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Sotiriou cancer

Fani-Marlen Roumelioti, Sotirios K Sotiriou, Vasiliki Katsini, Maria Chiourea, Thanos D Halazonetis, Sarantis Gagos
Human malignancies overcome replicative senescence either by activating the reverse-transcriptase telomerase or by utilizing a homologous recombination-based mechanism, referred to as alternative lengthening of telomeres (ALT). In budding yeast, ALT exhibits features of break-induced replication (BIR), a repair pathway for one-ended DNA double-strand breaks (DSBs) that requires the non-essential subunit Pol32 of DNA polymerase delta and leads to conservative DNA replication. Here, we examined whether ALT in human cancers also exhibits features of BIR A telomeric fluorescence in situ hybridization protocol involving three consecutive staining steps revealed the presence of conservatively replicated telomeric DNA in telomerase-negative cancer cells...
October 19, 2016: EMBO Reports
Rico D Bense, Christos Sotiriou, Martine J Piccart-Gebhart, John B A G Haanen, Marcel A T M van Vugt, Elisabeth G E de Vries, Carolien P Schröder, Rudolf S N Fehrmann
BACKGROUND: Not all breast cancer patients benefit from neoadjuvant or adjuvant therapy, resulting in considerable undertreatment or overtreatment. New insights into the role of tumor-infiltrating immune cells suggest that their composition, as well as their functionality, might serve as a biomarker to enable optimal patient selection for current systemic therapies and upcoming treatment options such as immunotherapy. METHODS: We performed several complementary unbiased in silico analyses on gene expression profiles of 7270 unrelated tumor samples of nonmetastatic breast cancer patients with known clinical follow-up...
January 2017: Journal of the National Cancer Institute
Debora Fumagalli, David Venet, Michail Ignatiadis, Hatem A Azim, Marion Maetens, Françoise Rothé, Roberto Salgado, Ian Bradbury, Lajos Pusztai, Nadia Harbeck, Henry Gomez, Tsai-Wang Chang, Maria Antonia Coccia-Portugal, Serena Di Cosimo, Evandro de Azambuja, Lorena de la Peña, Paolo Nuciforo, Jan C Brase, Jens Huober, José Baselga, Martine Piccart, Sherene Loi, Christos Sotiriou
Importance: In neoadjuvant trials, treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancers with dual HER2 blockade resulted in increased pathologic complete response (pCR) rates compared with each targeted agent alone. Amplification and/or overexpression of HER2 currently remains the only biomarker for therapeutic decisions, but it is insufficient to explain the heterogeneous response to anti-HER2 agents. Objective: To investigate the ability of clinically and biologically relevant genes and gene signatures (GSs) measured by RNA sequencing to predict the efficacy of anti-HER2 agents...
September 29, 2016: JAMA Oncology
D Fumagalli, T R Wilson, R Salgado, X Lu, J Yu, C O'Brien, K Walter, L Y Huw, C Criscitiello, I Laios, V Jose, D N Brown, F Rothé, M Maetens, D Zardavas, P Savas, D Larsimont, M J Piccart-Gebhart, S Michiels, M R Lackner, C Sotiriou, S Loi
BACKGROUND: Estrogen receptor-positive (ER+) breast cancers (BCs) constitute the most frequent BC subtype. The molecular landscape of ER+ relapsed disease is not well characterized. In this study, we aimed to describe the genomic evolution between primary (P) and matched metastatic (M) ER+ BCs after failure of adjuvant therapy. MATERIALS AND METHODS: A total of 182 ER+ metastatic BC patients with long-term follow-up were identified from a single institution. P tumor tissue was available for all patients, with 88 having matched M material...
