Publications by authors named "Harold Varmus"

93 Publications

Science funding: Provocative questions in cancer research.

Nature 2012 Jan 25;481(7382):436-7. Epub 2012 Jan 25.

US National Cancer Institute, USA.

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http://dx.doi.org/10.1038/481436aDOI Listing
January 2012

Ubiquitination, localization, and stability of an anti-apoptotic BCL2-like protein, BCL2L10/BCLb, are regulated by Ubiquilin1.

Proc Natl Acad Sci U S A 2012 Jan 10;109(3):E119-26. Epub 2012 Jan 10.

Cancer Biology and Genetics Section, Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.

We have previously shown that all six members of the anti-apoptotic BCL2 gene family can cooperate with (myelocytomatosis oncogene) MYC in a mouse model of leukemia, but three of them are significantly less potent contributors to leukemogenicity than the other three. The protein encoded by one of these less potent genes, BCL2L10/BCLb, was recently shown to vary dramatically in many primary human cancers by immunohistochemistry, and the protein levels were inversely correlated with survival in patients with several cancer types. We examined BCLb mRNA in a panel of human cancer cell lines and did not observe the extensive variation in mRNA that would be required to explain the vast differences in protein levels. We found that the levels of BCLb protein diminish quickly after inhibition of protein synthesis with cycloheximide, so we searched for interacting proteins that might affect posttranslational stability of BCLb. Using a variety of approaches, including immunoaffinity and mass spectrometry, we identified a protein, Ubiquilin1 (Ubqln), that specifically interacts with BCLb, and not with other anti-apoptotic BCL2-like proteins. Ubqln stabilizes BCLb protein, while also promoting monoubiquitination on multiple lysine residues and relocation to the cytosol. Furthermore, primary lung adencarcinomas have more Ubqln mRNA than normal adjacent lung tissue, and higher Ubqln mRNA levels are associated with shorter survival of lung cancer patients, suggesting that potentiation of the anti-apoptotic potential of BCLb through regulation of its stability by Ubqln may be an important factor in tumor progression.
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http://dx.doi.org/10.1073/pnas.1119167109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271887PMC
January 2012

Epstein-Barr virus: an important vaccine target for cancer prevention.

Sci Transl Med 2011 Nov;3(107):107fs7

National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH), Bethesda, MD 20892, USA.

Participants at the February 2011 meeting at the U.S. National Institutes of Health on Epstein-Barr virus (EBV) vaccine research recommend that future clinical trials have two goals: prevention of infectious mononucleosis and EBV-associated cancers, facilitated by identification of disease-predictive surrogate markers.
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http://dx.doi.org/10.1126/scitranslmed.3002878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501269PMC
November 2011

Receptor for hyaluronan-mediated motility isoform B promotes liver metastasis in a mouse model of multistep tumorigenesis and a tail vein assay for metastasis.

Proc Natl Acad Sci U S A 2011 Oct 21;108(40):16753-8. Epub 2011 Sep 21.

Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

The gene encoding the receptor for hyaluronan-mediated motility (RHAMM) is overexpressed in many human cancers. However, it is unclear whether RHAMM plays a causal role in tumor initiation or progression. Using somatic gene transfer in a mouse model of islet cell tumorigenesis, we demonstrate that RHAMM isoform B (RHAMM(B)) promotes tumor growth and metastases to lymph nodes and the liver. The propensity of RHAMM(B)-expressing cells to metastasize to the liver was confirmed using an experimental metastasis assay in which cells were injected into the tail vein of immunodeficient mice. However, RHAMM(B) did not increase cell migration or proliferation in culture. In initial efforts to identify signaling pathways activated by RHAMM(B), we found that RHAMM(B) induced phosphorylation of epidermal growth factor receptor (EGFR), Erk1/2, and STAT3 and conferred susceptibility to apoptosis after treatment with an EGFR inhibitor, gefitinib. Taken together, the results indicate that RHAMM(B) promotes hepatic metastasis by islet tumor cells, perhaps through growth factor receptor-mediated signaling.
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http://dx.doi.org/10.1073/pnas.1114022108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189086PMC
October 2011

Integrating cancer control into global health.

