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Genomics of cancer progression and heterogeneity

Guest Editors: Elaine R. Mardis and Samuel Aparicio

Recent advances, such as single-cell sequencing technologies and new algorithmic methods, are allowing us to study cancer genomics at a depth and breadth that was not previously possible.

Genome Biology highlights the importance of this field with a special collection covering all aspects of cancer progression and heterogeneity, including methodological advances to study cancer evolution and clonality, insights into tumor heterogeneity, discussions on personalized genomics and ethics of cancer data sharing, and more.


    Fast and scalable inference of multi-sample cancer lineages

    Somatic variants can be used as lineage markers for the phylogenetic reconstruction of cancer evolution. Since somatic phylogenetics is complicated by sample heterogeneity, novel specialized tree-building meth...

    Victoria Popic, Raheleh Salari, Iman Hajirasouliha, Dorna Kashef-Haghighi, Robert B West and Serafim Batzoglou

    Genome Biology 2015 16:91

    Published on: 6 May 2015

  2. Research

    Methylation-dependent SOX9 expression mediates invasion in human melanoma cells and is a negative prognostic factor in advanced melanoma

    Melanoma is the most fatal skin cancer displaying a high degree of molecular heterogeneity. Phenotype switching is a mechanism that contributes to melanoma heterogeneity by altering transcription profiles for ...

    Phil F Cheng, Olga Shakhova, Daniel S Widmer, Ossia M Eichhoff, Daniel Zingg, Sandra C Frommel, Benedetta Belloni, Marieke IG Raaijmakers, Simone M Goldinger, Raffaella Santoro, Silvio Hemmi, Lukas Sommer, Reinhard Dummer and Mitchell P Levesque

    Genome Biology 2015 16:42

    Published on: 22 February 2015

  3. Research

    Unraveling heterogeneous susceptibility and the evolution of breast cancer using a systems biology approach

    An essential question in cancer is why individuals with the same disease have different clinical outcomes. Progress toward a more personalized medicine in cancer patients requires taking into account the under...

    Andrés Castellanos-Martín, Sonia Castillo-Lluva, María del Mar Sáez-Freire, Adrián Blanco-Gómez, Lourdes Hontecillas-Prieto, Carmen Patino-Alonso, Purificación Galindo-Villardon, Luis Pérez del Villar, Carmen Martín-Seisdedos, María Isidoro-Garcia, María del Mar Abad-Hernández, Juan Jesús Cruz-Hernández, César Augusto Rodríguez-Sánchez, Rogelio González-Sarmiento, Diego Alonso-López, Javier De Las Rivas…

    Genome Biology 2015 16:40

    Published on: 21 February 2015

  4. Research

    High-depth sequencing of over 750 genes supports linear progression of primary tumors and metastases in most patients with liver-limited metastatic colorectal cancer

    Colorectal cancer with metastases limited to the liver (liver-limited mCRC) is a distinct clinical subset characterized by possible cure with surgery. We performed high-depth sequencing of over 750 cancer-asso...

    Iain Beehuat Tan, Simeen Malik, Kalpana Ramnarayanan, John R McPherson, Dan Liang Ho, Yuka Suzuki, Sarah Boonhsui Ng, Su Yan, Kiat Hon Lim, Dennis Koh, Chew Min Hoe, Chung Yip Chan, Rachel Ten, Brian KP Goh, Alexander YF Chung, Joanna Tan…

    Genome Biology 2015 16:32

    Published on: 12 February 2015

  5. Research

    Deep sequencing of multiple regions of glial tumors reveals spatial heterogeneity for mutations in clinically relevant genes

    The extent of intratumoral mutational heterogeneity remains unclear in gliomas, the most common primary brain tumors, especially with respect to point mutation. To address this, we applied single molecule mole...

