Whole exome sequencing of benign pulmonary metastasizing leiomyoma reveals mutation in the BMP8B gene.

BACKGROUND: Benign metastasizing leiomyoma (BML) is an orphan neoplasm commonly characterized by pulmonary metastases consisting of smooth muscle cells. Patients with BML have usually a current or previous uterine leiomyoma, which is therefore suggested to be the most probable source of this tumour. The purpose of this case report was to determine the possible genetic grounds for pulmonary BML. CASE PRESENTATION: We present a case report in an asymptomatic 44-year-old female patient, who has developed uterine leiomyoma with subsequent pulmonary BML. Whole exome sequencing (WES) was used to detect somatic mutations in BML lesion. Somatic single nucleotide mutations were identified by comparing the WES data between the pulmonary metastasis and blood sample of the same BML patient. One heterozygous somatic mutation was selected for validation by Sanger sequencing. Clonality of the pulmonary metastasis and uterine leiomyoma was assessed by X-chromosome inactivation assay. CONCLUSIONS: We describe a potentially deleterious somatic heterozygous mutation in bone morphogenetic protein 8B (BMP8B) gene (c.1139A > G, Tyr380Cys) that was identified in the pulmonary metastasis and was absent from blood and uterine leiomyoma, and may play a facilitating role in the metastasizing of BML. The clonality assay confirmed a skewed pattern of X-chromosome inactivation, suggesting monoclonal origin of the pulmonary metastases.

Identification of miR-374a as a prognostic marker for survival in patients with early-stage nonsmall cell lung cancer.

Lung cancer is one of the deadliest types of cancer proven by the poor survival and high relapse rates after surgery. Recently discovered microRNAs (miRNAs), small noncoding RNA molecules, play a crucial role in modulating gene expression networks and are directly involved in the progression of a number of human cancers. In this study, we analyzed the expression profile of 858 miRNAs in 38 Estonian nonsmall cell lung cancer (NSCLC) samples (Stage I and II) and 27 adjacent nontumorous tissue samples using Illumina miRNA arrays. We found that 39 miRNAs were up-regulated and 33 down-regulated significantly in tumors compared with normal lung tissue. We observed aberrant expression of several well-characterized tumorigenesis-related miRNAs, as well as a number of miRNAs whose function is currently unknown. We show that low expression of miR-374a in early-stage NSCLC is associated with poor patient survival. The combinatorial effect of the up- and down-regulated miRNAs is predicted to most significantly affect pathways associated with cell migration, differentiation and growth, and several signaling pathways that contribute to tumorigenesis. In conclusion, our results demonstrate that expression of miR-374a at early stages of NSCLC progression can serve as a prognostic marker for patient risk stratification and may be a promising therapeutic target for the treatment of lung cancer.

An anaplastic lymphoma kinase (ALK) fusion oncogene positive metastatic sarcomatoid carcinoma of the lung with good response to crizotinib.

Primary sarcomatoid carcinoma (SC) of the lung is a rare tumor that accounts for less than 1% of all lung cancers and compared to other non-small cell lung cancers (NSCLC) they appear more aggressive with poorer prognosis and response to treatment. Carcinosarcoma is one of the subtypes of SC. We report a case of carcinosarcoma with ALK-EML4 fusion gene in a 50-year-old male patient with a good response to therapy with crizotinib. An ALK rearrangement is a rare finding in SC, but as this case demonstrates, it may occur and it is necessary to perform the ALK testing in these tumors to find possible targeted treatments for better outcomes.

Correction: Methylation Markers of Early-Stage Non-Small Cell Lung Cancer.

[This corrects the article DOI: 10.1371/journal.pone.0039813.].

Pulmonary intravascular talcosis mimicking miliary tuberculosis in an intravenous drug addict.

Pulmonary foreign body granulomatosis following intravenous administration of medications meant for oral use among drug addicts has been occasionally reported. This condition is often misdiagnosed because of its rarity, but rather due to its similarity to other pulmonary diseases that are more common. Here we report a case of pulmonary intravascular talcosis mimicking miliary tuberculosis in a young male intravenous drug addict from North-Eastern Estonia, known as a hotspot for tuberculosis and drug misuse. The condition was caused by intravenous administration of crushed tablets of diphenhydramine, but miliary tuberculosis was misdiagnosed on patient's demographical, clinical and radiological grounds and a decision to start treatment with four first-line antituberculosis drugs followed. The current report refers to the importance of considering rare causes of pulmonary disseminations with attempts to identify the causative agent and warns against the use of antituberculosis treatment without confirmation of microbiological diagnosis of tuberculosis.

Methylation markers of early-stage non-small cell lung cancer.