October 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Olivier Van Grembergen, Martin Bizet, Eric J de Bony, Emilie Calonne, Pascale Putmans, Sylvain Brohée, Catharina Olsen, Mingzhou Guo, Gianluca Bontempi, Christos Sotiriou, Matthieu Defrance, François Fuks
Evidence is emerging that long noncoding RNAs (lncRNAs) may play a role in cancer development, but this role is not yet clear. We performed a genome-wide transcriptional survey to explore the lncRNA landscape across 995 breast tissue samples. We identified 215 lncRNAs whose genes are aberrantly expressed in breast tumors, as compared to normal samples. Unsupervised hierarchical clustering of breast tumors on the basis of their lncRNAs revealed four breast cancer subgroups that correlate tightly with PAM50-defined mRNA-based subtypes...
September 2016: Science Advances
Fatima Cardoso, Laura J van't Veer, Jan Bogaerts, Leen Slaets, Giuseppe Viale, Suzette Delaloge, Jean-Yves Pierga, Etienne Brain, Sylvain Causeret, Mauro DeLorenzi, Annuska M Glas, Vassilis Golfinopoulos, Theodora Goulioti, Susan Knox, Erika Matos, Bart Meulemans, Peter A Neijenhuis, Ulrike Nitz, Rodolfo Passalacqua, Peter Ravdin, Isabel T Rubio, Mahasti Saghatchian, Tineke J Smilde, Christos Sotiriou, Lisette Stork, Carolyn Straehle, Geraldine Thomas, Alastair M Thompson, Jacobus M van der Hoeven, Peter Vuylsteke, René Bernards, Konstantinos Tryfonidis, Emiel Rutgers, Martine Piccart
BACKGROUND: The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy. METHODS: In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online)...
August 25, 2016: New England Journal of Medicine
Matilde Murga, Emilio Lecona, Irene Kamileri, Marcos Díaz, Natalia Lugli, Sotirios K Sotiriou, Marta E Anton, Juan Méndez, Thanos D Halazonetis, Oscar Fernandez-Capetillo
The Pold3 gene encodes a subunit of the Polδ DNA polymerase complex. Pold3 orthologs are not essential in Saccharomyces cerevisiae or chicken DT40 cells, but the Schizosaccharomyces pombe ortholog is essential. POLD3 also has a specialized role in the repair of broken replication forks, suggesting that POLD3 activity could be particularly relevant for cancer cells enduring high levels of DNA replication stress. We report here that POLD3 is essential for mouse development and is also required for viability in adult animals...
September 1, 2016: Molecular Cell
Michail Ignatiadis, Dimitrios Zardavas, Marc Lemort, Celine Wilke, Marie-Catherine Vanderbeeken, Veronique D'Hondt, Evandro De Azambuja, Andrea Gombos, Fabienne Lebrun, Lissandra Dal Lago, Fanny Bustin, Marion Maetens, Lieveke Ameye, Isabelle Veys, Stefan Michiels, Marianne Paesmans, Denis Larsimont, Christos Sotiriou, Jean-Marie Nogaret, Martine Piccart, Ahmad Awada
BACKGROUND: EndoTAG-1, a tumor endothelial targeting agent has shown activity in metastatic triple-negative breast cancer (BC) in combination with paclitaxel. METHODS: HER2-negative BC patients candidates for neoadjuvant chemotherapy were scheduled to receive 12 cycles of weekly EndoTAG-1 22mg/m2 plus paclitaxel 70mg/m2 followed by 3 cycles of FEC (Fluorouracil 500mg/m2, Epirubicin 100mg/m2, Cyclophosphamide 500mg/m2) every 3 weeks followed by surgery. Primary endpoint was percent (%) reduction in Magnetic Resonance Imaging (MRI) estimated Gadolinium (Gd) enhancing tumor volume at the end of EndoTAG-1 plus paclitaxel administration as compared to baseline...