    Akash Kumar, Evan A Boyle, Mari Tokita, Andrei M Mikheev, Michelle C Sanger, Emily Girard, John R Silber, Luis F Gonzalez-Cuyar, Joseph B Hiatt, Andrew Adey, Choli Lee, Jacob O Kitzman, Donald E Born, Daniel L Silbergeld, James M Olson, Robert C Rostomily…

    Genome Biology 2014 15:530

    Published on: 3 December 2014

  6. Method

    Deciphering clonality in aneuploid breast tumors using SNP array and sequencing data

    Intra-tumor heterogeneity concerns the existence of genetically different subclones within the same tumor. Single sample quantification of heterogeneity relies on precise determination of chromosomal copy numb...

    Ingrid M Lönnstedt, Franco Caramia, Jason Li, Debora Fumagalli, Roberto Salgado, Andrew Rowan, Max Salm, Nnennaya Kanu, Peter Savas, Stuart Horswell, Stephan Gade, Sibylle Loibl, Patrick Neven, Christos Sotiriou, Charles Swanton, Sherene Loi…

    Genome Biology 2014 15:470

    Published on: 1 October 2014

  7. Method

    Dynamic evolution of clonal epialleles revealed by methclone

    We describe methclone, a novel method to identify epigenetic loci that harbor large changes in the clonality of their epialleles (epigenetic alleles). Methclone efficiently analyzes genome-wide DNA methylation...

    Sheng Li, Francine Garrett-Bakelman, Alexander E Perl, Selina M Luger, Chao Zhang, Bik L To, Ian D Lewis, Anna L Brown, Richard J D’Andrea, M Elizabeth Ross, Ross Levine, Martin Carroll, Ari Melnick and Christopher E Mason

    Genome Biology 2014 15:472

    Published on: 27 September 2014

  8. Research

    Spatial and temporal evolution of distal 10q deletion, a prognostically unfavorable event in diffuse low-grade gliomas

    The disease course of patients with diffuse low-grade glioma is notoriously unpredictable. Temporal and spatially distinct samples may provide insight into the evolution of clinically relevant copy number aber...

    Hinke F van Thuijl, Ilari Scheinin, Daoud Sie, Agusti Alentorn, Hendrik F van Essen, Martijn Cordes, Ruth Fleischeuer, Anja M Gijtenbeek, Guus Beute, Wimar A van den Brink, Gerrit A Meijer, Miek Havenith, Ahmed Idbaih, Khê Hoang-Xuan, Karima Mokhtari, Roel GW Verhaak…

    Genome Biology 2014 15:471

    Published on: 23 September 2014

  9. Opinion

    Toward better benchmarking: challenge-based methods assessment in cancer genomics

    Rapid technological development has created an urgent need for improved evaluation of algorithms for the analysis of cancer genomics data. We outline how challenge-based assessment may help fill this gap by le...

    Paul C Boutros, Adam A Margolin, Joshua M Stuart, Andrea Califano and Gustavo Stolovitzky

    Genome Biology 2014 15:462

    Published on: 17 September 2014

  10. Opinion

    The multitude of molecular analyses in cancer: the opening of Pandora’s box

    The availability of large amounts of molecular data of unprecedented depth and width has instigated new paths of interdisciplinary activity in cancer research. Translation of such information to allow its opti...

    Hege G Russnes, Per E Lønning, Anne-Lise Børresen-Dale and Ole C Lingjærde

    Genome Biology 2014 15:447

    Published on: 3 September 2014

  11. Research

    DNMT inhibitors reverse a specific signature of aberrant promoter DNA methylation and associated gene silencing in AML

    Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are neoplastic disorders of hematopoietic stem cells. DNA methyltransferase inhibitors, 5-azacytidine and 5-aza-2′-deoxycytidine (decitabine), be...

    Kirstin Lund, John J Cole, Nathan D VanderKraats, Tony McBryan, Nikolay A Pchelintsev, William Clark, Mhairi Copland, John R Edwards and Peter D Adams

    Genome Biology 2014 15:406

    Published on: 30 August 2014

  12. Research

    Deep sequencing of the X chromosome reveals the proliferation history of colorectal adenomas

    Mismatch repair deficient colorectal adenomas are composed of transformed cells that descend from a common founder and progressively accumulate genomic alterations. The proliferation history of these tumors is...

