Somatic Evolution and Early Detection

Junior Research Group Somatic Evolution and Early Detection

Dr. Angela Goncalves

Dissecting a complex tissue with single-cell RNA-sequencing.
© dkfz.de

Our group aims to understand how mutant clones arise and expand during the stages preceding the development of malignancy. We combine experimental approaches with bioinformatic analyses and statistical modelling to study these early stages, with a long-term view of improving early detection of cancer. 
It has long been known that mutant clonal evolution by natural selection plays a defining role in the development of cancer. However, this process has been challenging to study in detail prior to the development of cost-effective high-throughput Next-Generation Sequencing. Using NGS, alterations present in even very small proportions of cells can now be detected. Modelling these alterations can in turn improve our understanding of the emergence of mutant alleles within tissues. Moreover, recently developed single cell RNA sequencing methods can be used to identify somatic mutations in individual cells and assess their effects on the expression of genes, an approach that has been highly informative in the interpretation of the effects of germline variation. A major component of our work is therefore to interpret and develop novel methods for the analysis of NGS data in the context of cancer evolution.
Another component of our work is the more general understanding and prediction of genotype to phenotype relationships. For this, we contribute through the development of computational methods for high-dimensional data, including tools for feature selection and differential testing.

Future Outlook
The analysis of longitudinally acquired non-cancerous tissue proffers an effective means for studying the evolution of somatic mutations. Our research uses human gynaecological tissue as a model system because of its ease of acquisition from healthy individuals over time and because of its medical importance. In interdisciplinary research projects with cancer biologists and clinicians, we aim to analyse high-depth DNA and single-cell RNA sequencing data from tissue samples to achieve a quantitative understanding of somatic evolution.

Contact

Dr. Angela Goncalves
Somatic Evolution and Early Detection (B210)
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 580
69120 Heidelberg

Selected Publications

  • Helena Kilpinen*, Angela Goncalves*, Andreas Leha, Vackar Afzal, Kaur Alasoo, Sofie Ashford, Sendu Bala, Dalila Bensaddek, Francesco Paolo Casale, Oliver J Culley, Petr Danecek, Adam Faulconbridge, Peter W Harrison, Annie Kathuria, Davis McCarthy, Sh (2017). Common genetic variation drives molecular heterogeneity in human iPSCs. Nature 546, 370–375.
  • Paulina A Latos, Angela Goncalves, David Oxley, Hisham Mohammed, Ernest Turro, Myriam Hemberger (2015). Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells. Nature communications, 6.
  • Angela Goncalves*, Sarah Leigh-Brown*, David Thybert, Klara Stefflova, Ernest Turro, Paul Flicek, Alvis Brazma, Duncan T Odom, John C Marioni (2012). Extensive compensatory cis-trans regulation in the evolution of mouse gene expression (2012). Genome Research 22: 2376-2384.
  • Ernest Turro, SY Su, Angela Goncalves, LJM Coin, S Richardson, A Lewin (2011). Haplotype and isoform specific expression estimation using multi-mapping RNA-seq reads. Genome biology 12 (2), R13.
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