Aneuploidy drives lethal progression in prostate cancer
Menée à partir de données génétiques du projet "The Cancer Genome Atlas" portant sur 333 patients atteints d'un cancer de la prostate et à partir de l'analyse du transcriptome d'échantillons tumoraux prélevés sur 404 patients complémentaires, cette étude met en évidence une corrélation entre la présence d'une aneuploïdie et le caractère létal de la maladie
Aneuploidy is usually quantified by measuring intracellular DNA content or chromosome structure and number. We show that the number of altered chromosome arms can be estimated from transcriptome profiling, which allows for assessing aneuploidy within repositories of archival, formalin-fixed, paraffin-embedded tumors. While aneuploidy impedes proliferation in primary cells, we show that it is a feature of aggressiveness in primary prostate cancers that are more likely to become lethal. Our data suggest that losses or gains of entire chromosome arms confers aggressiveness beyond affecting copy numbers of tumor suppressors or oncogenes on those arms. Beyond helping understand the etiology of aggressive prostate cancer, we propose that extent of aneuploidy could also be employed clinically to inform risk stratification and treatment.Aneuploidy, defined as chromosome gains and losses, is a hallmark of cancer. However, compared with other tumor types, extensive aneuploidy is relatively rare in prostate cancer. Thus, whether numerical chromosome aberrations dictate disease progression in prostate cancer patients is not known. Here, we report the development of a method based on whole-transcriptome profiling that allowed us to identify chromosome-arm gains and losses in 333 primary prostate tumors. In two independent cohorts (n = 404) followed prospectively for metastases and prostate cancer-specific death for a median of 15 years, increasing extent of tumor aneuploidy as predicted from the tumor transcriptome was strongly associated with higher risk of lethal disease. The 23% of patients whose tumors had five or more predicted chromosome-arm alterations had 5.3 times higher odds of lethal cancer (95% confidence interval, 2.2 to 13.1) than those with the same Gleason score and no predicted aneuploidy. Aneuploidy was associated with lethality even among men with high-risk Gleason score 8-to-10 tumors. These results point to a key role of aneuploidy in driving aggressive disease in primary prostate cancer.
Proceedings of the National Academy of Sciences , résumé, 2018