Alex H Ramos

Publications (22)585.54 Total impact

• Source

  Available from: Gunther Boysen

  Article: Punctuated evolution of prostate cancer genomes.

  Sylvan C Baca, Davide Prandi, Michael S Lawrence, Juan Miguel Mosquera, Alessandro Romanel, Yotam Drier, Kyung Park, Naoki Kitabayashi, Theresa Y Macdonald, Mahmoud Ghandi, [......], Michael F Berger, Stacey B Gabriel, Todd R Golub, Matthew Meyerson, Eric S Lander, Olivier Elemento, Gad Getz, Francesca Demichelis, Mark A Rubin, Levi A Garraway
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  ABSTRACT: The analysis of exonic DNA from prostate cancers has identified recurrently mutated genes, but the spectrum of genome-wide alterations has not been profiled extensively in this disease. We sequenced the genomes of 57 prostate tumors and matched normal tissues to characterize somatic alterations and to study how they accumulate during oncogenesis and progression. By modeling the genesis of genomic rearrangements, we identified abundant DNA translocations and deletions that arise in a highly interdependent manner. This phenomenon, which we term "chromoplexy," frequently accounts for the dysregulation of prostate cancer genes and appears to disrupt multiple cancer genes coordinately. Our modeling suggests that chromoplexy may induce considerable genomic derangement over relatively few events in prostate cancer and other neoplasms, supporting a model of punctuated cancer evolution. By characterizing the clonal hierarchy of genomic lesions in prostate tumors, we charted a path of oncogenic events along which chromoplexy may drive prostate carcinogenesis.
  Cell 04/2013; 153(3):666-77. · 32.40 Impact Factor
• Article: Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity.

  Austin M Dulak, Petar Stojanov, Shouyong Peng, Michael S Lawrence, Cameron Fox, Chip Stewart, Santhoshi Bandla, Yu Imamura, Steven E Schumacher, Erica Shefler, [......], Arjun Pennathur, Shuji Ogino, James D Luketich, Todd R Golub, Stacey B Gabriel, Eric S Lander, David G Beer, Tony E Godfrey, Gad Getz, Adam J Bass
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  ABSTRACT: The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a 5-year survival rate of ∼15%, the identification of new therapeutic targets for EAC is greatly important. We analyze the mutation spectra from whole-exome sequencing of 149 EAC tumor-normal pairs, 15 of which have also been subjected to whole-genome sequencing. We identify a mutational signature defined by a high prevalence of A>C transversions at AA dinucleotides. Statistical analysis of exome data identified 26 significantly mutated genes. Of these genes, five (TP53, CDKN2A, SMAD4, ARID1A and PIK3CA) have previously been implicated in EAC. The new significantly mutated genes include chromatin-modifying factors and candidate contributors SPG20, TLR4, ELMO1 and DOCK2. Functional analyses of EAC-derived mutations in ELMO1 identifies increased cellular invasion. Therefore, we suggest the potential activation of the RAC1 pathway as a contributor to EAC tumorigenesis.
  Nature Genetics 03/2013; · 35.53 Impact Factor
• Article: The genetic landscape of high-risk neuroblastoma.

  Trevor J Pugh, Olena Morozova, Edward F Attiyeh, Shahab Asgharzadeh, Jun S Wei, Daniel Auclair, Scott L Carter, Kristian Cibulskis, Megan Hanna, Adam Kiezun, [......], Michael D Hogarty, Steven J M Jones, Eric S Lander, Stacey B Gabriel, Gad Getz, Robert C Seeger, Javed Khan, Marco A Marra, Matthew Meyerson, John M Maris
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  ABSTRACT: Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 affected individuals (cases) using a combination of whole-exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.60 per Mb (0.48 nonsilent) and notably few recurrently mutated genes in these tumors. Genes with significant somatic mutation frequencies included ALK (9.2% of cases), PTPN11 (2.9%), ATRX (2.5%, and an additional 7.1% had focal deletions), MYCN (1.7%, causing a recurrent p.Pro44Leu alteration) and NRAS (0.83%). Rare, potentially pathogenic germline variants were significantly enriched in ALK, CHEK2, PINK1 and BARD1. The relative paucity of recurrent somatic mutations in neuroblastoma challenges current therapeutic strategies that rely on frequently altered oncogenic drivers.
  Nature Genetics 01/2013; · 35.53 Impact Factor
• Article: Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations.