2016: PloS One
Michail Ignatiadis, Brigitte Rack, Francoise Rothé, Sabine Riethdorf, Charles Decraene, Hervé Bonnefoi, Christian Dittrich, Carlo Messina, Melanie Beauvois, Elisabeth Trapp, Theodora Goulioti, Konstantinos Tryfonidis, Klaus Pantel, Madeline Repollet, Wolfgang Janni, Martine Piccart, Christos Sotiriou, Saskia Litiere, Jean-Yves Pierga
There is increasing evidence that breast cancer evolves over time under the selection pressure of systemic treatment. Today, treatment decisions in early breast cancer are based on primary tumour characteristics without considering the disease evolution. Chemoresistant micrometastatic disease is poorly characterised and thus it is not used in current clinical practice as a tool to personalise treatment approaches. The detection of chemoresistant circulating tumour cells (CTCs) has been shown to be associated with worse prognosis in early breast cancer...
August 2016: European Journal of Cancer
S Loibl, I Majewski, V Guarneri, V Nekljudova, E Holmes, E Bria, C Denkert, C Schem, C Sotiriou, S Loi, M Untch, P Conte, R Bernards, M Piccart, G von Minckwitz, J Baselga
BACKGROUND: The predictive value of PIK3CA mutations in HER2 positive (HER2+) breast cancer treated with neoadjuvant anti-HER2 and chemotherapy has been reported, but the power for subgroup analyses was lacking. PATIENTS AND METHODS: We combined individual patient data from five clinical trials evaluating PIK3CA mutations and associations with pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Patients received either trastuzumab (T), lapatinib (L) or the combination T/L in addition to a taxane-based chemotherapy...
August 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Katrien Berns, Amir Sonnenblick, Annemiek Gennissen, Sylvain Brohée, Marielle E Hijmans, Bastiaan Evers, Debora Fumagalli, Christine Desmedt, Sibylle Loibl, Carsten Denkert, Patrick Neven, Wei Guo, Fan Zhang, Theo A Knijnenburg, Tjalling Bosse, Michiel S van der Heijden, Sanne Hindriksen, Wouter Nijkamp, Lodewyk F A Wessels, Heikki Joensuu, Gordon B Mills, Roderick L Beijersbergen, Christos Sotiriou, Rene Bernards
PURPOSE: Despite the substantial progress in the development of targeted anti-cancer drugs, treatment failure due to primary or acquired resistance is still a major hurdle in the effective treatment of most advanced human cancers. Understanding these resistance mechanisms will be instrumental to improve personalized cancer treatment. EXPERIMENTAL DESIGN: Genome wide loss-of-function genetic screens were performed to identify genes implicated in resistance to HER2/PI3K/mTOR targeting agents in HER2+ breast cancer cell lines...
May 12, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
C Swanton, J-C Soria, A Bardelli, A Biankin, C Caldas, S Chandarlapaty, L de Koning, C Dive, J Feunteun, S-Y Leung, R Marais, E R Mardis, N McGranahan, G Middleton, S A Quezada, J Rodón, N Rosenfeld, C Sotiriou, F André
Recent advances in biotechnologies have led to the development of multiplex genomic and proteomic analyses for clinical use. Nevertheless, guidelines are currently lacking to determine which molecular assays should be implemented in metastatic cancers. The first MAP conference was dedicated to exploring the use of genomics to better select therapies in the treatment of metastatic cancers. Sixteen consensus items were covered. There was a consensus that new technologies like next-generation sequencing of tumors and ddPCR on circulating free DNA have convincing analytical validity...
August 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Sandro Morganella, Ludmil B Alexandrov, Dominik Glodzik, Xueqing Zou, Helen Davies, Johan Staaf, Anieta M Sieuwerts, Arie B Brinkman, Sancha Martin, Manasa Ramakrishna, Adam Butler, Hyung-Yong Kim, Åke Borg, Christos Sotiriou, P Andrew Futreal, Peter J Campbell, Paul N Span, Steven Van Laere, Sunil R Lakhani, Jorunn E Eyfjord, Alastair M Thompson, Hendrik G Stunnenberg, Marc J van de Vijver, John W M Martens, Anne-Lise Børresen-Dale, Andrea L Richardson, Gu Kong, Gilles Thomas, Julian Sale, Cristina Rada, Michael R Stratton, Ewan Birney, Serena Nik-Zainal
Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, here we show that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization...
