Dataset Information

Characterizing the cancer genome in lung adenocarcinoma.

ABSTRACT: Somatic alterations in cellular DNA underlie almost all human cancers. The prospect of targeted therapies and the development of high-resolution, genome-wide approaches are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours (n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in approximately 12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.

SUBMITTER: Weir BA

PROVIDER: S-EPMC2538683 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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Characterizing the cancer genome in lung adenocarcinoma.

Weir Barbara A BA Woo Michele S MS Getz Gad G Perner Sven S Ding Li L Beroukhim Rameen R Lin William M WM Province Michael A MA Kraja Aldi A Johnson Laura A LA Shah Kinjal K Sato Mitsuo M Thomas Roman K RK Barletta Justine A JA Borecki Ingrid B IB Broderick Stephen S Chang Andrew C AC Chiang Derek Y DY Chirieac Lucian R LR Cho Jeonghee J Fujii Yoshitaka Y Gazdar Adi F AF Giordano Thomas T Greulich Heidi H Hanna Megan M Johnson Bruce E BE Kris Mark G MG Lash Alex A Lin Ling L Lindeman Neal N Mardis Elaine R ER McPherson John D JD Minna John D JD Morgan Margaret B MB Nadel Mark M Orringer Mark B MB Osborne John R JR Ozenberger Brad B Ramos Alex H AH Robinson James J Roth Jack A JA Rusch Valerie V Sasaki Hidefumi H Shepherd Frances F Sougnez Carrie C Spitz Margaret R MR Tsao Ming-Sound MS Twomey David D Verhaak Roel G W RG Weinstock George M GM Wheeler David A DA Winckler Wendy W Yoshizawa Akihiko A Yu Soyoung S Zakowski Maureen F MF Zhang Qunyuan Q Beer David G DG Wistuba Ignacio I II Watson Mark A MA Garraway Levi A LA Ladanyi Marc M Travis William D WD Pao William W Rubin Mark A MA Gabriel Stacey B SB Gibbs Richard A RA Varmus Harold E HE Wilson Richard K RK Lander Eric S ES Meyerson Matthew M

Nature 20071104 7171

Somatic alterations in cellular DNA underlie almost all human cancers. The prospect of targeted therapies and the development of high-resolution, genome-wide approaches are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours (n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurre ...[more]

PMID: 17982442

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Project description:Simple Summary The clinical behavior and progression of lung cancer vary case by case. Therefore, understanding the factors that contribute to aggressive lung cancer cases is crucially needed. Previously, we showed that transcription factor MYBL2 expression is associated with the survival of lung adenocarcinoma patients. In this study, we characterized the functions of MYBL2 in lung adenocarcinoma cells by generating global binding profiles of MYBL2 and transcriptome profiles upon knockdown experiments. We discovered that MYBL2 regulates cell cycle genes by binding to the promoters of highly expressed genes in lung adenocarcinoma cells working with FOXM1. Moreover, we found that a previously reported FOXM1 inhibitor, FDI-6 (forkhead domain inhibitor 6), suppresses lung adenocarcinoma cell proliferation by inhibiting the activities of MYBL2 and FOXM1 and controlling cell death and cell cycle genes. Our findings provide valuable insights into the molecular mechanisms of aggressive lung cancer and suggest potential targets and treatments for the disease. Abstract Overexpression of MYBL2 is associated with poor survival of lung adenocarcinoma patients, but the molecular mechanism by which it regulates transcription and carcinogenesis has not yet been elucidated. In this study, we performed ChIP-seq using an MYBL2-targeted antibody and discovered that MYBL2 primarily binds to the promoters of highly expressed genes in lung adenocarcinoma cells. Using a knockdown experiment of MYBL2 and global transcriptome profiling, we identified that over a thousand genes are dysregulated by MYBL2, and MYBL2 acts as a transcriptional activator in lung adenocarcinoma cells. Moreover, we revealed that the binding sites of FOXM1 are largely shared with MYBL2 binding sites, and genes involved in cell cycle phase transitions are regulated by these transcription factors. We furthermore investigated the effect of a previously reported FOXM1 inhibitor, FDI-6, in lung adenocarcinoma cells. We demonstrated that FDI-6 decreases the proliferation of lung adenocarcinoma cells and inhibits the activities of FOXM1 as well as MYBL2. Moreover, we found that genes involved in cell death and cell cycle are inhibited by FDI-6. Overall, our findings suggest that MYBL2 and FOXM1 activate cell cycle genes together, acting as oncogenic transcription factors in lung adenocarcinoma cells, and they are potential treatment targets for the disease.

Dataset Information

Characterizing the cancer genome in lung adenocarcinoma.

Publications

Characterizing the cancer genome in lung adenocarcinoma.

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