The Matrix Metalloproteinase-7 Polymorphism Rs10895304 Is Associated With Increased Recurrence Risk in Patients With Clinically Localized Prostate Cancer

Abstract

Objectives To investigate whether selected high-risk MMP7 single nucleotide polymorphisms influence tumor biology or clinical outcomes in patients with clinical early-stage prostate cancer undergoing prostatectomy. Methods Two hundred twelve human prostate cancer patients treated with radical prostatectomy were included in the study. Median follow-up was approximately 9.8 years. Genotyping was performed using TaqMan™ technology and custom-designed probes. Three single nucleotide polymorphisms within various regions of the MMP7 gene were assessed with correlation to age at diagnosis, margin status, extracapsular extension, lymph node metastasis, local recurrence and tumor survival in paraffin-embedded prostate tissue specimens from patients with early-stage prostate cancer receiving radical prostatectomy alone. Results Rs10895304 was the sole significant polymorphism. The SNP correlated to increased recurrence rates in post-prostatectomy patients (P<0.0094, Log Rank Test). The frequency of the homozygous dominant (A/A) is 74%, the heterozygote (A/G) is 20% and the homozygous recessive (G/G) is 6%. Multivariate analysis (using Chi square analysis) did not detect a confounding relationship between recurrence and age at diagnosis, PSA or Gleason score. None of the other assayed polymorphisms were significant, and no correlations were made to other clinical variables. Conclusions The G allele of the rs10895304 polymorphism is predictive of increased local recurrence risk in patients with clinically localized prostate cancer. For this subset of patients, prostatectomy alone may not be adequate for local control. This is a novel and relevant marker that should be evaluated for improved risk stratification of patients who may be candidates for early post-operative radiation therapy to improve local control.

Genetic variants associated with predisposition to prostate cancer and potential clinical implications

“…Several papers have adopted the candidate gene approach, analysing SNPs associated with genes thought to be related with aggressiveness and progression. Amongst the genes reported to be associated with progression in surgical cohorts include the androgen pathway genes [70], encoding ribonuclease L ( RNASEL ) [71], Wnt signalling pathway genes [69], B‐cell lymphoma gene 2 ( Bcl2 ) [72], matrix metalloproteinases ( MMP ) [73] and KLK [74]. Toll like receptors ( TLR ) SNPs have also been associated with progression postprostatectomy [74].…”

The Role of the Metzincin Superfamily in Prostate Cancer Progression: A Systematic-Like Review

“…However, others have identified no change in expression in PrCa [ 42 ] or, indeed, a negative correlation with disease [ 52 ], including when examining the levels of the active form of this enzyme [ 29 , 101 ]. For MMP-7, gene polymorphisms may be important in terms of the risk of the disease [ 28 ] and recurrence [ 63 ], while the relative levels of the inhibitors may also influence the impact of MMP-7 on PrCa progression [ 60 ]. An enforced expression of MMP-7 in PrCa cells has been shown to mediate an increased invasion [ 110 ], while a mouse MMP-7 knockout model exhibited reduced tumor-induced osteolysis [ 88 ], indicating the source of this enzyme may not be critical.…”

“…Finally, other MMPs appear to be less significantly involved in PrCa. Thus, most studies reported no association between PrCa and MMP-1 in terms of the expression [ 31 , 48 , 52 , 68 , 74 , 83 ], activation [ 29 ] or polymorphism [ 28 , 44 , 60 , 63 , 64 , 68 , 74 , 81 , 88 , 90 , 110 , 155 ]. However, other studies have reported associations between expression and PrCa [ 46 ], including grade/stage [ 105 , 139 ] and metastatic properties, with MMP-1 ablation shown to reduce invasion [ 154 ].…”

“…The clearest evidence for positive contributions to PrCa and its progression was for MMP-2, MMP-7, MMP-9, MT1-MMP, ADAM-15, ADAM-17 and ADAM-28, with supporting evidence for MMP-1, MT3-MMP, MT6-MMP and ADAM-9 ( Table 1 , Table 2 and Table 4 ). This is underpinned by studies that have identified associations between the expression and PrCa, which, in the case of MMP-7 expression [ 60 , 63 , 73 , 88 , 99 , 104 , 106 , 110 , 135 , 147 ] and ADAM-15 expression [ 190 , 199 , 200 ], correlated with the pathological stage and poorer outcomes for patients. This was supported by functional analyses that consistently identified enhancements in the proliferation, invasion/spread and metastasis/migration facilitated by them [ 56 , 106 , 110 , 200 ] ( Figure 2 ).…”

Translating Genetic Risk Factors for Prostate Cancer to the Clinic: 2013 and Beyond

“…Hirata et al examined six candidate genes including PTEN and P53, but only SNPs in the BCL-2 gene were an independent risk factor for biochemical relapse [74]. A SNP identified as rs10895304 within the MMP7 gene has been reported as predictive of decreased recurrence-free survival [75]. Morote et al tested 703 patients with localized PrCa, who underwent radical prostatectomy, for a panel of 83 SNPs; 35% of those relapsed within 5 years.…”