BACKGROUND: Despite of intense research in early cancer detection, there is a lack of biomarkers for the reliable detection of malignant tumors, including non-small cell lung cancer (NSCLC). DNA methylation changes are common and relatively stable in various types of cancers, and may be used as diagnostic or prognostic biomarkers. METHODS: We performed DNA methylation profiling of samples from 48 patients with stage I NSCLC and 18 matching cancer-free lung samples using microarrays that cover the promoter regions of more than 14,500 genes. We correlated DNA methylation changes with gene expression levels and performed survival analysis. RESULTS: We observed hypermethylation of 496 CpGs in 379 genes and hypomethylation of 373 CpGs in 335 genes in NSCLC. Compared to adenocarcinoma samples, squamous cell carcinoma samples had 263 CpGs in 223 hypermethylated genes and 513 CpGs in 436 hypomethylated genes. 378 of 869 (43.5%) CpG sites discriminating the NSCLC and control samples showed an inverse correlation between CpG site methylation and gene expression levels. As a result of a survival analysis, we found 10 CpGs in 10 genes, in which the methylation level differs in different survival groups. CONCLUSIONS: We have identified a set of genes with altered methylation in NSCLC and found that a minority of them showed an inverse correlation with gene expression levels. We also found a set of genes that associated with the survival of the patients. These newly-identified marker candidates for the molecular screening of NSCLC will need further analysis in order to determine their clinical utility.

Metagenes associated with survival in non-small cell lung cancer.

NSCLC (non-small cell lung cancer) comprises about 80% of all lung cancer cases worldwide. Surgery is most effective treatment for patients with early-stage disease. However, 30%-55% of these patients develop recurrence within 5 years. Therefore, markers that can be used to accurately classify early-stage NSCLC patients into different prognostic groups may be helpful in selecting patients who should receive specific therapies.A previously published dataset was used to evaluate gene expression profiles of different NSCLC subtypes. A moderated two-sample t-test was used to identify differentially expressed genes between all tumor samples and cancer-free control tissue, between SCC samples and AC/BC samples and between stage I tumor samples and all other tumor samples. Gene expression microarray measurements were validated using qRT-PCR.Bayesian regression analysis and Kaplan-Meier survival analysis were performed to determine metagenes associated with survival. We identified 599 genes which were down-regulated and 402 genes which were up-regulated in NSCLC compared to the normal lung tissue and 112 genes which were up-regulated and 101 genes which were down-regulated in AC/BC compared to the SCC. Further, for stage Ib patients the metagenes potentially associated with survival were identified.Genes that expressed differently between normal lung tissue and cancer showed enrichment in gene ontology terms which were associated with mitosis and proliferation. Bayesian regression and Kaplan-Meier analysis showed that gene-expression patterns and metagene profiles can be applied to predict the probability of different survival outcomes in NSCLC patients.

Gene Expression-Based Approaches in Differentiation of Metastases and Second Primary Tumour.

A 64-year-old male patient was diagnosed with 3 consecutive non-small cell lung carcinomas (NSCLC). In the current study, we applied whole-genome gene expression analysis to control, primary and locally recurrent cancer, and supposed metastasis samples of a single patient. According to our knowledge, there are no published papers describing the gene expression profiles of a single patient's squamous cell lung cancers. As the histology and differentiation grade of the primary cancer and the supposed metastasis differed minimally, but local recurrence was poorly differentiated, molecular profiling of the samples was carried out in order to confirm or reject the hypothesis of second primary cancer. Principal component analysis of the gene expression data revealed distinction of the local recurrence. Gene ontology analysis showed no molecular characteristics of metastasis in the supposed metastasis. Gene expression analysis is valuable and can be supportive in decision-making of diagnostically complicated cancer cases.

Fourth meeting of the European Network of Research Tissue Banks - future strategy to increase collaborations in the supply of human tissue for biomedical research.

This report records the Fourth meeting of the European Network of Research Tissue Bank (Brussels, 18th March 2004) which was attended by Mel Read MEP. The existing membership of this informal group represents European Human Research Tissue Bankers, biomedical researchers seeking access to human tissue and allied groups including animal welfare representatives. This Fourth meeting provided a forum to update members on individual activity in this area. A particular focus of this meeting was to consider the status of this group and future affiliations to increase the profile and activity of this Network. This meeting addressed differences in legislative and ethical requirements governing the use of human tissue in biomedical research in the different countries represented. Future activity of the ENRTB, planned at this meeting, will target harmonisation of current differences which are currently barriers to increased access to human tissue for biomedical research. Through the harmonisation of procurement, processing and distribution of human tissue specimens the ENRTB will provide a mechanism to benefit human health through increased use of human tissue in pharmacotoxicological studies and the associated replacement of animal tests.