    Anna De Grassi, Fabio Iannelli, Matteo Cereda, Sara Volorio, Valentina Melocchi, Alessandra Viel, Gianluca Basso, Luigi Laghi, Michele Caselle and Francesca D Ciccarelli

    Genome Biology 2014 15:437

    Published on: 30 August 2014

  13. Review

    The promise of circulating tumor cell analysis in cancer management

    Enumeration and molecular characterization of circulating tumor cells isolated from peripheral blood of patients with cancer can aid selection of targeted therapy for patients, monitoring of response to therap...

    Joaquin Mateo, Marco Gerlinger, Daniel Nava Rodrigues and Johann S de Bono

    Genome Biology 2014 15:448

    Published on: 30 August 2014

  14. Review

    Cancer genomics: one cell at a time

    The study of single cancer cells has transformed from qualitative microscopic images to quantitative genomic datasets. This paradigm shift has been fueled by the development of single-cell sequencing technolog...

    Nicholas E Navin

    Genome Biology 2014 15:452

    Published on: 30 August 2014

  15. Research

    Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions

    Colorectal cancer is the second leading cause of cancer death in the United States, with over 50,000 deaths estimated in 2014. Molecular profiling for somatic mutations that predict absence of response to anti...

    A Rose Brannon, Efsevia Vakiani, Brooke E Sylvester, Sasinya N Scott, Gregory McDermott, Ronak H Shah, Krishan Kania, Agnes Viale, Dayna M Oschwald, Vladimir Vacic, Anne-Katrin Emde, Andrea Cercek, Rona Yaeger, Nancy E Kemeny, Leonard B Saltz, Jinru Shia…

    Genome Biology 2014 15:454

    Published on: 28 August 2014

  16. Opinion

    Organizing knowledge to enable personalization of medicine in cancer

    Interpretation of the clinical significance of genomic alterations remains the most severe bottleneck preventing the realization of personalized medicine in cancer. We propose a knowledge commons to facilitate...

    Benjamin M Good, Benjamin J Ainscough, Josh F McMichael, Andrew I Su and Obi L Griffith

    Genome Biology 2014 15:438

    Published on: 27 August 2014

  17. Research

    Metastatic tumor evolution and organoid modeling implicate TGFBR2as a cancer driver in diffuse gastric cancer

    Gastric cancer is the second-leading cause of global cancer deaths, with metastatic disease representing the primary cause of mortality. To identify candidate drivers involved in oncogenesis and tumor evolutio...

    Lincoln D Nadauld, Sarah Garcia, Georges Natsoulis, John M Bell, Laura Miotke, Erik S Hopmans, Hua Xu, Reetesh K Pai, Curt Palm, John F Regan, Hao Chen, Patrick Flaherty, Akifumi Ootani, Nancy R Zhang, James M Ford, Calvin J Kuo…

    Genome Biology 2014 15:428

    Published on: 27 August 2014

  18. Research

    Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution

    Genomic analysis of multi-focal renal cell carcinomas from an individual with a germline VHL mutation offers a unique opportunity to study tumor evolution.

    Rosalie Fisher, Stuart Horswell, Andrew Rowan, Maximilian P Salm, Elza C de Bruin, Sakshi Gulati, Nicholas McGranahan, Mark Stares, Marco Gerlinger, Ignacio Varela, Andrew Crockford, Francesco Favero, Virginie Quidville, Fabrice André, Carolina Navas, Eva Grönroos…

    Genome Biology 2014 15:433

    Published on: 27 August 2014

  19. Method

    Unraveling the clonal hierarchy of somatic genomic aberrations

    Defining the chronology of molecular alterations may identify milestones in carcinogenesis. To unravel the temporal evolution of aberrations from clinical tumors, we developed CLONET, which upon estimation of ...