  Trevor J Pugh, Shyamal Dilhan Weeraratne, Tenley C Archer, Daniel A Pomeranz Krummel, Daniel Auclair, James Bochicchio, Mauricio O Carneiro, Scott L Carter, Kristian Cibulskis, Rachel L Erlich, [......], Stacey B Gabriel, Gad Getz, Natalie Jäger, David T W Jones, Peter Lichter, Stefan M Pfister, Thomas M Roberts, Matthew Meyerson, Scott L Pomeroy, Yoon-Jae Cho
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  ABSTRACT: Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR and LDB1. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild-type, β-catenin. Together, our study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic β-catenin signalling in medulloblastoma.
  Nature 07/2012; 488(7409):106-10. · 36.28 Impact Factor
• Source

  Available from: Dirk Schadendorf

  Article: A landscape of driver mutations in melanoma.

  Eran Hodis, Ian R Watson, Gregory V Kryukov, Stefan T Arold, Marcin Imielinski, Jean-Philippe Theurillat, Elizabeth Nickerson, Daniel Auclair, Liren Li, Chelsea Place, [......], Michael A Davies, Jeffrey E Gershenwald, Stephan N Wagner, Dave S B Hoon, Dirk Schadendorf, Eric S Lander, Stacey B Gabriel, Gad Getz, Levi A Garraway, Lynda Chin
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  ABSTRACT: Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic UV light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19, and ARID2), three of which-RAC1, PPP6C, and STK19-harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis.
  Cell 07/2012; 150(2):251-63. · 32.40 Impact Factor
• Article: Sequence analysis of mutations and translocations across breast cancer subtypes.

  Shantanu Banerji, Kristian Cibulskis, Claudia Rangel-Escareno, Kristin K Brown, Scott L Carter, Abbie M Frederick, Michael S Lawrence, Andrey Y Sivachenko, Carrie Sougnez, Lihua Zou, [......], Gerardo Jimenez-Sanchez, Eric S Lander, Stacey B Gabriel, Levi A Garraway, Todd R Golub, Jorge Melendez-Zajgla, Alex Toker, Gad Getz, Alfredo Hidalgo-Miranda, Matthew Meyerson
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  ABSTRACT: Breast carcinoma is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.38 million new cases and 458,000 deaths in 2008 alone. This malignancy represents a heterogeneous group of tumours with characteristic molecular features, prognosis and responses to available therapy. Recurrent somatic alterations in breast cancer have been described, including mutations and copy number alterations, notably ERBB2 amplifications, the first successful therapy target defined by a genomic aberration. Previous DNA sequencing studies of breast cancer genomes have revealed additional candidate mutations and gene rearrangements. Here we report the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. Beyond confirming recurrent somatic mutations in PIK3CA, TP53, AKT1, GATA3 and MAP3K1, we discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1. Furthermore, we have identified a recurrent MAGI3-AKT3 fusion enriched in triple-negative breast cancer lacking oestrogen and progesterone receptors and ERBB2 expression. The MAGI3-AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATP-competitive AKT small-molecule inhibitor.
  Nature 06/2012; 486(7403):405-9. · 36.28 Impact Factor
• Source

  Available from: Dirk Schadendorf

  Article: Melanoma genome sequencing reveals frequent PREX2 mutations.

  Michael F Berger, Eran Hodis, Timothy P Heffernan, Yonathan Lissanu Deribe, Michael S Lawrence, Alexei Protopopov, Elena Ivanova, Ian R Watson, Elizabeth Nickerson, Papia Ghosh, [......], Jennifer Wargo, Dirk Schadendorf, Matthew Meyerson, Stacey B Gabriel, Todd R Golub, Stephan N Wagner, Eric S Lander, Gad Getz, Lynda Chin, Levi A Garraway
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  ABSTRACT: Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those originating from hair-bearing skin of the trunk (5-55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)--a PTEN-interacting protein and negative regulator of PTEN in breast cancer--as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumours revealed genomic evidence of ultraviolet pathogenesis and discovered a new recurrently mutated gene in melanoma.
  Nature 05/2012; 485(7399):502-6. · 36.28 Impact Factor
• Source

  Available from: Gunther Boysen

  Article: Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer.

