IMSA: Integrated Metagenomic Sequence Analysis for Identification of Exogenous Reads in a Host Genomic Background

Metagenomics, the study of microbial genomes within diverse environments, is a rapidly developing field. The identification of microbial sequences within a host organism enables the study of human intestinal, respiratory, and skin microbiota, and has allo

Investigation of the genes for RET and its ligand complex, GDNF/GFR alpha-1, in small cell lung carcinoma

RET is a receptor tyrosine kinase expressed in neuroendocrine cells and in tumors of these cell types. RET activation may be mediated by a ligand complex comprising glial cell line-derived neurotrophic factor (GDNF) and GDNF family receptor alpha-1 (GFR alpha-1). Activating RET mutations are found in the inherited cancer syndrome multiple endocrine neoplasia type 2 and in a subset of the related sporadic tumors, medullary thyroid carcinoma and pheochromocytoma, both being derived from neuroendocrine tissues, In one small study, mutations were identified in another tumor with neuroendocrine features, small cell lung carcinoma (SCLC), To determine whether RET mutations contribute to the pathogenesis of SCLC, we examined a panel of 54 SCLC cell lines. No mutations were identified in RET exons 10, I I, and 13-16, regions previously implicated in SCLC or other neuroendocrine tumors, We further examined the expression pattern of RET and the genes encoding the components of its ligand complex GDNF and GFR alpha-1, in 21 SCLC lines by using RT-PCR. Although we found no consistent pattern of expression for these three genes, RET was expressed in 57% of SCLC lines. Thus, although RET mutations appear unlikely to be an important step in the tumorigenesis of SCLC, the frequent expression of this gene suggests that RET may have a mitogenic role in a subset of SCLC cell lines, (C) 1998 Wiley-Liss, Inc

Investigation of the genes for RET and its ligand complex, GDNF/GFR alpha-1, in small cell lung carcinoma

RET is a receptor tyrosine kinase expressed in neuroendocrine cells and in tumors of these cell types. RET activation may be mediated by a ligand complex comprising glial cell line-derived neurotrophic factor (GDNF) and GDNF family receptor alpha-1 (GFR alpha-1). Activating RET mutations are found in the inherited cancer syndrome multiple endocrine neoplasia type 2 and in a subset of the related sporadic tumors, medullary thyroid carcinoma and pheochromocytoma, both being derived from neuroendocrine tissues, In one small study, mutations were identified in another tumor with neuroendocrine features, small cell lung carcinoma (SCLC), To determine whether RET mutations contribute to the pathogenesis of SCLC, we examined a panel of 54 SCLC cell lines. No mutations were identified in RET exons 10, I I, and 13-16, regions previously implicated in SCLC or other neuroendocrine tumors, We further examined the expression pattern of RET and the genes encoding the components of its ligand complex GDNF and GFR alpha-1, in 21 SCLC lines by using RT-PCR. Although we found no consistent pattern of expression for these three genes, RET was expressed in 57% of SCLC lines. Thus, although RET mutations appear unlikely to be an important step in the tumorigenesis of SCLC, the frequent expression of this gene suggests that RET may have a mitogenic role in a subset of SCLC cell lines, (C) 1998 Wiley-Liss, Inc

Somatic genetic changes accompanying lung tumor development.

Carcinomas are believed to develop by incremental steps of increasingly abnormal morphology driven by accumulating somatic genetic changes. This process is often difficult to study, as the early stages are undetectable. We used fluorescence bronchoscopy, which enhances detection of preinvasive bronchial lesions, and have obtained sequential biopsies of carcinoma in situ (CIS) from a patient with no detectable tumor and from a squamous cell carcinoma that developed 19 months after presentation at the site of one of the previous CIS lesions. Biopsies of preinvasive CIS, which follow-up showed had different pathologic outcomes, and tumor were microdissected to obtain enriched cell populations and DNA prepared from them. Molecular characteristics of these biopsies were compared by loss of heterozygosity analysis, TP53 mutation analysis, and comparative genomic hybridization. Although all lesions examined had the same TP53 mutation and almost identical allelotypes, differences were observed. Loss in 5q21 and amplification of 3q25-26 were associated with the lesion that progressed and the subsequent carcinoma. Allele loss at 4p16 was detected in the tumor but not in any of the CIS lesions, suggesting it was a late event associated with tumor invasion. Amplification at 4q12 was specifically observed in the tumor and in the CIS at the site of eventual tumor formation. Although these findings may be unique to this one patient, the successful demonstration of sequential genetic changes raises the possibility that this approach, unencumbered by interpatient variability between lesions, will greatly facilitate the identification of molecular events driving the invasive proces

Surveillance for the detection of early lung cancer in patients with bronchial dysplasia.

BACKGROUND: The natural history of bronchial preinvasive lesions and the risk of developing lung cancer in patients with these lesions are not clear. Previous studies have treated severe dysplasia and carcinoma in situ (CIS) on the assumption that most will progress to invasive carcinoma. AIMS: To define the natural history of preinvasive lesions and assess lung cancer risk in patients with these lesions. HYPOTHESIS: Most preinvasive lesions will not progress to invasive carcinoma but patients with these lesions will be at high risk. METHODS: A cohort of patients with preinvasive lesions underwent fluorescence bronchoscopy every 4-12 months and computed tomography of the chest annually. The main end point was the development of invasive carcinoma. RESULTS: 22 patients with 53 lesions were followed up for 12-85 months. 11 cancers were diagnosed in 9 patients. Of the 36 high-grade lesions (severe dysplasia and CIS), 6 progressed to invasive cancers. 5 separate cancers developed at remote sites in patients with high-grade lesions. All cancers were N0M0 and curative treatment was given to 8 of the 9 patients. The cumulative risk of developing lung cancer in a patient with a high-grade lesion was 33% and 54% at 1 and 2 years, respectively. Of the 17 low-grade lesions, none progressed to invasive carcinoma. CONCLUSIONS: Although the risk of malignant progression of individual preinvasive lesions is relatively small, patients with high-grade lesions are at high risk of lung cancer. Surveillance facilitated early detection and treatment with curative intent in most patients