// Chao-Hua Chiu 1,2,4,* , Hsiang-Ling Ho 5,* , Howard Doong 6 , Yi-Chen Yeh 1,5 , Mei-Yu Chen 3 , Teh-Ying Chou 1,5 and Chun-Ming Tsai 2,4 1 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 2 Department of Medicine, National Yang-Ming University, Taipei, Taiwan 3 Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan 4 Division of Thoracic Oncology, Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 5 Division of Molecular Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 6 Taipei VGH-Lihpao Laboratory of Cancer Genomic Medicine, Lihpao Life Science Corporation, Taipei, Taiwan * These authors contributed equally to this work Correspondence to: Teh-Ying Chou, email: // Chun-Ming Tsai, email: // Keywords : MLH1, EGFR, Lung adenocarcinoma, Tyrosine kinase inhibitor, Resistance Received : January 05, 2015 Accepted : February 02, 2015 Published : March 08, 2015 Abstract A significant fraction of patients with lung adenocarcinomas harboring activating epidermal growth factor receptor (EGFR) mutations do not experience clinical benefits from EGFR tyrosine kinase inhibitor (TKI) therapy. Using next-generation sequencing, we screened 739 mutation hotspots in 46 cancer-related genes in EGFR L858R-mutant lung adenocarcinomas from 29 patients who received EGFR-TKI therapy; 13 had short (< 3 months) and 16 had long (> 1 year) progression-free survival (PFS). We discovered MLH1 V384D as a genetic variant enriched in the group of patients with short PFS. Next, we investigated this genetic variation in 158 lung adenocarcinomas with the EGFR L858R mutation and found 14 (8.9%) patients had MLH1 V384D; available blood or non-tumor tissues from patients were also tested positive for MLH1 V384D. Patients with MLH1 V384D had a significantly shorter median PFS than those without (5.1 vs. 10.6 months; P= 0.001). Multivariate analysis showed that MLH1 V384D polymorphism was an independent predictor for a reduced PFS time (hazard ratio, 3.5; 95% confidence interval, 1.7 to 7.2; P= 0.001). In conclusion, MLH1 V384D polymorphism is associated with primary resistance to EGFR-TKIs in patients with EGFR L858R-positive lung adenocarcinoma and may potentially be a novel biomarker to guide treatment decisions.
Metanephric adenoma (MA) and Wilms tumor (WT) represent 2 prototypes of primary renal neoplasms closely resembling embryonal renal tubules. Tumors with overlapping features may occur, requiring differential diagnoses between the 2. Evidence of divergent oncogenic pathways has been reported, suggesting that MA is driven by BRAF mutation while most WT is of the BRAF wild-type. We collected 4 MA cases, 3 cases of monophasic epithelial WT, and 1 overlap metanephric tumor that contains both conventional MA and high-grade components similar to epithelial WT. Whole-exome sequencing and whole transcriptome sequencing were performed to discover mutations, somatic copy number variation, and differential expression. The findings were compared with those of WT of the TARGET database (WT-TARGET). BRAF V600E mutation was detected in all MAs as well as the overlap tumor but was undetectable in all epithelial WTs and WT-TARGET. The overlap tumor showed an additional pathogenic mutation of SETD2. Three frequent gene mutations observed in WT-TARGET were not common in epithelial WT, in which the mutations appeared sporadic. The profiles of recurrent copy number variations were all different among MA, epithelial WT, and WT-TARGET. Differential expression and unsupervised hierarchical cluster analyses revealed distinct clusters of the 3 categories. Remarkably, the overlap tumor coclustered with MA, separated from epithelial WT and WT-TARGET. The distinctiveness of MA and WT were demonstrated corresponding to BRAF-mutated and non-BRAF-mutated pathways from the molecular perspective. BRAF assay has diagnostic implication for overlap tumors.
