ICGC Project on Early Onset Prostate Cancer
Prostate cancer is the most frequent malignant tumor in males and the second most frequent cause of cancer-related death. Currently, in Germany, more than 60,000 prostate cancers are diagnosed every year. Although most of these patients are treated in a curative attempt, more than 10,000 German men die from prostate cancer annually. Owing to the demographic changes of our society, a further doubling of prostate cancer incidences during the next 20 years is expected.
In cooperation with partners from the University Medical Center Hamburg-Eppendorf (UKE), Max Planck Institute for Molecular Genetics (MPI-MG), European Molecular Biology Laboratory (EMBL), National Center for Tumor Diseases Heidelberg (NCT) and several groups from the German Cancer Researhc Center (DKFZ) we have analyzed the genomes and epigenomes of early onset prostate cancers (i.e. diagnosis below the age of 50).
To compare the genomic alteration landscapes of EO-PCA with "classical" (elderly-onset) PCA, we performed deep sequencing-based genomics analyses in 11 tumors diagnosed at young age, and pursued comparative assessments with seven elderly-onset PCA genomes. Remarkable age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms. Whereas EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG, elderly-onset PCAs displayed primarily non-androgen-associated SRs. Data from a validation cohort of > 10,000 patients showed age-dependent androgen receptor levels and a prevalence of SRs affecting androgen-regulated genes, further substantiating the activity of a characteristic "androgen-type" pathomechanism in EO-PCA (Weischenfeldt et al., 2013).
Gerhauser et al. molecularly characterize prostate cancers diagnosed before 56 years old, which reveals an APOBEC- driven mutational process and identifies an aggressive subgroup with increased expression of ESRP1. They develop a framework to predict the order of somatic alterations and clinical outcome (Gerhauser et al. Cancer Cell 2018).
© Cancer Cell
Further characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Our integrative analysis identified four molecular subgroups, including a particularly aggressive subgroup with recurrent duplications associated with increased expression of ESRP1, which we validate in 12,000 tissue microarray tumors. Finally, we combined the patterns of molecular co-occurrence and risk-based subgroup information to deconvolve the molecular and clinical trajectories of prostate cancer from single patient samples (Gerhauser et al., Cancer Cell 2018).
Publications:
- Weischenfeldt et al., Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer. Cancer Cell (2013)
- Brocks et al., Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer. Cell Reports (2014)
- Steurer et al., TMPRSS2-ERG fusions are strongly linked to young patient age in low-grade prostate cancer. Eur. Urol. (2014)
- Gu et al., BAZ2A (TIP5) is involved in epigenetic alterations in prostate cancer and its overexpression predicts disease recurrence. Nat. Genet. (2015)
- Schlomm et al., The aging prostate is never "normal": implications from the genomic characterization of multifocal prostate cancers. Eur.Urol. (2015)
- Gerhauser et al., Molecular evolution of early onset prostate cancer identifies molecular risk markers and clinical trajectories. Cancer Cell (2018)
- Toth et al., Random forest-based modelling to detect biomarkers for prostate cancer progression (Clinical Epigenetics 2019)
- PCAWG, Pan-cancer analysis of whole genomes (Nature 2020)