  Christopher E Barbieri, Sylvan C Baca, Michael S Lawrence, Francesca Demichelis, Mirjam Blattner, Jean-Philippe Theurillat, Thomas A White, Petar Stojanov, Eliezer Van Allen, Nicolas Stransky, [......], Colm Morrissey, Peter S Nelson, Philip W Kantoff, Stacey B Gabriel, Todd R Golub, Matthew Meyerson, Eric S Lander, Gad Getz, Mark A Rubin, Levi A Garraway
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  ABSTRACT: Prostate cancer is the second most common cancer in men worldwide and causes over 250,000 deaths each year. Overtreatment of indolent disease also results in significant morbidity. Common genetic alterations in prostate cancer include losses of NKX3.1 (8p21) and PTEN (10q23), gains of AR (the androgen receptor gene) and fusion of ETS family transcription factor genes with androgen-responsive promoters. Recurrent somatic base-pair substitutions are believed to be less contributory in prostate tumorigenesis but have not been systematically analyzed in large cohorts. Here, we sequenced the exomes of 112 prostate tumor and normal tissue pairs. New recurrent mutations were identified in multiple genes, including MED12 and FOXA1. SPOP was the most frequently mutated gene, with mutations involving the SPOP substrate-binding cleft in 6-15% of tumors across multiple independent cohorts. Prostate cancers with mutant SPOP lacked ETS family gene rearrangements and showed a distinct pattern of genomic alterations. Thus, SPOP mutations may define a new molecular subtype of prostate cancer.
  Nature Genetics 05/2012; 44(6):685-9. · 35.53 Impact Factor
• Source

  Available from: epigenebase.org

  Article: Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion.

  Adam J Bass, Michael S Lawrence, Lear E Brace, Alex H Ramos, Yotam Drier, Kristian Cibulskis, Carrie Sougnez, Douglas Voet, Gordon Saksena, Andrey Sivachenko, [......], Ronald A Depinho, Lynda Chin, Levi A Garraway, Charles S Fuchs, Jose Baselga, Josep Tabernero, Stacey Gabriel, Eric S Lander, Gad Getz, Matthew Meyerson
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  ABSTRACT: Prior studies have identified recurrent oncogenic mutations in colorectal adenocarcinoma and have surveyed exons of protein-coding genes for mutations in 11 affected individuals. Here we report whole-genome sequencing from nine individuals with colorectal cancer, including primary colorectal tumors and matched adjacent non-tumor tissues, at an average of 30.7× and 31.9× coverage, respectively. We identify an average of 75 somatic rearrangements per tumor, including complex networks of translocations between pairs of chromosomes. Eleven rearrangements encode predicted in-frame fusion proteins, including a fusion of VTI1A and TCF7L2 found in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which cooperates with β-catenin in colorectal carcinogenesis, the fusion lacks the TCF4 β-catenin-binding domain. We found a colorectal carcinoma cell line harboring the fusion gene to be dependent on VTI1A-TCF7L2 for anchorage-independent growth using RNA interference-mediated knockdown. This study shows previously unidentified levels of genomic rearrangements in colorectal carcinoma that can lead to essential gene fusions and other oncogenic events.
  Nature Genetics 09/2011; 43(10):964-8. · 35.53 Impact Factor
• Source

  Available from: Alfredo Hidalgo-Miranda

  Article: The Mutational Landscape of Head and Neck Squamous Cell Carcinoma

  Nicolas Stransky, Ann Marie Egloff, Aaron D. Tward, Aleksandar D. Kostic, Kristian Cibulskis, Andrey Sivachenko, Gregory V. Kryukov, Michael S. Lawrence, Carrie Sougnez, Aaron McKenna, [......], Jorge Melendez-Zajgla, Wendy Winckler, Kristin Ardlie, Stacey B. Gabriel, Matthew Meyerson, Eric S. Lander, Gad Getz, Todd R. Golub, Levi A. Garraway, Jennifer R. Grandis
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  ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), our analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.
  Science 08/2011; 333(6046):1157-1160. · 31.20 Impact Factor
• Article: Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer.

