A F Gazdar

..Our preliminary data on the analysis of sputum DNA specimens from cancer patients further support these observations...

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..Our data constitute the first direct functional evidence for CYGB, the newest member of the globin family, as a tumor suppressor gene...

..However, the role of miRNAs in the pathogenesis and diagnosis of small cell carcinoma (SCLC), the majority of which represent the most aggressive lung tumors, has not been investigated...

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..For the patient to obtain maximum benefit from the recent developments in therapeutics, a multidisciplinary approach is required with co-operation between oncologists, surgeons, radiologists and pathologists...

..However, major problems including misidentification or cell line contamination remain. Ongoing studies and new approaches are expected to reveal the full potential of the lung cancer cell line panel...

..A study of preinvasive lung cancer has yielded much valuable biologic information that impacts on clinical management...

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..Various second-generation EGFR TKIs are currently being evaluated and may have the potential to overcome T790M-mediated resistance by virtue of their irreversible inhibition of the receptor TK domain...

..Finally the issue of cell line contamination must be addressed and safeguarded against. A full understanding of the advantages and shortcomings of cell lines is required for the investigator to derive the maximum benefit from their use...

..These studies demonstrate that multiple, often overlapping, mechanisms of disruption are present in lung cancer cells, presenting a plethora of molecular targets...

..The role of apoptosis regulation in lung cancer with major focus on the differential sensitivities of the major subtypes is reviewed...

..The molecular changes caused by each of these major etiologic factors and their interrelationships are the focus of this review...

..While a weak carcinogen, nicotine promotes carcinogenesis by a number of different mechanisms. The authors' findings provide further evidence of the harmful effects of ETS and indicate the desirability of reducing exposure to it...

..Cancer cells with mutant EGFR genes might become physiologically dependent on the continued activity of the gene for the maintenance of their malignant phenotype; however, this might also be a target for therapy...

..Our results demonstrate frequent aberrant methylation of CDH13 in breast and lung cancers accompanied by loss of gene expression, although expression may occasionally be lost by other mechanisms...

..Our findings may be of biological and clinical importance...

..Methylation of FHIT commences during lung cancer pathogenesis and may represent a marker for risk assessment...

..Our results demonstrate a relationship between SV40 and aberrant methylation in MMs...

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..Our results provide strong evidence that these TGFbeta-related genes are frequently deregulated through aberrant methylation in many human malignancies...

..We conclude that SCLC, carcinoids, squamous cell carcinomas, and adenocarcinomas of the lung have unique profiles of aberrant methylation. Our findings should help us understand differences in the pathogenetic mechanisms of lung cancers...

..We examined abnormalities in FHIT and its RNA transcripts in cervical cancer cell lines and tumors. We also investigated the relationship between loss of heterozygosity (LOH) in FHIT/FRA3B and the presence of oncogenic HPV types...

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..Aneuploidy was not found in preinvasive lesions accompanying the five metastatic cases. Our findings provide strong support for the concept of field cancerisation...

..These findings indicate that abnormalities of the p53 gene are involved in carcinogenesis and/or progression of this tumor and, furthermore, suggest that molecular analyses of ACC may provide information of prognostic importance...

..001). Our findings are of biological interest and potentially of clinical importance in human lung cancers...

..These findings indicate that p53 gene mutation is an early event and occurs frequently at an early stage of precancerous lesions and may be responsible for most cases of malignant transformation of PA...

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..Our method appears to be highly specific and increases the sensitivity of detection of malignant cells; it may be a useful adjunct to routine cytopathological examination...

..These results are consistent with SEMA3B functioning as a TSG, the expression of which is inactivated frequently in lung cancers by allele loss and promoter region methylation...

..Our results suggest that there may be multiple putative tumor suppressor genes located on both arms of chromosome 4 whose inactivation are important early events in the pathogenesis of colorectal carcinoma...

..3 that frequently undergoes allele loss in lung and breast cancers. We explored the hypothesis that RASSF1 encodes a tumor suppressor gene for lung and breast cancers...

..Our results suggest that methylation of TMS1 may play a role in the pathogenesis of small cell and non small lung and breast cancers...