Sci Transl Med 2011 Sep;3(101):101cm28

National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.

Many in the global health community have recently proposed that current efforts be expanded to include diseases typically associated with advanced economies, such as heart disease, mental health disorders, diabetes, and cancers. Here, we discuss ways in which the National Cancer Institute's newly formed Center for Global Health plans to stem the rising cancer burden in developing countries.
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http://dx.doi.org/10.1126/scitranslmed.3002321DOI Listing
September 2011

Superoxide dismutase 1 (SOD1) is a target for a small molecule identified in a screen for inhibitors of the growth of lung adenocarcinoma cell lines.

Proc Natl Acad Sci U S A 2011 Sep 19;108(39):16375-80. Epub 2011 Sep 19.

High Throughput Screening Core Facility, and Organic Synthesis Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. or

We previously described four small molecules that reduced the growth of lung adenocarcinoma cell lines with either epidermal growth factor receptor (EGFR) or KRAS mutations in a high-throughout chemical screen. By combining affinity proteomics and gene expression analysis, we now propose superoxide dismutase 1 (SOD1) as the most likely target of one of these small molecules, referred to as lung cancer screen 1 (LCS-1). siRNAs against SOD1 slowed the growth of LCS-1 sensitive cell lines; conversely, expression of a SOD1 cDNA increased proliferation of H358 cells and reduced sensitivity of these cells to LCS-1. In addition, SOD1 enzymatic activity was inhibited in vitro by LCS-1 and two closely related analogs. These results suggest that SOD1 is an LCS-1-binding protein that may act in concert with mutant proteins, such as EGFR and KRAS, to promote cell growth, providing a therapeutic target for compounds like LCS-1.
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http://dx.doi.org/10.1073/pnas.1113554108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182729PMC
September 2011

Lung cancer signatures in plasma based on proteome profiling of mouse tumor models.

Cancer Cell 2011 Sep;20(3):289-99

Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

We investigated the potential of in-depth quantitative proteomics to reveal plasma protein signatures that reflect lung tumor biology. We compared plasma protein profiles of four mouse models of lung cancer with profiles of models of pancreatic, ovarian, colon, prostate, and breast cancer and two models of inflammation. A protein signature for Titf1/Nkx2-1, a known lineage-survival oncogene in lung cancer, was found in plasmas of mouse models of lung adenocarcinoma. An EGFR signature was found in plasma of an EGFR mutant model, and a distinct plasma signature related to neuroendocrine development was uncovered in the small-cell lung cancer model. We demonstrate relevance to human lung cancer of the protein signatures identified on the basis of mouse models.
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http://dx.doi.org/10.1016/j.ccr.2011.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406925PMC
September 2011

NIH cancer chief wants more with less: by Meredith Wadman.

Authors:
Harold Varmus

Nature 2011 Jul 6;475(7354):18. Epub 2011 Jul 6.

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http://dx.doi.org/10.1038/475018aDOI Listing
July 2011

Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy.

Nat Genet 2010 Aug 4;42(8):715-21. Epub 2010 Jul 4.

Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts, USA.

