Abstract 4470: Aneuploidy drives lethal progression in prostate cancer
Authors: Stopsack Konrad H. , Whittaker Charles A. , Gerke Travis A. , Loda Massimo , Kantoff Philip W. , Mucci Lorelei A. , Amon Angelika 
Published: August 2019

Abstract
Purpose: Aneuploidy, defined as chromosome gains and losses, is a hallmark of cancer. However, extensive aneuploidy is relatively rare in prostate cancer. We sought to investigate whether extent of aneuploidy is associated with lethal progression in a large cohort of prostate cancer patients, an untested hypothesis.
Methods: To assess chromosome arm gains and losses in archival tumor specimens, we developed a computational method based on normalized gene expression sums of whole-transcriptome profiling in primary prostate tumors from The Cancer Genome Atlas (TCGA) and validated it against DNA copy numbers. We applied this method to tumor tissue from cancer diagnosis from patients diagnosed during prospective follow-up of two cohort studies, the Health Professionals Follow-up Study (HPFS) and the Physicians’ Health Study (PHS). These tumors underwent centralized histopathologic review including Gleason grading and immunohistochemistry to characterize proliferation (Ki-67), apoptosis (TUNEL), PTEN loss, and MYC amplification. Patients were followed for lethal disease (metastases and prostate cancer-specific death) on median for 15 years.
Results: Extensive aneuploidy (&gt;=5 gained or lost chromosome arms) was present in 23% of the 333 primary prostate cancers from TCGA. Even 68% of low-risk cancers (Gleason grade &lt;=3+4) had &gt;= 1 altered chromosome arm. Our algorithm detected aneuploidy based on transcriptome profiling with high discriminative accuracy (area under the curve [AUC] for any aneuploidy, 0.83; AUC for &gt;=5 chromosome arms, 0.87). Tumors with greater extent of aneuploidy had higher Gleason scores, but little to no increase in proliferative and apoptotic indices. Among the 404 patients from HPFS and PHS, 113 lethal events occurred. Greater extent of aneuploidy was strongly associated with a higher risk of lethal disease. Patients with &gt;=5 predicted altered chromosome arms had 5.3 times higher odds of lethal disease (95% confidence interval, 2.2-13.1) compared to those without aneuploidy after adjusting for Gleason grade. Aneuploidy was strongly associated with lethal disease even among men with high-risk Gleason grade 8-10 tumors. Chromosome arms 8q and 10q were among the commonly altered arms. The elevated risk associated with 10q deletion and 8q gain was not considerably attenuated when accounting for PTEN loss and MYC overexpression on the respective arms.
Conclusions: The extent of aneuploidy can be estimated from transcriptome profiling, which allows assessment of archival, formalin-fixed paraffin-embedded tumors. Given the complex interactions between genes colocalized on a chromosome arm, the loss or gain of an entire chromosome arm confers aggressiveness beyond affecting well-described tumor suppressors or oncogenes on that arm and beyond altering histologic tumor grade. Our results have clinical implications and point to a key role of aneuploidy in driving aggressive disease in primary prostate cancer.
Citation Format: Konrad H. Stopsack, Charles A. Whittaker, Travis A. Gerke, Massimo Loda, Philip W. Kantoff, Lorelei A. Mucci, Angelika Amon. Aneuploidy drives lethal progression in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4470.