  Peter S Hammerman, Martin L Sos, Alex H Ramos, Chunxiao Xu, Amit Dutt, Wenjun Zhou, Lear E Brace, Brittany A Woods, Wenchu Lin, Jianming Zhang, [......], Wendy Winckler, Heidi Greulich, Adam J Bass, Jeonghee Cho, Daniel Rauh, Nathanael S Gray, Kwok-Kin Wong, Eric B Haura, Roman K Thomas, Matthew Meyerson
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  ABSTRACT: While genomically targeted therapies have improved outcomes for patients with lung adenocarcinoma, little is known about the genomic alterations which drive squamous cell lung cancer. Sanger sequencing of the tyrosine kinome identified mutations in the DDR2 kinase gene in 3.8% of squamous cell lung cancers and cell lines. Squamous lung cancer cell lines harboring DDR2 mutations were selectively killed by knock-down of DDR2 by RNAi or by treatment with the multi-targeted kinase inhibitor dasatinib. Tumors established from a DDR2 mutant cell line were sensitive to dasatinib in xenograft models. Expression of mutated DDR2 led to cellular transformation which was blocked by dasatinib. A squamous cell lung cancer patient with a response to dasatinib and erlotinib treatment harbored a DDR2 kinase domain mutation. These data suggest that gain-of-function mutations in DDR2 are important oncogenic events and are amenable to therapy with dasatinib. As dasatinib is already approved for use, these findings could be rapidly translated into clinical trials. SIGNIFICANCE: DDR2 mutations are present in 4% of lung SCCs, and DDR2 mutations are associated with sensitivity to dasatinib. These findings provide a rationale for designing clinical trials with the FDA-approved drug dasatinib in patients with lung SCCs.
  Cancer discovery. 04/2011; 1(1):78-89.
• Article: Initial genome sequencing and analysis of multiple myeloma.

  Michael A Chapman, Michael S Lawrence, Jonathan J Keats, Kristian Cibulskis, Carrie Sougnez, Anna C Schinzel, Christina L Harview, Jean-Philippe Brunet, Gregory J Ahmann, Mazhar Adli, [......], Wendy Winckler, Todd Zimmerman, John Carpten, Jeff Trent, William C Hahn, Levi A Garraway, Matthew Meyerson, Eric S Lander, Gad Getz, Todd R Golub
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  ABSTRACT: Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signalling was indicated by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.
  Nature 03/2011; 471(7339):467-72. · 36.28 Impact Factor
• Article: 񌴔qgOBɌQm̕G

  Michael F. Berger, Michael S. Lawrence, Francesca Demichelis, Yotam Drier, Kristian Cibulskis, Andrey Y. Sivachenko, Andrea Sboner, Raquel Esgueva, Dorothee Pflueger, Carrie Sougnez, [......], Lynda Chin, Stacey B. Gabriel, Mark B. Gerstein, Todd R. Golub, Matthew Meyerson, Ashutosh Tewari, Eric S. Lander, Gad Getz, Mark A. Rubin, Levi A. Garraway
  Nature 02/2011; 470(7333):214-220. · 36.28 Impact Factor
• Article: The genomic complexity of primary human prostate cancer.

  Michael F Berger, Michael S Lawrence, Francesca Demichelis, Yotam Drier, Kristian Cibulskis, Andrey Y Sivachenko, Andrea Sboner, Raquel Esgueva, Dorothee Pflueger, Carrie Sougnez, [......], Lynda Chin, Stacey B Gabriel, Mark B Gerstein, Todd R Golub, Matthew Meyerson, Ashutosh Tewari, Eric S Lander, Gad Getz, Mark A Rubin, Levi A Garraway
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  ABSTRACT: Prostate cancer is the second most common cause of male cancer deaths in the United States. However, the full range of prostate cancer genomic alterations is incompletely characterized. Here we present the complete sequence of seven primary human prostate cancers and their paired normal counterparts. Several tumours contained complex chains of balanced (that is, 'copy-neutral') rearrangements that occurred within or adjacent to known cancer genes. Rearrangement breakpoints were enriched near open chromatin, androgen receptor and ERG DNA binding sites in the setting of the ETS gene fusion TMPRSS2-ERG, but inversely correlated with these regions in tumours lacking ETS fusions. This observation suggests a link between chromatin or transcriptional regulation and the genesis of genomic aberrations. Three tumours contained rearrangements that disrupted CADM2, and four harboured events disrupting either PTEN (unbalanced events), a prostate tumour suppressor, or MAGI2 (balanced events), a PTEN interacting protein not previously implicated in prostate tumorigenesis. Thus, genomic rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms.
  Nature 02/2011; 470(7333):214-20. · 36.28 Impact Factor
• Source

  Available from: Heidi Greulich

  Article: Inhibitor-sensitive FGFR1 amplification in human non-small cell lung cancer.

