Project Clonal evolution

We are interested in the evolutionary analysis of the relative time of genetic events underlying tumorigenesis in human bladder cancers using multiregional whole exome sequencing and bioinformatics. We aim to time bladder cancer drivers, mutational signatures, ploidy and copy number alterations and correlate these alterations with tumor areas and histological phenotypes.

In our past projects (Heide et al., 2019) we found that heterogeneous tumor areas/phenotypes had distinct driver mutations, and ancestral tumor cells either divide early into two separately evolving branches, or confer important subclonal mutations by parallel evolution. APOBEC mutational signatures were found to be very early events, active in carcinoma in situ (CIS), and often remained a dominant source of mutations throughout tumour evolution.

The figure illustrates the importance of the clonal tumor architecture for targeted therapy. A tumor with subclonal FGFR3-alterations in tumor parts only (orange clades in left picture) is likely to respond to anti-FGFR3-treatment in these areas, however other areas (red clades in left picture) will take advantage and overgrow the whole tumor with probably fatal outcome. Thus, it is very important to know and analyze clonal tumor structures for a successful treatment.

Therefore, there is a more divers mutational trajectory of bladder tumorigenesis than we previously expected, and we are currently pursuing further analyses to underpin the importance of timing of mutational processes and clonal architecture in several bladder cancer types as important aspects for successful prognostication and therapy.