Soft-tissue sarcomas, which result in approximately 10,700 diagnoses and 3,800 deaths per year in the United States, show remarkable histologic diversity, with more than 50 recognized subtypes. However, knowledge of their genomic alterations is limited. We describe an integrative analysis of DNA sequence, copy number and mRNA expression in 207 samples encompassing seven major subtypes. Frequently mutated genes included TP53 (17% of pleomorphic liposarcomas), NF1 (10.5% of myxofibrosarcomas and 8% of pleomorphic liposarcomas) and PIK3CA (18% of myxoid/round-cell liposarcomas, or MRCs). PIK3CA mutations in MRCs were associated with Akt activation and poor clinical outcomes. In myxofibrosarcomas and pleomorphic liposarcomas, we found both point mutations and genomic deletions affecting the tumor suppressor NF1. Finally, we found that short hairpin RNA (shRNA)-based knockdown of several genes amplified in dedifferentiated liposarcoma, including CDK4 and YEATS4, decreased cell proliferation. Our study yields a detailed map of molecular alterations across diverse sarcoma subtypes and suggests potential subtype-specific targets for therapy.
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http://dx.doi.org/10.1038/ng.619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911503PMC
August 2010

Ten years on--the human genome and medicine.

Authors:
Harold Varmus

N Engl J Med 2010 May;362(21):2028-9

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http://dx.doi.org/10.1056/NEJMe0911933DOI Listing
May 2010

Erlotinib resistance in mouse models of epidermal growth factor receptor-induced lung adenocarcinoma.

Dis Model Mech 2010 Jan-Feb;3(1-2):111-9. Epub 2009 Dec 9.

Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Seventy-five percent of lung adenocarcinomas with epidermal growth factor receptor (EGFR) mutations respond to treatment with the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib; however, drug-resistant tumors eventually emerge. In 60% of cases, resistant tumors carry a secondary mutation in EGFR (T790M), amplification of MET, or both. Here, we describe the establishment of erlotinib resistance in lung tumors, which were induced by mutant EGFR, in transgenic mice after multiple cycles of drug treatment; we detect the T790M mutation in five out of 24 tumors or Met amplification in one out of 11 tumors in these mice. This preclinical mouse model, therefore, recapitulates the molecular changes responsible for resistance to TKIs in human tumors and holds promise for the discovery of additional mechanisms of drug resistance in lung cancer.
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http://dx.doi.org/10.1242/dmm.003681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806903PMC
March 2010

Identification and preliminary characterization of novel small molecules that inhibit growth of human lung adenocarcinoma cells.

J Biomol Screen 2009 Dec;14(10):1176-84

Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Drug treatment for human lung cancers remains unsatisfactory, despite the identification of many potential therapeutic targets (such as mutant KRAS protein) and the approval of agents that inhibit the tyrosine kinase activity of mutant epidermal growth factor receptor (EGFR). To seek new therapeutic strategies against lung tumors, the authors have screened 189,290 small molecules for their ability to retard growth of human lung adenocarcinoma cell lines, which harbor mutations in EGFR or KRAS. Four candidates that are structurally different from common tyrosine kinase inhibitors were selected for further study. The authors describe one small molecule (designated lung cancer screen-1 [LCS-1]) in detail here. Identification of the targets of LCS-1 and other growth inhibitors found in this screen may help to develop new agents for the treatment of lung adenocarcinomas, including those driven by mutant EGFR and KRAS.
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http://dx.doi.org/10.1177/1087057109350919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146390PMC
December 2009

Activation of PyMT in beta cells induces irreversible hyperplasia, but oncogene-dependent acinar cell carcinomas when activated in pancreatic progenitors.

PLoS One 2009 Sep 7;4(9):e6932. Epub 2009 Sep 7.

Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

It is unclear whether the cellular origin of various forms of pancreatic cancer involves transformation or transdifferentiation of different target cells or whether tumors arise from common precursors, with tumor types determined by the specific genetic alterations. Previous studies suggested that pancreatic ductal carcinomas might be induced by polyoma middle T antigen (PyMT) expressed in non-ductal cells. To ask whether PyMT transforms and transdifferentiates endocrine cells toward exocrine tumor phenotypes, we generated transgenic mice that carry tetracycline-inducible PyMT and a linked luciferase reporter. Induction of PyMT in beta cells causes beta-cell hyperplastic lesions that do not progress to malignant neoplasms. When PyMT is de-induced, beta cell proliferation and growth cease; however, regression does not occur, suggesting that continued production of PyMT is not required to maintain the viable expanded beta cell population. In contrast, induction of PyMT in early pancreatic progenitor cells under the control of Pdx1 produces acinar cell carcinomas and beta-cell hyperplasia. The survival of acinar tumor cells is dependent on continued expression of PyMT. Our findings indicate that PyMT can induce exocrine tumors from pancreatic progenitor cells, but cells in the beta cell lineage are not transdifferentiated toward exocrine cell types by PyMT; instead, they undergo oncogene-dependent hyperplastic growth, but do not require PyMT for survival.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0006932PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758666PMC
September 2009