  Amit Dutt, Alex H Ramos, Peter S Hammerman, Craig Mermel, Jeonghee Cho, Tanaz Sharifnia, Ajit Chande, Kumiko Elisa Tanaka, Nicolas Stransky, Heidi Greulich, Nathanael S Gray, Matthew Meyerson
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  ABSTRACT: Squamous cell lung carcinomas account for approximately 25% of new lung carcinoma cases and 40,000 deaths per year in the United States. Although there are multiple genomically targeted therapies for lung adenocarcinoma, none has yet been reported in squamous cell lung carcinoma. Using SNP array analysis, we found that a region of chromosome segment 8p11-12 containing three genes-WHSC1L1, LETM2, and FGFR1-is amplified in 3% of lung adenocarcinomas and 21% of squamous cell lung carcinomas. Furthermore, we demonstrated that a non-small cell lung carcinoma cell line harboring focal amplification of FGFR1 is dependent on FGFR1 activity for cell growth, as treatment of this cell line either with FGFR1-specific shRNAs or with FGFR small molecule enzymatic inhibitors leads to cell growth inhibition. These studies show that FGFR1 amplification is common in squamous cell lung cancer, and that FGFR1 may represent a promising therapeutic target in non-small cell lung cancer.
  PLoS ONE 01/2011; 6(6):e20351. · 4.09 Impact Factor
• Article: SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas.

  Adam J Bass, Hideo Watanabe, Craig H Mermel, Soyoung Yu, Sven Perner, Roel G Verhaak, So Young Kim, Leslie Wardwell, Pablo Tamayo, Irit Gat-Viks, [......], Olav Dahl, Ramesh A Shivdasani, Ming-Sound Tsao, Mark A Rubin, Kwok K Wong, Aviv Regev, William C Hahn, David G Beer, Anil K Rustgi, Matthew Meyerson
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  ABSTRACT: Lineage-survival oncogenes are activated by somatic DNA alterations in cancers arising from the cell lineages in which these genes play a role in normal development. Here we show that a peak of genomic amplification on chromosome 3q26.33 found in squamous cell carcinomas (SCCs) of the lung and esophagus contains the transcription factor gene SOX2, which is mutated in hereditary human esophageal malformations, is necessary for normal esophageal squamous development, promotes differentiation and proliferation of basal tracheal cells and cooperates in induction of pluripotent stem cells. SOX2 expression is required for proliferation and anchorage-independent growth of lung and esophageal cell lines, as shown by RNA interference experiments. Furthermore, ectopic expression of SOX2 here cooperated with FOXE1 or FGFR2 to transform immortalized tracheobronchial epithelial cells. SOX2-driven tumors show expression of markers of both squamous differentiation and pluripotency. These characteristics identify SOX2 as a lineage-survival oncogene in lung and esophageal SCC.
  Nature Genetics 10/2009; 41(11):1238-42. · 35.53 Impact Factor
• Article: Focal gains of VEGFA and molecular classification of hepatocellular carcinoma.