..These advances highlight the translation of molecular discoveries on lung cancer pathogenesis from the laboratory to the clinic...

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..Second, mammary small-cell carcinoma is clonally related to ductal carcinoma in situ and might represent an example of divergent differentiation occurring in a multipotential neoplastic stem cell...

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..CDH1 methylation positive status was independently associated with poor survival in multivariate analyses. Our results suggest that the methylation profile may be a potential new biomarker of risk prediction in bladder cancer...

..CONCLUSIONS: The use of in situ hybridization technique bypasses the need for stringent specimen processing and allows identification of the specific cell type that expresses telomerase. Cancer (Cancer Cytopathol)..

..Our panel of paired tumor and non-malignant cell lines should provide important new reagents for breast cancer research...

..Our results demonstrate that DcR1 and DcR2 genes are frequently methylated in various tumor types, and that the role of decoy receptors in tumor pathogenesis needs to be re-evaluated...

..These results provide direct evidence that loss of DNMT1 expression abrogates tumor-associated promoter methylation and the resultant silencing of multiple genes implicated in the pathogenesis of human lung and breast cancer...

..Our findings demonstrate important smoke exposure, histologic type and geography-related differences in the methylation profiles of NSCLC tumors...

..CASP8 may function as a tumor suppressor gene in neuroendocrine lung tumors...

..This Review summarizes our current knowledge of this unique and poorly understood disease...

..In five of six cell lines, restoration of RASSF1A mRNA was confirmed by RT-PCR. Our findings indicate that aberrant promoter methylation of RASSF1A may contribute to the pathogenesis of many different forms of pediatric tumors...

..Importantly, it is now possible to analyze many of the genetic changes that precede cancer, thereby identifying populations "at risk" for developing malignancies in the future...

..This breast tumor-derived cell line may provide a useful model system for the study of familial breast cancer pathogenesis and for elucidating BRCA1 function and localization...

..In this study, we investigated the loss of expression of three LN5-encoding genes in breast cancer cell lines and elucidated the mechanism of silencing of the genes in breast cancer cell lines and tumors...

..These results suggest different roles for CAV1 in SCLC, where CAV1 acts like a tumor suppressor gene, and NSCLC, where it appears required for survival and growth...

..Our results demonstrate a relationship between SV40 and methylation of multiple genes in MM, indicating that the virus plays a role in the pathogenesis of MM...

..Our findings suggest that detection of methylation should be investigated as an intermediate marker for lung cancer risk assessment and response to chemopreventive regimens...

..Taken together, these data suggest that SRC-3 may be an important oncogene and therapeutic target for lung cancer...

..CONCLUSIONS: Our results demonstrate frequent epigenetic inactivation of LN5-encoding genes in lung cancers, and these findings are of biological interest and are potentially of clinical importance...

..Our results show that DNA methylation patterns differ between NSCLC and SCLC cell lines and suggest that these patterns could be developed into a powerful molecular marker to achieve accurate diagnosis of lung cancer...

..CONCLUSIONS: We found differential FEZ1 expression in NSCLC and SCLC cell lines, and the absent expression in 3 of 6 short-term cultures of NSCLC tumors. FEZ1 may be related to tumorigenesis of lung cancer...

..Our results suggest that epigenetic or mutational inactivation of hSRBC may contribute to the pathogenesis of several types of human cancers, marking hSRBC as a candidate tumor suppressor gene...

..Our findings strongly suggest that 10p15.1 harbours a gene involved in repression of telomerase RNA component in human somatic cells and each putative repressor (on 3p and 10p) may act independently...

..Thus, we review recent findings on DNA methylation based cancer biomarkers with particular focus on these applicable to the clinical specimens obtained non-invasively from cancer patients...

..The profile of aberrant methylation suggests that an accumulation of events at specific genes may trigger malignant transformation of some benign cystadenomas and LMP tumors...

..We conclude that abnormalities of BAF180 are not frequently involved in the pathogenesis of lung cancer...

..These data indicate that Reprimo methylation is frequent in lung cancers and occurs independently of p53 status. Methylation of Reprimo may play a role in the pathogenesis of lung cancers...

