognostic factor [hazard ratio = 0.645, 95% confidence interval (CI) 0.456-0.914], as were limited disease (HR = 0.372, 95% CI 0.294-0.471), and lower age (HR = 0.709, 95% CI 0.566-0.888). The objective response rates to first-line etoposide/cisplatin therapy were similar between never-smokers and smokers (75% versus 81%). Of 28 genetically evaluable never-smokers, EGFR mutations were detected in four cases (two L858R, one deletion in exon 19, and one G719A). Other mutations were in TP53 (n = 26), RB1 (n = 7), PTEN (n = 5), MET (n = 4), and SMAD4 (n = 3). CONCLUSIONS: Never-smokers with SCLC are increasingly prevalent and have a better prognosis than smokers with SCLC in Korea. Our study warrants further investigation in this group.
Subject(s)
Adenocarcinoma/genetics , ErbB Receptors/genetics , Lung Neoplasms/genetics , Small Cell Lung Carcinoma/genetics , Adenocarcinoma/diagnosis , Adult , Aged , Aged, 80 and over , Base Sequence , Cisplatin/therapeutic use , Etoposide/therapeutic use , Female , High-Throughput Nucleotide Sequencing , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Male , Middle Aged , PTEN Phosphohydrolase/genetics , Proto-Oncogene Proteins c-met/genetics , Retinoblastoma Protein/genetics , Sequence Analysis, DNA , Smad4 Protein/genetics , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/mortality , Smoking , Tumor Suppressor Protein p53/genetics , Young AdultABSTRACT
BACKGROUND: The aim of this study was to investigate the role of human epidermal growth factor receptor (HER3) and PTEN expression in patients with HER2-overexpressing metastatic breast cancer (MBC). METHODS: One hundred twenty-five MBC patients who were treated with taxane plus trastuzumab chemotherapy as first-line therapy were included in this analysis. Immunohistochemical (IHC) staining with HER3 and PTEN antibodies were conducted retrospectively. RESULTS: Patients who had negative HER3 staining (62.4%) had a better progression-free survival (PFS) than did those who had positive HER3 staining (P=0.001; median PFS, 21 vs 11 months). Patients who had a PTEN score >20 (78.1%) showed longer PFS than did those with a PTEN score ≤20 (P=0.006; median PFS, 13 vs 9 months). Patients who had a PTEN score >20 exhibited a longer overall survival (OS) than did those with a PTEN score ≤20 (P=0.005; median OS, 48 vs 25 months). HER3 negativity and PTEN loss were identified as independent risk factors for PFS. PTEN loss was identified as an independent risk factor for OS. CONCLUSION: HER3 and PTEN expressions may be predictive markers, and PTEN expression may be a predictive and prognostic biomarker for trastuzumab treatment in HER2-positive MBCs.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/enzymology , PTEN Phosphohydrolase/deficiency , Receptor, ErbB-2/genetics , Receptor, ErbB-3/biosynthesis , Adult , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Breast Neoplasms/genetics , Bridged-Ring Compounds/administration & dosage , Disease-Free Survival , Female , Humans , Middle Aged , PTEN Phosphohydrolase/genetics , Prognosis , Receptor, ErbB-3/genetics , Retrospective Studies , Taxoids/administration & dosage , TrastuzumabABSTRACT
BACKGROUND: The mammalian target of rapamycin (mTOR) pathway is dysregulated in small-cell lung cancer (SCLC) and everolimus is an oral mTOR inhibitor. METHODS: This phase-1b study assessed everolimus safety at the levels of 2.5, 5, or 10 mg once daily in combination with paclitaxel (175 mg m(-2)) once every 3 weeks in previously treated SCLC patients. The primary end point was to determine the maximum tolerated dose of everolimus. RESULTS: Among 21 enrolled patients, common drug-related adverse events were anaemia, neutropenia, thrombocytopenia, pain, hyperglycemia, and stomatitis. Out of 11 evaluable patients treated with everolimus at the level of 5 mg, 1 patient experienced dose-limiting toxicity (DLT) of grade 4 febrile neutropenia and grade 3 thrombocytopenia. The other two DLTs (grade 4 thrombocytopenia and grade 3 hyperglycemia) occurred in two out of three patients receiving everolimus 10 mg. The overall objective response rate was 28%. CONCLUSION: Everolimus showed an acceptable safety profile and preliminary antitumour activity at the dose of 5 mg once daily when combined with 3-weekly paclitaxel 175 mg m(-2) in patients with SCLC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lung Neoplasms/drug therapy , Small Cell Lung Carcinoma/drug therapy , Dose-Response Relationship, Drug , Everolimus , Female , Humans , Male , Middle Aged , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Sirolimus/administration & dosage , Sirolimus/adverse effects , Sirolimus/analogs & derivativesABSTRACT
We investigated the clinical response to arthroscopic synovectomy in patients with undifferentiated chronic monoarthritis (UCMA) of the wrist. Arthroscopic synovectomy was performed on 20 wrists in 20 patients with UCMA of the wrist who had not responded to non-steroidal anti-inflammatory drugs. The mean duration of symptoms at the time of surgery was 4.3 months (3 to 7) and the mean follow-up was 51.8 months (24 to 94). Inflamed synovium was completely removed from the radiocarpal, midcarpal and distal radioulnar joints using more portals than normal. After surgery, nine patients had early remission of synovitis and 11 with uncontrolled synovitis received antirheumatic medication. Overall, there was significant improvement in terms of pain relief, range of movement and Mayo score. Radiological deterioration was seen in five patients who were diagnosed as having rheumatoid arthritis during the follow-up period. Lymphoid follicles and severe lymphocyte infiltration were seen more often in synovial biopsies from patients with uncontrolled synovitis. These results suggest that arthroscopic synovectomy provides pain relief and functional improvement, and allows rapid resolution of synovitis in about half of patients with UCMA of the wrist.
