Abstract
The RTK/ERK signaling pathway has been implicated in prostate cancer progression. However, the genetic relevance of this pathway to aggressive prostate cancer at the SNP level remains undefined. Here we performed a SNP and gene-based association analysis of the RTK/ERK pathway with aggressive prostate cancer in a cohort comprising 956 aggressive and 347 non-aggressive cases. We identified several loci including rs3217869/CCND2 within the pathway shown to be significantly associated with aggressive prostate cancer. Our functional analysis revealed a statistically significant relationship between rs3217869 risk genotype and decreased CCND2 expression levels in a collection of 119 prostate cancer patient samples. Reduced expression of CCND2 promoted cell proliferation and its overexpression inhibited cell growth of prostate cancer. Strikingly, CCND2 downregulation was consistently observed in the advanced prostate cancer in 18 available clinical data sets with a total amount of 1,095 prostate samples. Furthermore, the lower expression levels of CCND2 markedly correlated with prostate tumor progression to high Gleason score and elevated PSA levels, and served as an independent predictor of biochemical relapse and overall survival in a large cohort of prostate cancer patients. Together, we have identified an association of genetic variants and genes in the RTK/ERK pathway with prostate cancer aggressiveness, and highlighted the potential importance of CCND2 in prostate cancer susceptibility and tumor progression to metastasis.
Highlights
Prostate cancer remains the second most commonly diagnosed cancer and one of the leading causes of cancer-related deaths in men worldwide
On the basis of these associations, we proposed to illustrate the effects of the pathway on aggressive prostate cancer, which could help understand the pathogenesis and the genetic basis underlying the disease susceptibility and progression
We found that the mutation of rs12643184 (PDGF-C) (Additive model: P = 3.612 × 10−2, odd ratios (OR) = 1.374, 95% confidence intervals (CI) = 1.021–1.848; Dominant model: P = 2.094 × 10−2, OR = 1.484, 95% CI = 1.062–2.075) (Supplementary Table 1) was suggested to be the risk factor increasing the risk of aggressive prostate cancer (GS: mutation = 7.72 ± 1.45, wild type = 7.43 ± 1.71, P = 0.034) (Supplementary Table 2)
Summary
Prostate cancer remains the second most commonly diagnosed cancer and one of the leading causes of cancer-related deaths in men worldwide. Investigation on the associations of the RTK/ERK pathway with prostate cancer risk can provide new insight into the molecular mechanisms underlying the susceptibility, and development of prostate cancer at the pathway-level, and reveal novel links between the pathway genes and disease progression to advanced stage and metastasis. The potential association of the RTK/ERK pathway with prostate cancer risk has been suggested by our previous study[10,11,12], the genetic and functional link of the pathway to aggressive prostate cancer have not been elucidated. Our study investigated the effects of the RTK/ERK pathway on the progression of prostate cancer, and revealed the genetic factors responsible for aggressive disease susceptibility, highlighted the potential role of CCND2 in disease progression
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