Regulation of transgenes in three-dimensional cultures of primary mouse mammary cells demonstrates oncogene dependence and identifies cells that survive deinduction.

Genes Dev 2009 Jul;23(14):1677-88

Program in Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.

The advent of targeted therapies for cancer has provoked interest in experimental models for the systematic study of oncogene dependence. To that end, we developed a three-dimensional (3D) culture system to analyze the responses of primary mouse mammary epithelial cells to the induction and deinduction of oncogenes. Mammary cells derived from normal virgin mice, or from tritransgenic mice (TetO-MYC;TetO-Kras(G12D);MMTV-rtTA) in which MYC and mutant Kras can be regulated by doxycycline, develop from single cells into polarized acini. Lumen formation occurs without apparent apoptosis, and the hollow spheres of cells enlarge by division, with metaphase plates oriented perpendicularly to the apical surface. When MYC and Kras(G12D) are induced, the acini enlarge and form solid, depolarized spheres. Upon deinduction of MYC and Kras(G12D) the solid structures regress, leaving a repolarized monolayer of viable cells. These cells display a phenotype consistent with progenitors of mammary epithelium: They exclude Hoechst dye 33342, and reform acini in 3D cultures and repopulate mammary fat pads more efficiently than cells harvested from uninduced acini. Moreover, cells in the surviving spheres retain the ability to respond to reinduction and thus may represent the type of cells that give rise to recurrent tumors.
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http://dx.doi.org/10.1101/gad.1801809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714708PMC
July 2009

The enlightenment returns.

Science 2009 Mar;323(5921):1538

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http://dx.doi.org/10.1126/science.1173563DOI Listing
March 2009

Cell-specific transduction of Prdm1-expressing lineages mediated by a receptor for avian leukosis virus subgroup B.

J Virol 2009 May 11;83(10):4835-43. Epub 2009 Mar 11.

Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.

The transcription factor Blimp-1 has emerged as a regulator of cell fate in embryonic (germ cell) and adult (B- and T-cell immune effector and epithelial) lineages. It has also been proposed to act as a tumor suppressor in B-cell malignancy. Here, we present a novel in vivo system enabling the targeted genetic manipulation of cells expressing Prdm1, the gene encoding Blimp-1. We created bacterial artificial chromosome-transgenic mice expressing the avian leukosis virus (ALV) receptor TVB, fused to monomeric red fluorescent protein, under regulation by Prdm1 transcriptional elements, and we achieved transduction of TVB-expressing lymphocytes by ALV vectors bearing a subgroup B envelope. The system presented here incorporates a number of innovations. First, it is the first mammalian transgenic system that employs the ALV receptor TVB, thus expanding the flexibility and scope of ALV-mediated gene delivery. Second, it represents the first ALV-based system that allows gene transfer and expression into in vivo-activated mature lymphocytes, a cell type that has traditionally presented formidable challenges to efficient retroviral transduction. Third, Prdm1:TVB-mRFP transgenic animals could provide an invaluable tool for exploring the diverse roles of Blimp-1 in lineage commitment, immune regulation, and tumorigenesis.
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http://dx.doi.org/10.1128/JVI.02254-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682090PMC
May 2009

Somatic mutations affect key pathways in lung adenocarcinoma.

