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Q&A: German Cancer Research Center's Holger Sültmann on Analyzing Prostate Cancer Genomes


Holger_Sueltmann_Photo2.jpgName: Holger Sültmann
Age: 49
Title: Head, cancer genome research group, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany, since 2010
Experience and Education:
Group head, division of molecular genome analysis, DKFZ, 2000-2010
Postdoc and assistant professor, Max Planck Institute for Biology, Tübingen, Germany, 1994-2000
PhD, MPI for Biology, Tübingen, 1994
Undergraduate degree in biochemistry, University of Tübingen, 1991

Holger Sültmann coordinates a research network in Germany that has been studying the genetics of prostate cancer, a large-scale sequencing project that kicked off a year ago.

The project, which operates under the umbrella of the International Cancer Genome Consortium, is funded with €7.5 million ($9.7 million) from the German Federal Ministry of Education and Research and involves scientists at the German Cancer Research Center (DKFZ), the National Center for Tumor Diseases (NCT), and the European Molecular Biology Laboratory in Heidelberg; the University Medical Center Hamburg-Eppendorf and the Martini Hospital in Hamburg; and the Max Planck Institute for Molecular Genetics in Berlin.

All prostate cancer patients recruited for the project underwent surgery at the Martini Klinik, the only hospital in Germany that focuses exclusively on this type of cancer and operates on more than 2,000 prostate cancer patients each year.

The study is one of three ICGC projects in Germany, joining the PedBrain project, which focuses on pediatric brain cancers (CSN 12/7/2011), and a project on malignant lymphomas.

Clinical Sequencing News recently spoke with Sültmann at his office at the NCT about the progress of the prostate cancer project. Below is an edited transcript of the conversation.

Can you provide some background on the aims of the prostate cancer project and an update of its current status?

The project focuses on younger prostate cancer patients, meaning men diagnosed with this cancer at the age of under 50 years, which is not very frequent — the median age of diagnosis is about 65 years. We are focusing on these early-onset patients because we are hoping to find more driver mutation in these patients. Maybe we will also find hereditary mutations, [especially] in collaboration with other consortia in the ICGC. If we compare our datasets, maybe we will have a chance to find such changes.

The aim is to sequence 250 tumors and 250 control samples within five years. We plan to do paired-end whole-genome sequencing with 30x coverage or more, plus mate-pair sequencing to get the structural variations, which are of course important in prostate cancer. There is a very prominent rearrangement, the TMPRSS2-ERG gene fusion, but there are probably also others.

We also do RNA sequencing, including mRNA and microRNA, for a subset of these tumors, and we also do methylation analysis of selected regions.

We started early in 2011, and we are now at a stage where we have 12 pairs fully characterized at all the levels I mentioned. The sequencing was done at the MPI for Molecular Genetics, which did the major part of the whole-genome sequencing, and here at the DKFZ. The structural variation mate-pair sequencing is done at the EMBL. So far, we have mainly used the Illumina HiSeq, and for the methylation data, the Life Technologies SOLiD platform was also used.

Currently, we are struggling hard to get the most interesting findings out of these data. The data analysis is done by Benedikt Brors, who is a group head in Roland Eils' division here at the DKFZ. There are also smaller data analysis parts within each of the partners’ groups at the MPI or the EMBL, and also in my group here.

Have you found anything interesting so far?

Yes. We found very interesting results, which at present I really can't say much about because this is all work in progress. We found, as expected, a number of gene fusions and translocations. We also found that the tumors are very heterogeneous, which could also be expected, not only in prostate cancer.

What do you think will be the first outcome of this project that will be useful for patient care?

That is probably still far from where we are now. As it is the case in many other genome sequencing projects in cancer, the diverse picture makes the identification of particular targets very difficult.

What we will have to do, in my opinion, is to map the variations that we find onto particular pathways that are currently druggable, or that will become druggable within a few years, so those that are in clinical trials currently.

For particular small patient groups, there may be findings which could allow for very quick translation into therapeutic applications, but these groups are expected to be very small, a few percent of the tumors.

Are you reporting any results to patients whose genomes you are analyzing?

No. The study went through an ethical review board at Hamburg University, and all the patients gave informed consent, but there is no reporting back. We are basically not allowed to do this.

What have been the greatest challenges in this project so far, in terms of getting suitable samples, technical, or analytical challenges?

Samples have become available very quickly, and the supply is developing very well. Of course, heterogeneity is an issue with prostate cancer. The samples are characterized very well in the pathology department in Hamburg, so the pathologists know very well what they provided for the DNA and RNA isolation procedures. Of course there is still a lot of stromal tissue involved in these samples, but we have a threshold of 70 percent epithelial tumor tissue as a quality criterion for inclusion into our study.

Due to the heterogeneity of the samples, we will probably have to go higher with the sequencing coverage. That is something we are currently in the process of discussing. So far, we are at a 30x-plus coverage level, but we are discussing how to improve the coverage and the reliability of calling. Base calling and, especially, mutation calling is still an issue. There are several algorithms used within the different groups, which of course lead to heterogeneous results, and that is something we are discussing very deeply — which strategy we should use to increase the likelihood to really find the interesting mutations.

Do you analyze variations outside of coding or regulatory regions?

Presently, we are really focused on variations that affect coding genes. We are trying to see where we have loss of heterozygosity, or loss of function. If we have a mutation in a gene which is maybe deactivating, the question is, what happens to the other allele? Is it epigenetically silenced in some way, by methylation of DNA, or is there microRNA overexpressed that could silence that gene? But that can be looked at in the consortium only at a case-by-case level; we have no systematic way to look at these things at present.

Are you involved in any other projects that use next-generation sequencing to characterize cancer?

Currently, my group is not involved in any others, but of course we have some plans. Together with partners here in Heidelberg, we are trying to get sequencing of tumors, especially prostate cancer, onto a scale that is closer to the clinic.

That will probably focus not on whole-genome sequencing but rather on a selected panel of genes, initially — ideally in overlap with other tumors. I could envisage a panel of a few hundred genes, which could be systematically sequenced in a majority of tumors collected here at the NCT or elsewhere in Heidelberg. For prostate cancer, the characterization of gene fusions and translocations is certainly something that is very interesting that could be part of such a clinically focused research program of prostate cancer.

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