Abstract: As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non–BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.
Holly graduated from the University of Cambridge with a degree in Natural Sciences. For her thesis, she investigated the within-host diversity of influenza infections using statistical methods. In 2016, she undertook an internship at the Francis Crick Institute, London, during which she investigated potential new methods of influenza surveillance and vaccine research.
Holly joined the Huber group in September 2017 for a PhD, where her work focuses on using multi-omic data to understand drug responses in leukaemia patients. She is working jointly with the Dietrich group at the National Centre for Tumour Diseases, Heidelberg, performing experiments and gaining clinical insight to support her bioinformatic analysis.
Cécile is a master student in Computational Science at EPFL (Switzerland). She joined the Huber group for an internship in August 2017 and will work with Dorothee and Arne on proteomics data to study drug (off-)targets and systems-wide effects of drug treatment.
The race event of the National Center for Tumor Diseases (NCT) Heidelberg took place for the 6th time last Friday, 7 July 2017. More than 4.500 participants including patients and their families, physichians, scientists and friends of the NCT run “to opose cancer with a positive note” joined the event this year. An EMBL team supports this initiative every year.
See more (in German)
From the left to the right: Simone Bell, Olena Yavorska, Vladislav Kim, Frederik Ziebell, Almut Lütge and Britta Velten from the Huber Group.
On 30 June 2017 a group of 14 EMBL cyclists set off on an epic ride from Heidelberg to EMBL Grenoble over five days. Their goal is to raise money for the Kinderplanet, a charity that supports the families of children treated at the Heidelberg University Hospital. As the Kindergarten relies solely on donations in order to operate, their mission is to help Kinderplanet in supporting families of sick children.
30 June – 4 July 2017
5 days – 850 km distance – 16.500 m ascent
By completing this physically and mentally demanding cycling challenge they hope to spread the word about Kinderplanet charity and encourage our colleagues, friends and family members to donate for a great cause.
Almut Lütge and Mike Smith from the Huber Group are taking part in this epic ride!
CSAMA 2017 (15th edition)
Statistical Data Analysis for Genome Scale Biology
Bressanone-Brixen, Italy (South Tyrol Alps)
June 11-16, 2017
- Jennifer Bryan, RStudio and UBC
- Vincent J. Carey, Harvard Medical School
- Laurent Gatto, University of Cambridge
- Wolfgang Huber, European Molecular Biology Laboratory (EMBL), Heidelberg
- Martin Morgan, Roswell Park Cancer Institute, Buffalo
- Johannes Rainer, European Academy of Bozen (EURAC)
- Charlotte Soneson, University of Zurich
- Levi Waldron, CUNY School of Public Health at Hunter College, New York
- Simone Bell, EMBL, Heidelberg
- Vladislav Kim, EMBL, Heidelberg
- Lori Shepherd, RPCI, Buffalo
- Mike L. Smith, EMBL, Heidelberg
The one-week intensive course Statistical Data Analysis for Genome-Scale Biology teaches statistical and computational analysis of multi-omics studies in biology and biomedicine. It covers the underlying theory and state of the art (the morning lectures) and practical hands-on exercises based on the R / Bioconductor environment (the afternoon labs). At the end of the course, you should be able to run analysis workflows on your own (multi-)omic data, adapt and combine different tools, and make informed and scientifically sound choices about analysis strategies.
- Introduction to R and Bioconductor
- The elements of statistics: hypothesis testing, multiple testing, regression, regularization, clustering and classification, parallelization and performance (machine learning), visualisation
- RNA-Seq data analysis
- Computing with sequences and genomic intervals
- Working with annotation – genes, genomic features, variants, transcripts and proteins
- Gene set enrichment analysis
- Mass spec proteomics and metabolomics
- Basis of microbiome analysis
- Experimental design, batch effects and confounding
- Reproducible research and workflow authoring with R markdown
- Package development, version control and developer tools (incl. git, github, RStudio)
- Working with large data: performance parallelisation and cloud computing
The course consists of
- morning lectures: 20 x 45 minutes: Monday to Friday 8:30h – 12:00h
- 4 practical computer tutorials in the afternoons (13:30h – 16:30h) on Monday, Tuesday, Thursday and Friday
Visit the course’s website at: http://www.huber.embl.de/csama
Frederik has a PhD in Applied Mathematics from Heidelberg University and the German Cancer Research Center (DKFZ). He works on developing statistical methods for high-dimensional heterogeneous data and the analysis of multi-omic level drug treatment effects in collaboration with Cellzome.
Almut is a master student in molecular biotechnology at the University of Heidelberg. She joined the Huber group in 2017 and works on the analysis of RNA-seq data from Chronic lymphatic leukemia (CLL) samples.
Jennifer has a PhD in Biology from the University Heidelberg. She joined EMBL in January 2017 and is working on the SOUND project. Her main tasks are the management of data resources and data analysis workflows related to the SMART project “Drug perturbation profiling of primary blood cancers” which encompasses researchers and activities at EMBL, NCT Heidelberg, DKFZ and Heidelberg University Hospital.
The 14th edition of the course Statistical Data Analysis for Genome Scale Biology took place in July 2016 in Bressanone-Brixen. More than 70 participants spent a fantastic week studying in a mix of lectures and practical computer tutorials, learning from the lecturers Wolfgang Huber, Martin Morgan, Vincent Carey, Charlotte Soneson, Simon Anders, Michael Love, Levi Waldron and Jennifer Bryan. Senior scientists, Postdocs and students from the Huber group participated to this course as well. Additionally, everybody enjoyed biking and hiking in the high-alpine regions. One of the highlights of that week was a wonderful hiking tour into the Plose Mountain.
Wolfgang Huber, Mike Smith, Alejandro Reyes and Levi Waldron enjoyed a mountain bike tour in the late afternoon after the course.
Wolfgang Huber, Karsten Bach and Nils Kurzawa on another mountain bike tour on Saturday after the course.
The 2017 course will take place from 11 to 16 June.
Photos from Brixen by Junyan Lu.