Subject(s)
Arthritis/surgery , Arthroscopy/methods , Synovectomy , Synovitis/surgery , Wrist Joint/surgery , Adolescent , Adult , Chronic Disease , Female , Humans , Male , Middle Aged , Pain Measurement/methods , Range of Motion, Articular , Treatment Outcome , Wrist Joint/physiopathology , Young AdultABSTRACT
BACKGROUND: CD151 is a member of the tetraspanin family, which interacts with laminin-binding integrins and other tetraspanins. This protein is implicated in motility, invasion, and metastasis of cancer cells, but the prevalence of CD151 expression in subtypes of breast cancers and its influence on clinical outcome remains to be evaluated. METHODS AND RESULTS: The immunohistochemistry-based tissue microarray analysis showed that 127 (14.3%) cases overexpressed CD151 among 886 breast cancer patients. CD151 overexpression was found to be significantly associated with larger tumour size, higher nodal stage, advanced stage, absence of oestrogen receptor and progesterone receptor, and human epidermal growth factor receptor 2 overexpression. CD151 overexpression resulted in poorer overall survival (OS) (P<0.001) and disease-free survival (P=0.02), and stage II and III patients with CD151 overexpression demonstrated substantially poorer OS (P=0.0474 and 0.0169). In the five subtypes analyses, CD151 overexpression retained its adverse impact on OS in the Luminal A (P=0.0105) and quintuple-negative breast cancer (QNBC) subtypes, one subgroup of triple-negative breast cancer (P=0.0170). Multivariate analysis that included stage, subtype, and adjuvant chemotherapy showed that CD151 overexpression was independently associated with poor OS in invasive breast cancer. CONCLUSION: CD151 overexpression may be a potential molecular therapeutic target for breast cancer, especially in QNBC subtype and more advanced stages of breast cancer.
Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Neoplasm Invasiveness , Tetraspanin 24/biosynthesis , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/biosynthesis , Disease-Free Survival , Female , Humans , Immunohistochemistry , Middle Aged , Molecular Targeted Therapy , Prognosis , Receptor, ErbB-2/metabolism , Receptors, Estrogen/biosynthesis , Receptors, Progesterone/metabolism , Tissue Array AnalysisABSTRACT
Recently, the clonal integration of a new human polyomavirus (Merkel cell polyomavirus or MCPyV) has been reported in Merkel cell carcinoma (MCC). In order to investigate the presence of MCPyV in small cell carcinomas (SCCs) and small round cell tumors (SRCTs), we collected formalin-fixed paraffin-embedded tissue specimens including 14 MCCs, 24 SCCs, 7 Ewing sarcoma/primitive neuroectodermal tumors (ES/PNETs) and 5 neuroblastomas. We also collected specimens of other cancers including 12 malignant melanomas, 10 breast, 10 ovarian and 20 gastric cancers. We used 3 primer sets for which the sequences were previously published (LT1, LT3, and VP1) and 3 newly designed primer sets (LT1-1, LT1-1a, and LT3a). Quantitative real-time PCR was also performed with the LTq primer set. Nested PCR using the LT3a primer set detected more cases of MCPyV infection in MCC. In total, 12 of 14 (85.7%) MCC cases were positive for MCPyV by PCR, which was consistent with published data. Some SCC specimens were also positive for MCPyV (37.5%) by PCR. PCR products from MCC and SCC cases showed premature truncation and frameshift mutation. Furthermore, one case of ES/PNET and one gastric carcinoma showed MCPyV DNA. However, MCPyV DNA and transcript were only detected in MCCs with quantitative real-time PCR analysis. In addition, 11 of 13 (84.6%) MCC cases and 6 of 23 (26.1%) SCC cases showed immunoreactivity with monoclonal antibodies against MCPyV large T-antigen. Considering both PCR and IHC results, MCPyV was detected in all MCCs tested. The presence of MCPyV in all MCC cases tested and in some SCC cases suggests that MCPyV may be involved in the malignant transformation.
