document

Robust BRCA1-like classification of copy number profiles of samples repeated across different datasets and platforms

Schouten, P.C. (author), Grigoriadis, A. (author), Kuilman, T. (author), Mirza, H. (author), Watkins, J.A. (author), Cooke, S.A. (author), Van Dyk, E. (author), Severson, T.M. (author), Rueda, O.M. (author), Hoogstraat, M. (author), Verhagen, C. (author), Natrajan, R. (author), Chin, S.F. (author), Lips, E.H. (author), Kruizinga, J. (author), Velds, A. (author), Nieuwland, M. (author), Kerkhoven, R.M. (author), Krijgsman, O. (author), Vens, C. (author), Peeper, D. (author), Nederlof, P.M. (author), Caldas, C. (author), Tutt, A.N. (author), Wessels, L.F.A. (author), Linn, S.C. (author)

Breast cancers with BRCA1 germline mutation have a characteristic DNA copy number (CN) pattern. We developed a test that assigns CN profiles to be ‘BRCA1-like’ or ‘non-BRCA1-like’, which refers to resembling a BRCA1-mutated tumor or resembling a tumor without a BRCA1 mutation, respectively. Approximately one third of the BRCA1-like breast...

journal article 2015

document

Lack of Genomic Heterogeneity at High-Resolution aCGH between Primary Breast Cancers and Their Paired Lymph Node Metastases

Vollebergh, M.A. (author), Klijn, C. (author), Schouten, P.C. (author), Wesseling, J. (author), Israeli, D. (author), Ylstra, B. (author), Wessels, L.F.A. (author), Jonkers, J. (author), Linn, S.C. (author)

Lymph-node metastasis (LNM) predict high recurrence rates in breast cancer patients. Systemic treatment aims to eliminate (micro)metastatic cells. However decisions regarding systemic treatment depend largely on clinical and molecular characteristics of primary tumours. It remains, however, unclear to what extent metastases resemble the cognate...

journal article 2014

document

Genome-wide epigenetic profiling of breast cancer tumors treated with aromatase inhibitors

Nevedomskaya, E. (author), Wessels, L. (author), Zwart, W. (author)

Aromatase inhibitors (AI) are extensively used in the treatment of estrogen receptor-positive breast cancers, however resistance to AI treatment is commonly observed. Apart from Estrogen receptor (ER?) expression, no predictive biomarkers for response to AI treatment are clinically applied. Yet, since other therapeutic options exist in the...

journal article 2014

document

Genomic patterns resembling BRCA1- and BRCA2-mutated breast cancers predict benefit of intensified carboplatin-based chemotherapy

Vollebergh, M.A. (author), Lips, E.H. (author), Nederlof, P.M. (author), Wessels, L.F.A. (author), Wesseling, J. (author), Van de Vijver, M.J. (author), De vries, E.G.E. (author), Van Tinteren, H. (author), Jonkers, J. (author), Hauptman, M. (author), Rodenhuis, S. (author), Linn, S.C. (author)

Introduction: BRCA-mutated breast cancer cells lack the DNA-repair mechanism homologous recombination that is required for error-free DNA double-strand break (DSB) repair. Homologous recombination deficiency (HRD) may cause hypersensitivity to DNA DSB-inducing agents, such as bifunctional alkylating agents and platinum salts. HRD can be caused...

journal article 2014

document

Chromatin Landscapes of Retroviral and Transposon Integration Profiles

De Jong, J. (author), Akhtar, W. (author), Badhai, J. (author), Rust, A.G. (author), Rad, R. (author), Hilkens, J. (author), Berns, A. (author), Van Lohuizen, M. (author), Wessels, L.F.A. (author), De Ridder, J. (author)

The ability of retroviruses and transposons to insert their genetic material into host DNA makes them widely used tools in molecular biology, cancer research and gene therapy. However, these systems have biases that may strongly affect research outcomes. To address this issue, we generated very large datasets consisting of to unselected...

journal article 2014

document

Breast cancer subtype specific classifiers of response to neoadjuvant chemotherapy do not outperform classifiers trained on all subtypes

De Ronde, J.J. (author), Bonder, M.J. (author), Lips, E.H. (author), Rodenhuis, S. (author), Wessels, L.F.A. (author)

Introduction: Despite continuous efforts, not a single predictor of breast cancer chemotherapy resistance has made it into the clinic yet. However, it has become clear in recent years that breast cancer is a collection of molecularly distinct diseases. With ever increasing amounts of breast cancer data becoming available, we set out to study if...