Nature 2008 Oct;455(7216):1069-75

The Genome Center at Washington University, Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63108, USA.

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
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http://dx.doi.org/10.1038/nature07423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694412PMC
October 2008

Comparisons of tyrosine phosphorylated proteins in cells expressing lung cancer-specific alleles of EGFR and KRAS.

Proc Natl Acad Sci U S A 2008 Sep 5;105(37):14112-7. Epub 2008 Sep 5.

Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

We have used unbiased phosphoproteomic approaches, based on quantitative mass spectrometry using stable isotope labeling with amino acids in cell culture (SILAC), to identify tyrosine phosphorylated proteins in isogenic human bronchial epithelial cells (HBECs) and human lung adenocarcinoma cell lines, expressing either of the two mutant alleles of EGFR (L858R and Del E746-A750), or a mutant KRAS allele, which are common in human lung adenocarcinomas. Tyrosine phosphorylation of signaling molecules was greater in HBECs expressing the mutant EGFRs than in cells expressing WT EGFR or mutant KRAS. Receptor tyrosine kinases (such as EGFR, ERBB2, MET, and IGF1R), and Mig-6, an inhibitor of EGFR signaling, were more phosphorylated in HBECs expressing mutant EGFR than in cells expressing WT EGFR or mutant RAS. Phosphorylation of some proteins differed in the two EGFR mutant-expressing cells; for example, some cell junction proteins (beta-catenin, plakoglobin, and E-cadherin) were more phosphorylated in HBECs expressing L858R EGFR than in cells expressing Del EGFR. There were also differences in degree of phosphorylation at individual tyrosine sites within a protein; for example, a previously uncharacterized phosphorylation site in the nucleotide-binding loop of the kinase domains of EGFR (Y727), ERBB2 (Y735), or ERBB4 (Y733), is phosphorylated significantly more in HBECs expressing the deletion mutant than in cells expressing the wild type or L858R EGFR. Signaling molecules not previously implicated in ERBB signaling, such as polymerase transcript release factor (PTRF), were also phosphorylated in cells expressing mutant EGFR. Bayesian network analysis of these and other datasets revealed that PTRF might be a potentially important component of the ERBB signaling network.
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http://dx.doi.org/10.1073/pnas.0806158105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2531065PMC
September 2008

Seeding and propagation of untransformed mouse mammary cells in the lung.

Science 2008 Sep 28;321(5897):1841-4. Epub 2008 Aug 28.

Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

The acquisition of metastatic ability by tumor cells is considered a late event in the evolution of malignant tumors. We report that untransformed mouse mammary cells that have been engineered to express the inducible oncogenic transgenes MYC and Kras(D12), or polyoma middle T, and introduced into the systemic circulation of a mouse can bypass transformation at the primary site and develop into metastatic pulmonary lesions upon immediate or delayed oncogene induction. Therefore, previously untransformed mammary cells may establish residence in the lung once they have entered the bloodstream and may assume malignant growth upon oncogene activation. Mammary cells lacking oncogenic transgenes displayed a similar capacity for long-term residence in the lungs but did not form ectopic tumors.
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http://dx.doi.org/10.1126/science.1161621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694414PMC
September 2008

Harold Varmus. Interview by Errol C. Friedberg.

Authors:
Harold Varmus

Nat Rev Mol Cell Biol 2008 Jul;9(7):502-3

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http://dx.doi.org/10.1038/nrm2435DOI Listing
July 2008

NIH funds support more than a researcher's own lab.

Authors:
Harold Varmus

Nature 2008 Apr;452(7189):811

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http://dx.doi.org/10.1038/452811bDOI Listing
April 2008

Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras.

Proc Natl Acad Sci U S A 2008 Apr 20;105(13):5242-7. Epub 2008 Mar 20.

Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

Most, if not all, cancers are composed of cells in which more than one gene has a cancer-promoting mutation. Although recent evidence has shown the benefits of therapies targeting a single mutant protein, little attention has been given to situations in which experimental tumors are induced by multiple cooperating oncogenes. Using combinations of doxycycline-inducible and constitutive Myc and mutant Kras transgenes expressed in mouse mammary glands, we show that tumors induced by the cooperative actions of two oncogenes remain dependent on the activity of a single oncogene. Deinduction of either oncogene individually, or both oncogenes simultaneously, led to partial or complete tumor regression. Prolonged remission followed deinduction of Kras(G12D) in the context of continued Myc expression, deinduction of a MYC transgene with continued expression of mutant Kras produced modest effects on life extension, whereas simultaneous deinduction of both MYC and Kras(G12D) transgenes further improved survival. Disease relapse after deinduction of both oncogenes was associated with reactivation of both oncogenic transgenes in all recurrent tumors, often in conjunction with secondary somatic mutations in the tetracycline transactivator transgene, MMTV-rtTA, rendering gene expression doxycycline-independent. These results demonstrate that tumor viability is maintained by each gene in a combination of oncogenes and that targeted approaches will also benefit from combination therapies.
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http://dx.doi.org/10.1073/pnas.0801197105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2278195PMC
April 2008

Characterizing the cancer genome in lung adenocarcinoma.

Nature 2007 Dec 4;450(7171):893-8. Epub 2007 Nov 4.

Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

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.
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http://dx.doi.org/10.1038/nature06358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2538683PMC
December 2007

Assessing tumor progression factors by somatic gene transfer into a mouse model: Bcl-xL promotes islet tumor cell invasion.

PLoS Biol 2007 Oct;5(10):e276

Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

Tumors develop through multiple stages, implicating multiple effectors, but the tools to assess how candidate genes contribute to stepwise tumor progression have been limited. We have developed a novel system in which progression of phenotypes in a mouse model of pancreatic islet cell tumorigenesis can be used to measure the effects of genes introduced by cell-type-specific infection with retroviral vectors. In this system, bitransgenic mice, in which the rat insulin promoter (RIP) drives expression of both the SV40 T antigen (RIP-Tag) and the receptor for subgroup A avian leukosis virus (RIP-tva), are infected with avian viral vectors carrying cDNAs encoding candidate progression factors. Like RIP-Tag mice, RIP-Tag; RIP-tva bitransgenic mice develop isolated carcinomas by approximately 14 wk of age, after progression through well-defined stages that are similar to aspects of human tumor progression, including hyperplasia, angiogenesis, adenoma, and invasive carcinoma. When avian retroviral vectors carrying a green fluorescent protein marker were introduced into RIP-Tag; RIP-tva mice by intra-cardiac injection at the hyperplastic or early dysplastic stage of tumorigenesis, approximately 20% of the TVA-positive cells were infected and expressed green fluorescent proteins as measured by flow cytometry. Similar infection with vectors carrying cDNA encoding either of two progression factors, a dominant-negative version of cadherin 1 (dnE-cad) or Bcl-xL, accelerated the formation of islet tumors with invasive properties and pancreatic lymph node metastasis. To begin studying the mechanism by which Bcl-xL, an anti-apoptotic protein, promotes invasion and metastasis, RIP-Tag; RIP-tva pancreatic islet tumor cells were infected in vitro with RCASBP-Bcl-xL. Although no changes were observed in rates of proliferation or apoptosis, Bcl-xL altered cell morphology, remodeled the actin cytoskeleton, and down-regulated cadherin 1; it also induced cell migration and invasion, as evaluated using two-chamber transwell assays. In addition, myosin Va was identified as a novel Bcl-xL-interacting protein that might mediate the effects of Bcl-xL on tumor cell migration and invasion.
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http://dx.doi.org/10.1371/journal.pbio.0050276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2020504PMC
October 2007

Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4.

PLoS One 2007 May 9;2(5):e426. Epub 2007 May 9.

Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.

Background: Fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode proteins in the EGFR signaling pathway, i.e., EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this signaling pathway that could contribute to lung tumorigenesis.

Methodology/principal Findings: We analyzed genomic DNA from a total of 261 resected, clinically annotated non-small cell lung cancer (NSCLC) specimens. The coding sequences of 39 genes were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Sequencing of 9MB of tumor sequence identified 239 putative genetic variants. We further examined 22 variants found in RAS family genes and 135 variants localized to exons encoding the kinase domain of respective proteins. We identified a total of 37 non-synonymous somatic mutations; 36 were found collectively in EGFR, KRAS, BRAF, and PIK3CA. One somatic mutation was a previously unreported mutation in the kinase domain (exon 16) of FGFR4 (Glu681Lys), identified in 1 of 158 tumors. The FGFR4 mutation is analogous to a reported tumor-specific somatic mutation in ERBB2 and is located in the same exon as a previously reported kinase domain mutation in FGFR4 (Pro712Thr) in a lung adenocarcinoma cell line.

Conclusions/significance: This study is one of the first comprehensive mutational analyses of major genes in a specific signaling pathway in a sizeable cohort of lung adenocarcinomas. Our results suggest the majority of gain-of-function mutations within kinase genes in the EGFR signaling pathway have already been identified. Our findings also implicate FGFR4 in the pathogenesis of a subset of lung adenocarcinomas.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0000426PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1855985PMC
May 2007

Introduction of oncogenes into mammary glands in vivo with an avian retroviral vector initiates and promotes carcinogenesis in mouse models.

Proc Natl Acad Sci U S A 2006 Nov 7;103(46):17396-401. Epub 2006 Nov 7.

Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.

We have adapted the avian leukosis virus RCAS (replication-competent avian sarcoma-leukosis virus LTR splice acceptor)-mediated somatic gene transfer technique to introduce oncogenes into mammary cells in mice transgenic for the avian subgroup A receptor gene, tva, under control of the mouse mammary tumor virus (MMTV) promoter. Intraductal instillation of an RCAS vector carrying the polyoma middle T antigen (PyMT) gene (RCAS-PyMT) induced multiple, oligoclonal tumors within 3 weeks in infected mammary glands of MMTV-tva transgenic mice. The rapid appearance of these tumors from a relatively small pool of infected cells (estimated to be approximately 2 x 10(3) cells per gland by infection with RCAS carrying a GFP gene; RCAS-GFP) was accompanied by a high fraction of cells positive for Ki67, Cyclin D1, and c-Myc, implying strong proliferation competence. Furthermore, the tumors displayed greater cellular heterogeneity than did tumors arising in MMTV-PyMT mice, suggesting that RCAS-PyMT transforms a relatively immature cell type. Infection of mice transgenic for both MMTV-Wnt-1 and MMTV-tva with RCAS virus carrying an activated Neu oncogene dramatically enhanced tumor formation over what is observed in uninfected bitransgenic animals. We conclude that infection of mammary glands with retrovirus vectors is an efficient means to screen candidate oncogenes for their capacity to initiate or promote mammary carcinogenesis in the mouse.
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http://dx.doi.org/10.1073/pnas.0608607103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1635021PMC
November 2006

The new era in cancer research.

Authors:
Harold Varmus

Science 2006 May;312(5777):1162-5

Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

For many years, discoveries about the genetic determinants of cancer appeared to be having only minor effects on efforts to control the disease in the clinic. Following advances made over the past decade, however, a description of cancer in molecular terms seems increasingly likely to improve the ways in which human cancers are detected, classified, monitored, and (especially) treated. Achieving the medical promise of this new era in cancer research will require a deeper understanding of the biology of cancer and imaginative application of new knowledge in the clinic, as well as political, social, and cultural changes.
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http://dx.doi.org/10.1126/science.1126758DOI Listing
May 2006