Subject(s)
Carcinoma, Merkel Cell/virology , Carcinoma, Small Cell/virology , Merkel cell polyomavirus/isolation & purification , Polyomavirus Infections/virology , Tumor Virus Infections/virology , Adult , Aged , Aged, 80 and over , Carcinoma, Merkel Cell/pathology , Carcinoma, Small Cell/pathology , Female , Humans , Immunohistochemistry , Male , Middle Aged , Polyomavirus Infections/complications , Polyomavirus Infections/pathology , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Tumor Virus Infections/complications , Tumor Virus Infections/pathologyABSTRACT
To identify oncogenes in leukemias, we performed large-scale resequencing of the leukemia genome using DNA sequence arrays that determine approximately 9 Mbp of sequence corresponding to the exons or exon-intron boundaries of 5648 protein-coding genes. Hybridization of genomic DNA from CD34-positive blasts of acute myeloid leukemia (n=19) or myeloproliferative disorder (n=1) with the arrays identified 9148 nonsynonymous nucleotide changes. Subsequent analysis showed that most of these changes were also present in the genomic DNA of the paired controls, with 11 somatic changes identified only in the leukemic blasts. One of these latter changes results in a Met-to-Ile substitution at amino-acid position 511 of Janus kinase 3 (JAK3), and the JAK3(M511I) protein exhibited transforming potential both in vitro and in vivo. Further screening for JAK3 mutations showed novel and known transforming changes in a total of 9 out of 286 cases of leukemia. Our experiments also showed a somatic change responsible for an Arg-to-His substitution at amino-acid position 882 of DNA methyltransferase 3A, which resulted in a loss of DNA methylation activity of >50%. Our data have thus shown a unique profile of gene mutations in human leukemia.
Subject(s)
Genomics/methods , Leukemia/genetics , Oligonucleotide Array Sequence Analysis/methods , Sequence Analysis, DNA/methods , Amino Acid Sequence , Animals , Base Sequence , Cell Transformation, Neoplastic , DNA (Cytosine-5-)-Methyltransferases/chemistry , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA Methyltransferase 3A , Genome, Human/genetics , Humans , Janus Kinase 3/genetics , Leukemia/pathology , Mice , Molecular Sequence Data , MutationABSTRACT
BACKGROUND: Extranodal natural killer T (NK/T) cell lymphoma is subcategorized into 'nasal' and 'nasal-type' NK/T-cell lymphomas according to the primary sites of anatomical involvement. OBJECTIVES: The aim of this study was to characterize the cutaneous manifestations of the skin involving extranodal NK/T-cell lymphoma and to define the distinctive features of 'nasal' and 'nasal-type'. In addition, the prognostic factors that affect overall survival were investigated. METHODS: A retrospective case study of 18 patients with extranodal NK/T-cell lymphoma with cutaneous involvement was performed. RESULTS: The NK/T-cell lymphomas usually occurred in middle-aged, male patients. Most of the patients presented with either cellulitis or ulcer. A facial predilection for the location of the lesion was noted. The characteristic features of the 'nasal-type' compared with the 'nasal' were a localized involvement of the skin, less aggressive clinical course and better survival outcome. CONCLUSIONS: Extranodal NK/T-cell lymphomas are extremely aggressive regardless of their subgroup. However, the 'nasal-type' NK/T-cell lymphoma was clinically less aggressive, more localized and had a better outcome compared with the other type. Cellulitis and ulcer were the major cutaneous manifestations.