The thyroid hormone, 3,3',5-triiodo-l-thyronine (T3 ), mediates several physiological processes, including embryonic development, cellular differentiation, metabolism and regulation of cell proliferation. Thyroid hormone (T3 ) and its receptor (TR) are involved in metabolism and growth. In addition to their developmental and metabolic functions, TRs play a tumor suppressor role, and therefore, their aberrant expression can lead to tumor transformation. Aberrant epigenetic silencing of tumor suppressor genes promotes cancer progression. The epigenetic regulator, Ubiquitin-like with PHD and ring finger domains 1 (UHRF1), is overexpressed in various cancers. In our study, we demonstrated that T3 negatively regulates UHRF1 expression, both in vitro and in vivo. Our results further indicate that UHRF1 regulation by T3 is indirect and mediated by Sp1. Sp1-binding elements of UHRF1 were identified at positions -664/-505 of the promoter region using the luciferase and chromatin immunoprecipitation assays. Notably, UHRF1 and Sp1 levels were elevated in subgroups of hepatocellular carcinoma patients and inversely correlated with TRα1 expression. Knockdown of UHRF1 expression should therefore provide a means to inhibit hepatoma cell proliferation. Expression of UHRF1 was downregulated by TRs, in turn, relieving silencing of the UHRF1 target gene, p21. Based on the collective findings, we propose that T3 /TR signaling induces hepatoma cell growth inhibition via UHRF1 repression.
Alveolar adenoma is a rare tumour of the lung. It is typically found in asymptomatic adults as a peripheral or subplerual nodule on imaging examination. Microscopically, the tumour is composed of admixture of epithelial and mesenchymal component in variable sized cystic or alveolar structures. The tumour shows a benign nature. There have been no reported recurrences or metastases. Malignant transformation of alveolar adenoma and coexisting with lung carcinoma have been rarely described. In this article, we report a case of an alveolar adenoma and coexisting atypical adenomatous hyperplasia. This case, contributing to the limited numbers of cases described to date, illustrates the importance of awareness on the possibility of alveolar adenoma being associated with lung carcinoma and its precursor lesions especially when diagnosed by small biopsy specimens.
Abstract Micronodular thymoma with lymphoid stroma is a rare thymic neoplasm characterized by discrete nodules of epithelial tumor cells separated by abundant lymphoid stroma. The genetic features of micronodular thymoma with lymphoid stroma remain largely unexplored. Owing to the interference of abundant intra-tumoral non-neoplastic lymphoid cells, a highly sensitive approach is necessary to study the genetic changes in these tumors. In this study, we applied a highly sensitive next-generation sequencing assay using molecular barcoding Ion AmpliSeq HD technology to study the most commonly mutated genes in thymomas, including GTF2I , HRAS , NRAS , KRAS , and TP53 . A total of 12 cases of micronodular thymomas with lymphoid stroma were tested, and 2 cases also had areas of type A thymoma in their tumor bed. Two micronodular thymic carcinomas with lymphoid stroma, a histological mimic of micronodular thymoma, were also included for comparison. Recurrent GTF2I p.L424H mutations were found in all cases of micronodular thymoma with lymphoid stroma but not in micronodular thymic carcinomas. In addition, 3 cases of micronodular thymoma with lymphoid stroma also had concomitant HRAS and/or KRAS mutations. Our study shows that GTF2I p.L424H mutation is a constant genetic feature in micronodular thymoma with lymphoid stroma. This finding strongly suggests micronodular thymoma with lymphoid stroma is closely related to type A and type AB thymomas as they all share GTF2I p.L424H mutations.
Recently, membrane-type acoustic metamaterials have been found useful in eliminating low-frequency sound/noise. Those materials exhibit unusual vibroacosutic behavior and have a negative value in mass density. In this study, we present a new design of acoustic metamaterials that can effectively broaden sound attenuation zone and achieve acoustic negativity in mass density/bulk modulus. The proposed structure is comprised of two membranes and two ring masses which are attached on membrane surfaces, respectively. Both dipolar and monopolar resonance exist in the proposed coupled system, which makes acoustic negativity possible. By altering mass magnitude and membrane tension the transmission loss peak frequency can be easily tuned. With two membranes having two rings of different magnitudes, the attenuation bandwidth can be effectively broadened.
