Aneuploidy drives lethal progression in prostate cancer

Abstract

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.

Keywords: aneuploidy; lethal disease; prostate cancer; transcriptome.

Fig. 1.

Methods overview. Aneuploidy was assessed based on copy-number data from The Cancer Genome Atlas, measuring its frequency per chromosome arm. A nearly identical assessment of aneuploidy using the transcriptome was evaluated against DNA copy number-defined aneuploidy and then applied to whole-transcriptome profiling obtained from tumors of prostate cancer patients from the Health Professionals Follow-Up Study and Physicians’ Health Study as a predictor of long-term clinical outcomes.

Fig. 2.

Occurrence of aneuploidy in primary prostate cancer. (A) Aneuploidy measured by copy-number alterations. Gene copy-number alterations [from −2, indicating homozygous deletion (or two-copy loss); to 0, indicating diploidy/euploidy; to +2, indicating amplification (or two-copy gain)] were summed for each tumor and chromosome arm from TCGA. Plotted are distributions of these sums for each chromosome arm and tumor. The labels indicate the number of genes per chromosome arm. Copy-number sums that were more extreme than the number of genes were defined as chromosome-arm gains (yellow) and losses (blue). (B) Proportions of tumors with gained (yellow) or lost (blue) chromosome arms. Chromosome arms with more than 5% alterations are plotted. See SI Appendix, Fig. S1 for copy-number alterations in all chromosome arms. (C) Aneuploidy as predicted from the tumor transcriptome (TCGA). Shown is the distribution of each tumor’s sum of mRNA expression levels, normalized in SDs, per chromosome arm. Predicted chromosome-arm gains (yellow) and losses (blue) are highlighted.

Fig. 3.

Features of aneuploid tumors. (A) Numbers of altered chromosome arms in primary prostate cancer from TCGA, measured using copy numbers, overall, and by Gleason score. (B) Discrimination analysis for predicting aneuploidy (five or more altered chromosome arms) using the transcriptome (yellow line) compared with random chance (gray line). A larger area under the curve indicates better performance. (C) Number of predicted altered chromosome arms and expression of the cell-proliferation marker Ki-67 in tumors from the HPFS and PHS.

Fig. 4.

Aneuploidy and lethal disease. Aneuploidy predicted from the tumor transcriptome at cancer diagnosis (in categories) and odds ratios (with 95% CIs) for lethal disease (metastases and death from prostate cancer) over long-term follow-up, adjusted for age at cancer diagnosis, calendar year of cancer diagnosis, and Gleason score.