Subject(s)
Lymphoma, Extranodal NK-T-Cell/pathology , Nasal Cavity/pathology , Nose Neoplasms/pathology , Skin Neoplasms/pathology , Adult , Aged , Female , Humans , Male , Middle Aged , Prognosis , Regression Analysis , Retrospective Studies , Skin Neoplasms/secondary , Survival Analysis , Young AdultABSTRACT
Adult T-cell leukemia/lymphoma (ATLL) is a neoplasia characterized by the massive invasion of various organs by tumor cells. Previously, we found that expression of the gene for c-Met, a receptor tyrosine kinase for hepatocyte growth factor (HGF), was specific to the acute type among 41 patients with ATLL by microarray. First in the present study, we analyzed the survival of the patients in relation to expression of c-Met and HGF in ATLL cells. Expression of the former but not the latter was associated with poor prognosis. Then, we analyzed the growth of ATLL cells caused by HGF and c-Met. c-Met was expressed in 0/7 chronic ATLLs, 12/14 acute ATLLs, 1/1 IL-2-independent ATLL cell line and 1/7 IL-2-dependent ATLL cell lines as assessed by flow cytometry. HGF induced the proliferation of primary cells from most acute cases examined as well as the c-Met-positive KK1 cell line in contrast to c-Met-negative cells. HGF induced autophosphorylation of c-Met in c-Met-positive cells from an acute case and KK1 cells. The plasma level of HGF was elevated in acute as compared to chronic cases. The levels of HGF and/or IL-6 which induces the production of HGF by stromal cells, were elevated in the supernatant of short-term cultured cells from certain patients with acute or chronic disease. Finally, infiltrated ATLL cells and adjacent stromal cells in liver were shown to be positive for c-Met/HGF and HGF, respectively, in acute cases. Autocrine and/or paracrine growth caused by HGF and c-Met was suggested in aggressive ATLL cells secreting HGF and/or IL-6, respectively.
Subject(s)
Gene Expression Regulation, Leukemic , Gene Expression Regulation, Neoplastic , Hepatocyte Growth Factor/metabolism , Leukemia-Lymphoma, Adult T-Cell/immunology , Proto-Oncogene Proteins c-met/metabolism , Apoptosis , Cell Line, Tumor , Cell Membrane/metabolism , Cell Proliferation , Cytokines/metabolism , Humans , Interleukin-6/metabolism , Leukemia-Lymphoma, Adult T-Cell/metabolism , Models, Biological , Phosphorylation , Time FactorsABSTRACT
Angioimmunoblastic T-cell lymphoma (AILT) and peripheral T-cell lymphoma, unspecified (PTCL-u) are relatively frequent subtypes of T- or natural killer cell lymphoma. To characterize the structural anomalies of chromosomes associated with these disorders, we here determined chromosome copy number alterations (CNAs) and loss of heterozygosity (LOH) at >55,000 single nucleotide polymorphism loci for clinical specimens of AILT (n=40) or PTCL-u (n=33). Recurrent copy number gain common to both conditions was detected on chromosomes 8, 9 and 19, whereas common LOH was most frequent for a region of chromosome 2. AILT- or PTCL-u-specific CNAs or LOH were also identified at 21 regions, some spanning only a few hundred base pairs. We also identified prognosis-related CNAs or LOH by several approaches, including Cox's proportional hazard analysis. Among the genes that mapped to such loci, a poor prognosis was linked to overexpression of CARMA1 at 7p22 and of MYCBP2 at 13q22, with both genes being localized within regions of frequent copy number gain. For a frequent LOH region at 2q34, we also identified IKAROS family zinc-finger 2 cDNAs encoding truncated proteins. Our data indicate that AILT and PTCL-u consist of heterogeneous subgroups with distinct transforming genetic alterations.
Subject(s)
Chromosome Aberrations , Loss of Heterozygosity , Lymphoma, T-Cell, Peripheral/genetics , Lymphoma, T-Cell/genetics , Oligonucleotide Array Sequence Analysis , Polymorphism, Single Nucleotide , Adult , Aged , Aged, 80 and over , CARD Signaling Adaptor Proteins/genetics , DNA-Binding Proteins/genetics , Female , Guanylate Cyclase/genetics , Humans , Ikaros Transcription Factor/genetics , Lymphoma, T-Cell/mortality , Lymphoma, T-Cell, Peripheral/mortality , Male , Middle Aged , Neprilysin/analysis , Prognosis , Transcription Factors/geneticsABSTRACT
Lung cancer is a leading cause of cancer death, where the amplification of oncogenes contributes to tumorigenesis. Genomic profiling of 128 lung cancer cell lines and tumors revealed frequent focal DNA amplification at cytoband 14q13.3, a locus not amplified in other tumor types. The smallest region of recurrent amplification spanned the homeobox transcription factor TITF1 (thyroid transcription factor 1; also called NKX2-1), previously linked to normal lung development and function. When amplified, TITF1 exhibited increased expression at both the RNA and protein levels. Small interfering RNA (siRNA)-mediated knockdown of TITF1 in lung cancer cell lines with amplification led to reduced cell proliferation, manifested by both decreased cell-cycle progression and increased apoptosis. Our findings indicate that TITF1 amplification and overexpression contribute to lung cancer cell proliferation rates and survival and implicate TITF1 as a lineage-specific oncogene in lung cancer.