Abstract Background Breast cancer is one of the leading causes of cancer-related deaths in women. Limited therapeutic options currently available, especially for those with triple negative breast cancer, demands identification of more biomarkers to facilitate precision medicine. This study adopted an updated large comprehensive genomic profiling (CGP) for targeted sequencing to reveal actionable alterations associated with novel therapeutics from a sub-cohort of the VGH-TARLOR study. Method The study population comprised of patients with either early (defined by first-line surgery or neoadjuvant therapy) or late (defined by relapse or de novo metastatic disease) breast cancer. CGP was conducted with the Illumina TruSight Oncology 500 assay. Level of actionability was evaluated against the European Society for Medical Oncology (ESMO) Scale of Clinical Actionability of molecular Targets (ESCAT) criteria with additional annotations from the PierianDx software and the OncoKB database. Results A total of 108 breast cancers were successfully assayed, with the majority (n = 104) being triple. The most common alterations (> 5% of study cohort) among actionable genes were PIK3CA (39%), BRCA2 (24%), PTEN (15%), ERBB2 (13%), BRCA1 (12%), and ERBB3 (10%). With the standard cut-off of 10 mutations/mega-base, 25 samples were tumor mutation burden (TMB)-high and 83 were TMB-low. The proportion of TMB-high was much lower among the early than late breast cancer patients (19% vs. 34.5%, respectively; P = 0.0499). Conclusion Our study showed the clinical applicability and feasibility of large-sized CGP, with more genes and multi-gene signatures such as TMB and microsatellite instability (MSI) investigated. Detection of more actionable biomarkers could potentially expand therapeutic opportunities for patients: e.g., immune checkpoint inhibitors (for TMB-high and MSI), poly ADP- ribose polymerase (PARP) inhibitor (for BRCA1/2 and PALB2), selective estrogen receptor degrader (for ESR1), tyrosine kinase inhibitor (for ERBB2/3), phosphoinositide 3-kinase inhibitor (for PIK3CA).
Aims The Cancer Genome Atlas (TCGA) provides an integrated resource for investigating the genetic, phenotypical and clinical characteristics of cancer. In this study, we aimed to define distinct subsets of clear cell renal cell carcinoma (ccRCC) through differential expression and principal component analyses. Methods and results We used DESeq2 to examine the expression profiles of 472 cases in TCGA. After a process of segregation and regrouping, we compared the mutation and copy number variation landscapes to discern two major clusters: cluster 1, composed mainly of classic ccRCC, and cluster 2, which was associated with gains at chromosomes 7 and 12. Gene set enrichment analysis disclosed that cluster 2 tumours were enriched in genes involving epithelial–mesenchymal transition. Histologically, cluster 2 tumours frequently exhibited cell elongation or spindling. Patients with cluster 2 tumours or tumours harbouring chromosomes 7 or 12 gains had a significantly greater cumulative incidence of mortality. We then employed fluorescence in‐situ hybridisation with probes against chromosomes 7 and 12 in a cohort of 119 cases of ccRCC from our institute for validation. Chromosomes 7 and 12 gains were associated with lower survival rates in both univariate and multivariate analyses. Conclusions Our study demonstrates that genetic data obtained through appropriate molecular methodologies can be a useful adjunct to help predict prognosis. It also provides an example of exploring TCGA to extract meaningful information that can eventually contribute to precision medicine.
Occasionally, malignant pleural disease is only detected unexpectedly during surgery in patients with pulmonary adenocarcinoma. Previous studies mostly focused on the role of main tumor resection on patient's outcome, barely addressing the position of postoperative systemic therapy.The medical records of 5321 non-small cell lung cancer patients who underwent thoracic surgery between January 1990 and December 2012 were reviewed. Pulmonary adenocarcinoma patients with unexpected pleural spread noted during surgery were included. The clinical and postoperative treatment variables were assessed for correlation with overall survival.In 134 patients identified, main tumor resection was performed in 87 (64.9%) patients, while 89 (66.4%) and 57 (42.5%) patients received postoperative chemotherapy and epidermal growth factor receptor- tyrosine kinase inhibitor (EGFR -TKI) therapy, respectively. Overall, the 5-year survival rate was 30.2% and median survival time was 29.3 months. Multivariate analysis showed main tumor resection and EGFR-TKI therapy were associated with better survival. Mutational status of EGFR was available in 57 patients and 43 (75.4%) had activating mutations. Resection of the main tumor conferred a better outcome in patients without EGFR mutation or with unknown EGFR mutation status and had not been treated with EGFR-TKI therapy (P = 0.003), but not in those with activating EGFR mutation and had been treated with EGFR-TKI (P = 0.857).In pulmonary adenocarcinoma patients with unexpected pleural spread detected during surgery, main tumor resection and EGFR-TKI therapy correlated with better survival. Identifying EGFR mutation status before surgery can provide useful information for clinical decision during surgery.
'/%3e%3cuse xlink:href='%23a' transform='rotate(60)'/%3e%3ccircle r='17' fill='%23000095'/%3e%3ccircle r='15' fill='%23fff'/%3e%3c/svg%3e)