  Derek Y Chiang, Augusto Villanueva, Yujin Hoshida, Judit Peix, Philippa Newell, Beatriz Minguez, Amanda C LeBlanc, Diana J Donovan, Swan N Thung, Manel Solé, [......], Myron Schwartz, Samuel Waxman, Jordi Bruix, Vincenzo Mazzaferro, Azra H Ligon, Vesna Najfeld, Scott L Friedman, William R Sellers, Matthew Meyerson, Josep M Llovet
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  ABSTRACT: Hepatocellular carcinomas represent the third leading cause of cancer-related deaths worldwide. The vast majority of cases arise in the context of chronic liver injury due to hepatitis B virus or hepatitis C virus infection. To identify genetic mechanisms of hepatocarcinogenesis, we characterized copy number alterations and gene expression profiles from the same set of tumors associated with hepatitis C virus. Most tumors harbored 1q gain, 8q gain, or 8p loss, with occasional alterations in 13 additional chromosome arms. In addition to amplifications at 11q13 in 6 of 103 tumors, 4 tumors harbored focal gains at 6p21 incorporating vascular endothelial growth factor A (VEGFA). Fluorescence in situ hybridization on an independent validation set of 210 tumors found 6p21 high-level gains in 14 tumors, as well as 2 tumors with 6p21 amplifications. Strikingly, this locus overlapped with copy gains in 4 of 371 lung adenocarcinomas. Overexpression of VEGFA via 6p21 gain in hepatocellular carcinomas suggested a novel, non-cell-autonomous mechanism of oncogene activation. Hierarchical clustering of gene expression among 91 of these tumors identified five classes, including "CTNNB1", "proliferation", "IFN-related", a novel class defined by polysomy of chromosome 7, and an unannotated class. These class labels were further supported by molecular data; mutations in CTNNB1 were enriched in the "CTNNB1" class, whereas insulin-like growth factor I receptor and RPS6 phosphorylation were enriched in the "proliferation" class. The enrichment of signaling pathway alterations in gene expression classes provides insights on hepatocellular carcinoma pathogenesis. Furthermore, the prevalence of VEGFA high-level gains in multiple tumor types suggests indications for clinical trials of antiangiogenic therapies.
  Cancer Research 09/2008; 68(16):6779-88. · 7.86 Impact Factor
• Source

  Available from: Ingeborg B Engelsen

  Article: Drug-sensitive FGFR2 mutations in endometrial carcinoma.

  Amit Dutt, Helga B Salvesen, Tzu-Hsiu Chen, Alex H Ramos, Robert C Onofrio, Charlie Hatton, Richard Nicoletti, Wendy Winckler, Rupinder Grewal, Megan Hanna, [......], Ingunn M Stefansson, Tim Fennell, Kristian Cibulskis, Michael C Zody, Lars A Akslen, Stacey Gabriel, Kwok-Kin Wong, William R Sellers, Matthew Meyerson, Heidi Greulich
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  ABSTRACT: Oncogenic activation of tyrosine kinases is a common mechanism of carcinogenesis and, given the druggable nature of these enzymes, an attractive target for anticancer therapy. Here, we show that somatic mutations of the fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase gene, FGFR2, are present in 12% of endometrial carcinomas, with additional instances found in lung squamous cell carcinoma and cervical carcinoma. These FGFR2 mutations, many of which are identical to mutations associated with congenital craniofacial developmental disorders, are constitutively activated and oncogenic when ectopically expressed in NIH 3T3 cells. Inhibition of FGFR2 kinase activity in endometrial carcinoma cell lines bearing such FGFR2 mutations inhibits transformation and survival, implicating FGFR2 as a novel therapeutic target in endometrial carcinoma.
  Proceedings of the National Academy of Sciences 07/2008; 105(25):8713-7. · 9.68 Impact Factor
• Article: Characterizing the cancer genome in lung adenocarcinoma.

  Barbara A Weir, Michele S Woo, Gad Getz, Sven Perner, Li Ding, Rameen Beroukhim, William M Lin, Michael A Province, Aldi Kraja, Laura A Johnson, [......], Marc Ladanyi, William D Travis, William Pao, Mark A Rubin, Stacey B Gabriel, Richard A Gibbs, Harold E Varmus, Richard K Wilson, Eric S Lander, Matthew Meyerson
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  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.
  Nature 01/2008; 450(7171):893-8. · 36.28 Impact Factor
• Article: Characterizing the cancer genome in lung adenocarcinoma

  Barbara A Weir, Michele S Woo, Gad Getz, Sven Perner, Li Ding, Rameen Beroukhim, William M Lin, Michael A Province, Aldi Kraja, Laura A Johnson, [......], Marc Ladanyi, William D Travis, William Pao, Mark A Rubin, Stacey B Gabriel, Richard A Gibbs, Harold E Varmus, Richard K Wilson, Eric S Lander, Matthew Meyerson
  Nature, v.450, 893-898 (2007).