2016: Nature Communications
Serena Nik-Zainal, Helen Davies, Johan Staaf, Manasa Ramakrishna, Dominik Glodzik, Xueqing Zou, Inigo Martincorena, Ludmil B Alexandrov, Sancha Martin, David C Wedge, Peter Van Loo, Young Seok Ju, Marcel Smid, Arie B Brinkman, Sandro Morganella, Miriam R Aure, Ole Christian Lingjærde, Anita Langerød, Markus Ringnér, Sung-Min Ahn, Sandrine Boyault, Jane E Brock, Annegien Broeks, Adam Butler, Christine Desmedt, Luc Dirix, Serge Dronov, Aquila Fatima, John A Foekens, Moritz Gerstung, Gerrit K J Hooijer, Se Jin Jang, David R Jones, Hyung-Yong Kim, Tari A King, Savitri Krishnamurthy, Hee Jin Lee, Jeong-Yeon Lee, Yilong Li, Stuart McLaren, Andrew Menzies, Ville Mustonen, Sarah O'Meara, Iris Pauporté, Xavier Pivot, Colin A Purdie, Keiran Raine, Kamna Ramakrishnan, F Germán Rodríguez-González, Gilles Romieu, Anieta M Sieuwerts, Peter T Simpson, Rebecca Shepherd, Lucy Stebbings, Olafur A Stefansson, Jon Teague, Stefania Tommasi, Isabelle Treilleux, Gert G Van den Eynden, Peter Vermeulen, Anne Vincent-Salomon, Lucy Yates, Carlos Caldas, Laura van't Veer, Andrew Tutt, Stian Knappskog, Benita Kiat Tee Tan, Jos Jonkers, Åke Borg, Naoto T Ueno, Christos Sotiriou, Alain Viari, P Andrew Futreal, Peter J Campbell, Paul N Span, Steven Van Laere, Sunil R Lakhani, Jorunn E Eyfjord, Alastair M Thompson, Ewan Birney, Hendrik G Stunnenberg, Marc J van de Vijver, John W M Martens, Anne-Lise Børresen-Dale, Andrea L Richardson, Gu Kong, Gilles Thomas, Michael R Stratton
We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures...
May 2, 2016: Nature
Sherene Loi, Urania Dafni, Dimitris Karlis, Varvara Polydoropoulou, Brandon M Young, Scooter Willis, Bradley Long, Evandro de Azambuja, Christos Sotiriou, Giuseppe Viale, Josef Rüschoff, Martine J Piccart, Mitch Dowsett, Stefan Michiels, Brian Leyland-Jones
IMPORTANCE: A number of studies suggest that response to antihuman epidermal growth factor receptor-2 (currently known as ERBB2, butreferred to asHER2 in this study) agents differs by estrogen receptor (ER) level status. The clinical relevance of this is unknown. OBJECTIVE: To determine the magnitude of trastuzumab benefit according to quantitative levels of ER and HER2 in the HERceptin Adjuvant (HERA) trial. DESIGN, SETTING, AND PARTICIPANTS: The HERA trial was an international, multicenter, randomized trial that included 5099 patients with early-stage HER2-positive breast cancer, randomized between 2001 and 2005 to receive either no trastuzumab or trastuzumab, after adjuvant chemotherapy...
August 1, 2016: JAMA Oncology
Z Apalla, A Lallas, E Sotiriou, E Lazaridou, E Vakirlis, M Trakatelli, A Kyrgidis, D Ioannides
BACKGROUND: Ultraviolet radiation plays an important role in the pathogenesis of non-melanoma skin cancer. Outdoor workers, including farmers, experience higher exposure levels compared to the general population. Available literature data suggest that occupational ultraviolet exposure represents an independent risk factor for squamous cell carcinoma; whereas for basal cell carcinoma (BCC) this association still remains unclarified. OBJECTIVES: To analyse the epidemiological, clinical and histological data of patients diagnosed with BCC, and correlate them with outdoor occupation in farmers...