    Davide Prandi, Sylvan C Baca, Alessandro Romanel, Christopher E Barbieri, Juan-Miguel Mosquera, Jacqueline Fontugne, Himisha Beltran, Andrea Sboner, Levi A Garraway, Mark A Rubin and Francesca Demichelis

    Genome Biology 2014 15:439

    Published on: 26 August 2014

    The Erratum to this article has been published in Genome Biology 2017 18:80

  20. Method

    SubcloneSeeker: a computational framework for reconstructing tumor clone structure for cancer variant interpretation and prioritization

    Many tumors are composed of genetically divergent cell subpopulations. We report SubcloneSeeker, a package capable of exhaustive identification of subclone structures and evolutionary histories with bulk somat...

    Yi Qiao, Aaron R Quinlan, Amir A Jazaeri, Roeland GW Verhaak, David A Wheeler and Gabor T Marth

    Genome Biology 2014 15:443

    Published on: 26 August 2014

  21. Research

    Heterogeneity in the inter-tumor transcriptome of high risk prostate cancer

    Genomic analyses of hundreds of prostate tumors have defined a diverse landscape of mutations and genome rearrangements, but the transcriptomic effect of this complexity is less well understood, particularly a...

    Alexander W Wyatt, Fan Mo, Kendric Wang, Brian McConeghy, Sonal Brahmbhatt, Lina Jong, Devon M Mitchell, Rebecca L Johnston, Anne Haegert, Estelle Li, Janet Liew, Jake Yeung, Raunak Shrestha, Anna V Lapuk, Andrew McPherson, Robert Shukin…

    Genome Biology 2014 15:426

    Published on: 26 August 2014

  22. METHOD

    Cancer progression modeling using static sample data

    As molecular profiling data continue to accumulate, the design of integrative computational analyses that can provide insights into the dynamic aspects of cancer progression becomes feasible. Here, we present ...

    Yijun Sun, Jin Yao, Norma J Nowak and Steve Goodison

    Genome Biology 2014 15:440

    Published on: 26 August 2014

  23. Research

    Diverse modes of genomic alteration in hepatocellular carcinoma

    Hepatocellular carcinoma (HCC) is a heterogeneous disease with high mortality rate. Recent genomic studies have identified TP53, AXIN1, and CTNNB1 as the most frequently mutated genes. Lower frequency mutations h...

    Suchit Jhunjhunwala, Zhaoshi Jiang, Eric W Stawiski, Florian Gnad, Jinfeng Liu, Oleg Mayba, Pan Du, Jingyu Diao, Stephanie Johnson, Kwong-Fai Wong, Zhibo Gao, Yingrui Li, Thomas D Wu, Sharookh B Kapadia, Zora Modrusan, Dorothy M French…

    Genome Biology 2014 15:436

    Published on: 26 August 2014

  24. Research

    Genome-wide DNA methylation profiles in progression to in situand invasive carcinoma of the breast with impact on gene transcription and prognosis

    Ductal carcinoma in situ (DCIS) of the breast is a precursor of invasive breast carcinoma. DNA methylation alterations are thought to be an early event in progression of cancer, and may prove valuable as a tool i...

    Thomas Fleischer, Arnoldo Frigessi, Kevin C Johnson, Hege Edvardsen, Nizar Touleimat, Jovana Klajic, Margit LH Riis, Vilde D Haakensen, Fredrik Wärnberg, Bjørn Naume, Åslaug Helland, Anne-Lise Børresen-Dale, Jörg Tost, Brock C Christensen and Vessela N Kristensen

    Genome Biology 2014 15:435

    Published on: 22 August 2014

  25. Research

    Methylome analysis identifies a Wilms tumor epigenetic biomarker detectable in blood

    Wilms tumor is the most common pediatric renal malignancy and there is a clinical need for a molecular biomarker to assess treatment response and predict relapse. The known mutated genes in this tumor type sho...

