Project description:Lung carcinoids (LCs) are rare and slow growing primary lung neoplasms that are understudied. Here, we performed targeted exome sequencing using a 354-cancer gene panel (n=29), mRNA sequencing (n=30) and DNA methylation assay (n=18) on macro-dissected lung carcinoids. The mutations we identified were enriched for genes involved in covalent histone modification/chromatin remodeling (34.5%) (MEN1, ARID1A, KMT2C and KMT2A were recurrently mutated) as well as DNA repair (17.2%) pathways. Unsupervised clustering and principle component analysis on gene expression and DNA methylation profiles showed 3 robust molecular subtypes (LC1, LC2, LC3) with distinct clinical features. MEN1 gene mutations were found to be enriched and exclusively in the LC2 subtype (p-value<0.001). The LC3 subtype is predominately found at endobronchial lung and earlier age of diagnosis. Immunohistochemical staining of two biomarkers, ASCL1 and S100, is sufficient to stratify the three subtypes. This molecular classification of lung carcinoids into three subtypes may help improve treatment decision and clinical management.
Project description:DNA CpG methylation profiling of LC patients samples were performed to understand genotype to phenotype corrlelations , novel molecular subtypes and cell of origins Lung carcinoids (LCs) are rare and slow growing primary lung neoplasms that are understudied. Here, we performed targeted exome sequencing using a 354-cancer gene panel (n=29), mRNA sequencing (n=30) and DNA methylation assay (n=18) on macro-dissected lung carcinoids. The mutations we identified were enriched for genes involved in covalent histone modification/chromatin remodeling (34.5%) (MEN1, ARID1A, KMT2C and KMT2A were recurrently mutated) as well as DNA repair (17.2%) pathways. Unsupervised clustering and principle component analysis on gene expression and DNA methylation profiles showed 3 robust molecular subtypes (LC1, LC2, LC3) with distinct clinical features. MEN1 gene mutations were found to be enriched and exclusively in the LC2 subtype (p-value<0.001). The LC3 subtype is predominately found at endobronchial lung and earlier age of diagnosis. Immunohistochemical staining of two biomarkers, ASCL1 and S100, is sufficient to stratify the three subtypes. This molecular classification of lung carcinoids into three subtypes may help improve treatment decision and clinical management.
Project description:Global gene expression of 13 frozen samples, 6 from typical and 7 from atypical surgically resected primary lung carcinoids All the patients not chemo-radio naïve and with a second tumor were excluded from the study. A written informed consent for research use of biological samples was obtained from all the patients. tissue biopsies
Project description:Background: It is still uncertain whether carcinoids of the lung and gastrointestinal (GI) tract have a common origin or whether they are closer in origin to carcinomas of the same organs. MicroRNA (miRNA) expression may clarify their nature and origin. Methods: First, to verify whether formalin-fixed paraffin-embedded (FFPE) samples retain the expression signature of the tissue, miRNA expression was compared between FFPE and frozen samples. Second, we selected surgically resected FFPE samples of pulmonary and GI carcinoids, as well as other types of tumors and normal tissues from each organ, and we compared the comprehensive expression patterns of miRNAs by microarray. These data were analyzed by hierarchical clustering and consensus clustering with non-negative matrix factorization (NMF). Results: The miRNA expression profiles of FFPE and frozen samples correlated quite well. In the first hierarchical clustering, most of the carcinoids formed one major cluster with loose subpartitioning into each organ type, while the second major cluster mainly comprised adenocarcinomas and normal tissues. The NMF approach largely supported hierarchical clustering. In the additional cluster analysis comparing carcinoids to small-cell lung carcinomas (SCLCs), carcinoids formed a distinct cluster, while SCLCs grouped together with pulmonary adenocarcinomas and normal lung tissues in another major cluster. Furthermore, we found some miRNAs that exhibited significant expression in carcinoids. Conclusion: Carcinoids had a characteristic pattern of miRNA expression, suggesting a common origin for pulmonary and GI carcinoids. The expression profiles were different in carcinoids and SCLCs, indicating distinct histogenesis of these neuroendocrine tumors.
Project description:Global gene expression of 13 frozen samples, 6 from typical and 7 from atypical surgically resected primary lung carcinoids All the patients not chemo-radio naïve and with a second tumor were excluded from the study. A written informed consent for research use of biological samples was obtained from all the patients.