April 2016: Journal of the European Academy of Dermatology and Venereology: JEADV
I Gingras, A Sonnenblick, E de Azambuja, M Paesmans, S Delaloge, Philippe Aftimos, M J Piccart, C Sotiriou, M Ignatiadis, H A Azim
There is increasing availability of technologies that can interrogate the genomic landscape of an individual tumor; however, their impact on daily practice remains uncertain. We conducted a 28-item survey to investigate the current attitudes towards the integration of tumor genome sequencing in breast cancer management. A link to the survey was communicated via newsletters of several oncological societies, and dedicated mailing by academic research groups. Multivariable logistic regression modeling was carried out to determine the relationship between predictors and outcomes...
2016: Scientific Reports
Christine Desmedt, Gabriele Zoppoli, Gunes Gundem, Giancarlo Pruneri, Denis Larsimont, Marco Fornili, Debora Fumagalli, David Brown, Françoise Rothé, Delphine Vincent, Naima Kheddoumi, Ghizlane Rouas, Samira Majjaj, Sylvain Brohée, Peter Van Loo, Patrick Maisonneuve, Roberto Salgado, Thomas Van Brussel, Diether Lambrechts, Ron Bose, Otto Metzger, Christine Galant, François Bertucci, Martine Piccart-Gebhart, Giuseppe Viale, Elia Biganzoli, Peter J Campbell, Christos Sotiriou
PURPOSE: Invasive lobular breast cancer (ILBC) is the second most common histologic subtype after invasive ductal breast cancer (IDBC). Despite clinical and pathologic differences, ILBC is still treated as IDBC. We aimed to identify genomic alterations in ILBC with potential clinical implications. METHODS: From an initial 630 ILBC primary tumors, we interrogated oncogenic substitutions and insertions and deletions of 360 cancer genes and genome-wide copy number aberrations in 413 and 170 ILBC samples, respectively, and correlated those findings with clinicopathologic and outcome features...
June 1, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Michail Ignatiadis, Hatem A Azim, Christine Desmedt, Isabelle Veys, Denis Larsimont, Roberto Salgado, Maria B Lyng, Giuseppe Viale, Brian Leyland-Jones, Anita Giobbie-Hurder, Rosita Kammler, Patrizia Dell'Orto, Françoise Rothé, Ioanna Laïos, Henrik J Ditzel, Meredith M Regan, Martine Piccart, Stefan Michiels, Christos Sotiriou
IMPORTANCE: The Genomic Grade Index (GGI) was previously developed, evaluated on frozen tissue, and shown to be prognostic in early breast cancer. To test the GGI in formalin-fixed, paraffin-embedded breast cancer tumors, a quantitative reverse transcriptase polymerase chain reaction assay was developed and named the Genomic Grade (GG). The GG assay has the potential to increase the clinical application of the GGI, but robust demonstration of the clinical validity of the GG assay is required...
February 2016: JAMA Oncology
Hélène Denis, Olivier Van Grembergen, Benjamin Delatte, Sarah Dedeurwaerder, Pascale Putmans, Emilie Calonne, Françoise Rothé, Christos Sotiriou, François Fuks, Rachel Deplus
MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Alteration of miRNA levels is common in tumors and contributes to the pathogenesis of human malignancies. In the present study we examined the role played by miR-137 in breast tumorigenesis. We found miR-137 levels to be lower in breast cancer cells than in their non-tumorigenic counterparts and observed reduced proliferation and migration of breast cancer cells overexpressing miR-137. We further identified KDM5B, a histone demethylase known to be involved in breast cancer tumorigenesis, as a target of miR-137...
February 2016: Molecular BioSystems
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