    Jocelyn Charlton, Richard D Williams, Mark Weeks, Neil J Sebire, Sergey Popov, Gordan Vujanic, William Mifsud, Marisa Alcaide-German, Lee M Butcher, Stephan Beck and Kathy Pritchard-Jones

    Genome Biology 2014 15:434

    Published on: 19 August 2014

  26. Research

    Deep sequencing reveals clonal evolution patterns and mutation events associated with relapse in B-cell lymphomas

    Molecular mechanisms associated with frequent relapse of diffuse large B-cell lymphoma (DLBCL) are poorly defined. It is especially unclear how primary tumor clonal heterogeneity contributes to relapse. Here, ...

    Yanwen Jiang, David Redmond, Kui Nie, Ken W Eng, Thomas Clozel, Peter Martin, Leonard HC Tan, Ari M Melnick, Wayne Tam and Olivier Elemento

    Genome Biology 2014 15:432

    Published on: 15 August 2014

  27. Research

    Transcriptome sequencing reveals altered long intergenic non-coding RNAs in lung cancer

    Long intergenic non-coding RNAs (lncRNAs) represent an emerging and under-studied class of transcripts that play a significant role in human cancers. Due to the tissue- and cancer-specific expression patterns ...

    Nicole M White, Christopher R Cabanski, Jessica M Silva-Fisher, Ha X Dang, Ramaswamy Govindan and Christopher A Maher

    Genome Biology 2014 15:429

    Published on: 13 August 2014

  28. Opinion

    Building a data sharing model for global genomic research

    Data sharing models designed to facilitate global business provide insights for improving transborder genomic data sharing. We argue that a flexible, externally endorsed, multilateral arrangement, combined wit...

    Patricia Kosseim, Edward S Dove, Carman Baggaley, Eric M Meslin, Fred H Cate, Jane Kaye, Jennifer R Harris and Bartha M Knoppers

    Genome Biology 2014 15:430

    Published on: 11 August 2014

  29. Method

    Biased estimates of clonal evolution and subclonal heterogeneity can arise from PCR duplicates in deep sequencing experiments

    Accurate allele frequencies are important for measuring subclonal heterogeneity and clonal evolution. Deep-targeted sequencing data can contain PCR duplicates, inflating perceived read depth. Here we adapted t...

    Erin N Smith, Kristen Jepsen, Mahdieh Khosroheidari, Laura Z Rassenti, Matteo D’Antonio, Emanuela M Ghia, Dennis A Carson, Catriona HM Jamieson, Thomas J Kipps and Kelly A Frazer

    Genome Biology 2014 15:420

    Published on: 7 August 2014

  30. Method

    MBASED: allele-specific expression detection in cancer tissues and cell lines

    Allele-specific gene expression, ASE, is an important aspect of gene regulation. We developed a novel method MBASED, meta-analysis based allele-specific expression detection for ASE detection using RNA-seq dat...

    Oleg Mayba, Houston N Gilbert, Jinfeng Liu, Peter M Haverty, Suchit Jhunjhunwala, Zhaoshi Jiang, Colin Watanabe and Zemin Zhang

    Genome Biology 2014 15:405

    Published on: 7 August 2014

  31. Method

    MethylPurify: tumor purity deconvolution and differential methylation detection from single tumor DNA methylomes

    We propose a statistical algorithm MethylPurify that uses regions with bisulfite reads showing discordant methylation levels to infer tumor purity from tumor samples alone. MethylPurify can identify differenti...

    Xiaoqi Zheng, Qian Zhao, Hua-Jun Wu, Wei Li, Haiyun Wang, Clifford A Meyer, Qian Alvin Qin, Han Xu, Chongzhi Zang, Peng Jiang, Fuqiang Li, Yong Hou, Jianxing He, Jun Wang, Jun Wang, Peng Zhang…

    Genome Biology 2014 15:419

    Published on: 7 August 2014