..These data, together with our previous findings, support a causal relationship between SV40 infection, progressive RASSF1A methylation and its silencing, and the pathogenesis of mesothelioma...

..Aberrant methylation of Reprimo with loss of expression is a common event and may contribute to the pathogenesis of some types of human malignancy...

..Finally, correcting even single genetic abnormalities can reverse the malignant phenotype...

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..Thus, the mutations that altered signaling also decreased the interaction of EGFRs with the mechanisms responsible for endosomal sorting...

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..Our results suggest that deregulation of the death receptor pathway to apoptosis is frequent in many types of pediatric tumors and their cell lines...

..Mutations of EGFR (mEGFR) and copy number gains (CNGs) of EGFR (gEGFR) and HER2 (gHER2) have been reported to predict for TKI response. Mutations in KRAS (mKRAS) are associated with primary resistance to TKIs...

..These findings are of biological interest and potentially of clinical importance...

..We therefore conclude that epigenetic regulation plays a potential role in regulating hDAB2IP expression in PCa and that these results also provide a new therapeutic strategy for PCa patients...

..In tumors PCT changes were only present when the corresponding nonmalignant lung demonstrated a variation from the most common repeat number of seven...

..These differences were highly significant (P<0.0001). These findings suggest that methylation commences in UV exposed skin at a relatively early age and occurs in skin prior to the onset of recognizable preneoplastic changes...

..Accurate individualized breast cancer risk assessment may be possible based on molecular analysis of breast epithelial cells obtained by random FNA...

..In addition, for optimal therapeutic approach a comprehensive understanding of the genes related to EGFR signaling pathway, including RAS/RAF/MAPK and PI3K-AKT pathways, are required...

..In this study, we examined the effects of the histone deacetylase inhibitor, romidepsin, in combination with erlotinib, in NSCLC cell lines and xenografts...

..The objective of this study was to examine distributions of these three polymorphisms and their relationships to each other and to EGFR gene mutations and allelic imbalance (AI) in non-small cell lung cancers...

..We further showed similar applications with multiple other malignancies. Our assay might have important implications in early detection and surveillance of multiple malignancies...

..However, the role of such mutations in the pathogenesis of lung cancers is unclear...

..In this article, we review genome-wide and quantitative, high- resolution methods for methylation analysis that are used in the laboratory and clinic, and discuss their potential for use in a clinical setting...

..While there was no relationship between the other genes and survival, p16(INK4a) methylation was significantly related to unfavourable prognosis in lung adenocarcinomas...

..Of particular interest, methylation frequencies of LAMA3 helped to distinguish invasive (72%) from noninvasive (12%) tumors. These results suggest that methylation of LN5 genes has potential clinical applications in bladder cancers...

..The purpose of the current study was to determine the correlation between the aberrant promoter methylation of multiple genes and survival in patients with nonsmall cell lung carcinoma (NSCLC)...

..We used quantitative PCR assays to evaluate methylation in five candidate genes (TNFRSF10C, DAPK1, SOCS3, HS3ST2 and CDH1) previously demonstrated as methylated in cervical cancer...

..All these strategies should aid in reducing the number of newly diagnosed lung cancer cases and in increasing the survival and quality of life of patients with lung cancer...

..These HBEC lines are a valuable new tool for studying of the pathogenesis of lung cancer...

..CONCLUSIONS: The three major forms of lymphoid/hematopoietic malignancies show overlapping but individual patterns of methylation...

..5% nt identity to PTEN/MMAC1, that needs to be accounted for in cDNA mutation analysis. Our findings suggest that genetic abnormalities of the PTEN/MMAC1 gene are only involved in a relatively small subset of lung cancers...

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..Our findings indicate that mutation of the tyrosine kinase domain of EGFR is an early event in the pathogenesis of lung adenocarcinomas, and suggest EGFR mutations as an early detection marker and chemoprevention target...

..However, in a minority of these tumors, different areas may be derived from different precursor cells...

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..Our proposal will generate unique reagents useful for many studies, identify the sequential molecular changes during multistage pathogenesis and validate markers for early detection and risk assessment. ..

..A charge back fee system will recover some of the costs and will be used for future expansion of the Facility, which is anticipated to become self sustaining after five years. ..