journal article 2014

document

Current composite-feature classification methods do not outperform simple single-genes classifiers in breast cancer prognosis

Staiger, C. (author), Cadot, S. (author), Györffy, B. (author), Wessels, L.F.A. (author), Klau, G.W. (author)

Integrating gene expression data with secondary data such as pathway or protein-protein interaction data has been proposed as a promising approach for improved outcome prediction of cancer patients. Methods employing this approach usually aggregate the expression of genes into new composite features, while the secondary data guide this...

journal article 2013

document

Identifying subgroup markers in heterogeneous populations

De Ronde, J.J. (author), Rigaill, G. (author), Rottenberg, S. (author), Rodenhuis, S. (author), Wessels, L.F.A. (author)

Traditional methods that aim to identify biomarkers that distinguish between two groups, like Significance Analysis of Microarrays or the t-test, perform optimally when such biomarkers show homogeneous behavior within each group and differential behavior between the groups. However, in many applications, this is not the case. Instead, a subgroup...

journal article 2013

document

Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition

Roepman, P. (author), Schlicker, A. (author), Tabernero, J. (author), Majewski, I. (author), Tian, S. (author), Moreno, V. (author), Snel, M.H. (author), Chresta, C.M. (author), Rosenberg, R. (author), Nitsche, U. (author), Macarulla, T. (author), Capella, G. (author), Salazar, R. (author), Orphanides, G. (author), Wessels, L.F.A. (author), Bernards, R. (author), Simon, I.M. (author)

In most colorectal cancer (CRC) patients, outcome cannot be predicted because tumors with similar clinicopathological features can have differences in disease progression and treatment response. Therefore, a better understanding of the CRC biology is required to identify those patients who will benefit from chemotherapy and to find a more...

journal article 2013

document

Analysis of tumor heterogeneity and cancer gene networks using deep sequencing of MMTV-induced mouse mammary tumors

Klijn, C. (author), Koudijs, M.J. (author), Kool, J. (author), Ten Hoeve, J. (author), Boer, M. (author), De Moes, J. (author), Akhtar, W. (author), Van Miltenburg, M. (author), Vendel-Zwaagstra, A. (author), Reinders, M.J.T. (author), Adams, D.J. (author), Van Lohuizen, M. (author), Hilkens, J. (author), Wessels, L.F.A. (author), Jonkers, J. (author)

Cancer develops through a multistep process in which normal cells progress to malignant tumors via the evolution of their genomes as a result of the acquisition of mutations in cancer driver genes. The number, identity and mode of action of cancer driver genes, and how they contribute to tumor evolution is largely unknown. This study deployed...

journal article 2013

document

A scale-space method for detecting recurrent DNA copy number changes with analytical false discovery rate control

Van Dyk, E. (author), Reinders, M.J.T. (author), Wessels, L.F.A. (author)

Tumor formation is partially driven by DNA copy number changes, which are typically measured using array comparative genomic hybridization, SNP arrays and DNA sequencing platforms. Many techniques are available for detecting recurring aberrations across multiple tumor samples, including CMAR, STAC, GISTIC and KC SMART. GISTIC is widely used and...

journal article 2013

document

Subtypes of primary colorectal tumors correlate with response to targeted treatment in colorectal cell lines

Schlicker, A. (author), Beran, G. (author), Chresta, C.M. (author), McWalter, G. (author), Pritchard, A. (author), Weston, S. (author), Runswick, S. (author), Davenport, S. (author), Heathcote, K. (author), Alferez Castro, D. (author), Orphanides, G. (author), French, T. (author), Wessels, L.F.A. (author)

Background Colorectal cancer (CRC) is a heterogeneous and biologically poorly understood disease. To tailor CRC treatment, it is essential to first model this heterogeneity by defining subtypes of patients with homogeneous biological and clinical characteristics and second match these subtypes to cell lines for which extensive pharmacological...

journal article 2012

document

Integration of Clinical and Gene Expression Data Has a Synergetic Effect on Predicting Breast Cancer Outcome

Van Vliet, M.H. (author), Horlings, H.M. (author), Van de Vijver, M.J. (author), Reinders, M.J.T. (author), Wessels, L.F.A. (author)

Breast cancer outcome can be predicted using models derived from gene expression data or clinical data. Only a few studies have created a single prediction model using both gene expression and clinical data. These studies often remain inconclusive regarding an obtained improvement in prediction performance. We rigorously compare three different...

journal article 2012

document

Computational identification of insertional mutagenesis targets for cancer gene discovery

