Copy number alterations are associated with metastatic-lethal progression in prostate cancer



Aside from Gleason score few factors accurately identify the subset of prostate cancer (PCa) patients at high risk for metastatic progression. We hypothesized that copy number alterations (CNAs), assessed using CpG methylation probes on Illumina Infinium® Human Methylation450 (HM450K) BeadChip arrays, could identify primary prostate tumors with potential to develop metastatic progression.


Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from two cohorts of PCa patients with clinically localized disease who underwent radical prostatectomy (RP) as primary therapy and were followed prospectively for at least 5 years: (1) a Fred Hutchinson (FH) Cancer Research Center-based cohort (n = 323 patients); and (2) an Eastern Virginia (EV) Medical School-based cohort (n = 78 patients). CNAs were identified using the R package ChAMP. Metastasis was confirmed by positive bone scan, MRI, CT or biopsy, and death certificates confirmed cause of death.


We detected 15 recurrent CNAs were associated with metastasis in the FH cohort and replicated in the EV cohort (p < 0.05) without adjusting for Gleason score in the model. Eleven of the recurrent CNAs were associated with metastatic progression in the FH cohort and validated in the EV cohort (p < 0.05) when adjusting for Gleason score.


This study shows that CNAs can be reliably detected from HM450K-based DNA methylation data. There are 11 recurrent CNAs showing association with metastatic-lethal events following RP and improving prediction over Gleason score. Genes affected by these CNAs may functionally relate to tumor aggressiveness and metastatic progression.

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Fig. 1: CONSORT diagrams.
Fig. 2: Tuning of cutoffs for the HM450K-based CNA detection method.
Fig. 3: RCNA regions detected by GISTIC2.0 on the FH dataset.
Fig. 4: The validated 11 RCNAs (adjusting for Gleason score).


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This work was supported by grants from the National Cancer Institute (R01 CA222833, R01 CA056678, R01 CA092579, K05 CA175147 (JLS), and P50 CA097186), with additional support provided by the Fred Hutchinson Cancer Research Center (P30 CA015704). We acknowledge the support of the Eastern Virginia Medical School Biorepository, Norfolk, Virginia.

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Correspondence to Xiaoyu Wang or Janet L. Stanford.

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Wang, X., Grasso, C.S., Jordahl, K.M. et al. Copy number alterations are associated with metastatic-lethal progression in prostate cancer. Prostate Cancer Prostatic Dis (2020).

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