De Jong, J. (author), De Ridder, J. (author), Van der Weyden, L. (author), Sun, N. (author), Van Uitert, M. (author), Berns, A. (author), Van Lohuizen, M. (author), Jonkers, J. (author), Adams, D.J. (author), Wessels, L.F.A. (author)

Insertional mutagenesis is a potent forward genetic screening technique used to identify candidate cancer genes in mouse model systems. An important, yet unresolved issue in the analysis of these screens, is the identification of the genes affected by the insertions. To address this, we developed Kernel Convolved Rule Based Mapping (KC-RBM). KC...

journal article 2011

document

Specific genomic aberrations in primary colorectal cancer are associated with liver metastases

Bruin, S.C. (author), Klijn, C.N. (author), Liefers, G.J. (author), Braaf, L.M. (author), Joosse, S.A. (author), Van Beers, E.H. (author), Verwaal, V.J. (author), Morreau, H. (author), Wessels, L.F. (author), Van Velthuysen, M.L.F. (author), Tollenaar, R.A.E.M. (author), Van 't Veer, L.J. (author)

Background: Accurate staging of colorectal cancer (CRC) with clinicopathological parameters is important for predicting prognosis and guiding treatment but provides no information about organ site of metastases. Patterns of genomic aberrations in primary colorectal tumors may reveal a chromosomal signature for organ specific metastases. Methods:...

journal article 2010

document

KC-SMARTR: An R package for detection of statistically significant aberrations in multi-experiment aCGH data

De Ronde, J.J. (author), Klijn, C. (author), Velds, A. (author), Holstege, H. (author), Reinders, M.J.T. (author), Jonkers, J. (author), Wessels, L.F.A. (author)

Background: Most approaches used to find recurrent or differential DNA Copy Number Alterations (CNA) in array Comparative Genomic Hybridization (aCGH) data from groups of tumour samples depend on the discretization of the aCGH data to gain, loss or no-change states. This causes loss of valuable biological information in tumour samples, which are...

journal article 2010

document

Somatic structural rearrangements in genetically engineered mouse mammary tumors

Varela, I. (author), Klijn, C.N. (author), Stephens, P.J. (author), Mudie, L.J. (author), Stebbings, L. (author), Galappaththige, D. (author), Van der Gulden, H. (author), Schut, E. (author), Klarenbeek, S. (author), Campbell, P.J. (author), Wessels, L.F.A. (author), Stratton, M.R. (author), Jonkers, J. (author), Futreal, P.A. (author), Adams, D.J. (author)

Background: Here we present the first paired-end sequencing of tumors from genetically engineered mouse models of cancer to determine how faithfully these models recapitulate the landscape of somatic rearrangements found in human tumors. These were models of Trp53-mutated breast cancer, Brca1- and Brca2-associated hereditary breast cancer, and E...

journal article 2010

document

Cross-species comparison of aCGH data from mouse and human BRCA1- and BRCA2-mutated breast cancers

Holstege, H. (author), Van Beers, E. (author), Velds, A. (author), Liu, X. (author), Joosse, S.A. (author), Klarenbeek, S. (author), Schut, E. (author), Kerkhoven, R. (author), Klijn, C.N. (author), Wessels, L.F.A. (author), Nederlof, P.M. (author), Jonkers, J. (author)

Background: Genomic gains and losses are a result of genomic instability in many types of cancers. BRCA1- and BRCA2-mutated breast cancers are associated with increased amounts of chromosomal aberrations, presumably due their functions in genome repair. Some of these genomic aberrations may harbor genes whose absence or overexpression may give...

journal article 2010

document

Inferring combinatorial association logic networks in multimodal genome-wide screens

De Ridder, J. (author), Gerrits, A. (author), Bot, J. (author), De Haan, G. (author), Reinders, M. (author), Wessels, L. (author)

We propose an efficient method to infer combinatorial association logic networks from multiple genome-wide measurements from the same sample. We demonstrate our method on a genetical genomics dataset, in which we search for Boolean combinations of multiple genetic loci that associate with transcript levels. Our method provably finds the global...

journal article 2010

document

Identification of Networks of Co-Occurring, Tumor-Related DNA Copy Number Changes Using a Genome-Wide Scoring Approach

Klijn, C. (author), Bot, J. (author), Adams, D.J. (author), Reinders, M. (author), Wessels, L. (author), Jonkers, J. (author)

Tumorigenesis is a multi-step process in which normal cells transform into malignant tumors following the accumulation of genetic mutations that enable them to evade the growth control checkpoints that would normally suppress their growth or result in apoptosis. It is therefore important to identify those combinations of mutations that...

journal article 2010