vol.33 no.7 Carcinogenesis vol.00 no.0 pp.1259–1269, pp.1–11, 2012 2012 doi:10.1093/carcin/bgs150 Advance Access publication April April 20, 20, 2012 2012
REVIEW
Gene variants in the angiogenesis pathway and prostate cancer Ernest K.Amankwah, Thomas A.Sellers and Jong Y.Park� Department of Cancer Epidemiology, Division of Cancer Prevention and Control, Moffitt Cancer Center, Tampa, FL, USA � To whom correspondence should be addressed. Tel: þ1 813 745 1703; Fax: þ1 813 745 1720; Email:
[email protected]
Although the causes of prostate cancer are still unknown, numerous studies support the role of genetic factors in the development and progression of this disease. Single nucleotide polymorphisms (SNPs) in key angiogenesis genes have been studied in prostate cancer. In this review, we provide an overview of the current knowledge of the role of genetic variants in the angiogenesis pathway in prostate cancer risk and progression. Of the 17 prostate cancer genome-wide association studies (GWAS) conducted to date, only one identified disease-associated SNPs in a region of an angiogenesis pathway gene. An association was observed between aggressive disease and three intergenic SNPs (rs11199874, rs10749408 and rs10788165) in a region on chromosome 10q26 that encompasses FGFR2. The majority (27/32, 84.4%) of primary candidate gene studies reviewed had a small (n < 800, 20/ 32, 62.5%) to medium sample size (n 5 800–2000, 7/32, 21.9%), whereas only five (15.6%) had a large sample size (n ‡ 2000). Results from the large studies revealed associations with risk and aggressive disease for SNPs in NOS2A, NOS3 and MMP-2 and risk for HIF1-a. Meta-analyses have so far been conducted on FGFR2, TGF-b, TNF-a, HIF1-a and IL10 and the results reveal an association with risk for SNPs in FGFR2 and TGF-b and aggressive disease for SNPs in IL-10. Thus, existing evidence from GWAS and large candidate gene studies indicates that SNPs from a limited number of angiogenesis pathway genes are associated with prostate cancer risk and progression.
maintain their ability to divide rapidly into blood vessels in response to physiological stimuli, such as hypoxia, and angiogenesis is reactivated during wound healing and repair (6,7,9). The process of post-natal angiogenesis is regulated by a continuous interplay (that establishes a balance) of stimulators such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor, epidermal growth factor (EGF), interleukins (ILs), nitric oxide synthase (NOS), transforming growth factor beta (TGF-b), tumor necrosis factor alpha (TNF-a), platelet derived growth factor and matrix metalloproteinases (MMPs) and inhibitors such as endostatin, platelet factor-4, tumastin, thrombospondin-1, plasminogen activator inhibitor-1 and angiostatin (6–10) (Figure 1). However, in many disorders including cancer, the balance between stimulators and inhibitors is tilted to favor stimulators, resulting in an ‘angiogenic switch’ (11,12). The so-called ‘angiogenic switch’ may result from changes in the expression levels of genes in the angiogenesis pathway. Single nucleotide polymorphisms (SNPs) may alter gene expression and influence the process of angiogenesis. Indeed, several SNPs in angiogenesis genes that affect gene expression have been identified. These variants may potentially contribute to interindividual variation in the risk and progression of tumors (13) and have thus been studied in this context for various cancers, including prostate cancer. However, GWAS have so far only identified three intergenic SNPs in a region encompassing FGFR2 and SNPs in FGF10 and IL-16 that are not directly involved in angiogenesis. The majority (27/32, 84.4%) of primary candidate gene studies conducted to date have a small (n , 800, 20/32, 62.5%) to medium sample size (n 5 800–2000, 7/32, 21.9%) and may be underpowered. Only a small number (5/32, 15.6%, n � 2000) of large studies and meta-analyses have been conducted so far and very few SNPs have been identified. In this review, we provide an overview of the current knowledge of the role of genetic variants in the angiogenesis pathway in prostate cancer risk and progression. The role of angiogenesis in prostate cancer
Introduction Prostate cancer is the most common non-skin malignancy among men worldwide. In the USA, an estimated 240 890 new cases and 33 720 deaths are expected in 2011 (1). Although the causes of prostate cancer are still unknown, family history of the disease is one of the strongest risk factors. Twin studies suggest that �42% of the disease risk may be attributed to heritable factors (2). Furthermore, recent genome-wide association studies (GWAS) have identified susceptibility variants (3–5), providing evidence in support of the role of genetic susceptibility in the development of prostate cancer. Angiogenesis is a biological process that involves the division and migration of endothelial cells, resulting in microvasculature formation (6,7). The formation of blood vessels is important for organ development during embryogenesis and continues to contribute to organ growth after birth, but during adulthood, most blood vessels remain quiescent and angiogenesis is limited to the cycling ovary and in the placenta during pregnancy (6–8). Nonetheless, endothelial cells Abbreviations: ACE, angiotensin-converting enzyme; AIPC, androgenindependent prostate cancer; CGEMS, Cancer Genetic Markers of Susceptibility; CI, confidence interval; EGF, epidermal growth factor; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; GWAS, genome-wide association studies; HIF-1, hypoxia-inducible factor-1; ILs, interleukins; MMPs, matrix metalloproteinases; NOS, nitric oxide synthase; OR, odds ratio; PLCO, Prostate Lung Colon and Ovary; SNPs, single nucleotide polymorphisms; TGF-b, transforming growth factor beta; TNF-a, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor.
Angiogenesis is an important pathway for tumor progression (6,7,9,10) (Figure 1). A tumor can grow up to a diameter of 2–3 mm by diffusion of nutrients from existing blood vessels. Angiogenesis is therefore inevitable in tumor progression and metastasis since tumor growth requires the development and remodeling of blood vessels to ensure the supply of oxygen and nutrients (6,7). Similar to other solid tumors, progressive growth and metastasis of prostate cancer are dependent on angiogenesis and existing evidence supports a role for angiogenesis in prostate cancer. For instance, microvessel density is correlated with prostate cancer progression and the expression of angiogenic factors is altered in prostate cancer and associated with clinical stage, Gleason score, tumor stage, progression, metastasis and survival (14–17). Genetic variants in the angiogenesis pathway and prostate cancer Angiogenesis is a complex multifactorial process that reflects a finely tuned balance between a variety of angiogenic factors that act as activators or inhibitors (8). Several key pro-angiogenic and antiangiogenic factors have been implicated in prostate cancer and SNPs in these genes may alter expression and influence the process of angiogenesis, potentially leading to interindividual variation in the risk and progression of this disease. However, prostate cancer GWAS have directly or indirectly identified few SNPs in angiogenesis genes so far and SNPs in only a few angiogenesis genes have been studied in relation to prostate cancer risk and progression in candidate gene studies.
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Fig. 1. The role of angiogenesis in tumor progression. Post-natal angiogenesis is regulated by a balanced and continuous interplay of factors that act as proangiogenic (VEGFs, FGF, EGF, HIF, TGF-b and TNF-a), anti-angiogenic (endostatin and IFN) or both pro-/anti-angiogenic (MMPs and ILs). However, a growing tumor can tilt the balance toward pro-angiogenic factors to promote vascular growth and facilitate tumor invasion, regional lymph node and distant metastasis.
Genome-wide association studies A search of the GWAS catalogue of the National Human Genome Research Institute of the National Institute of Health indicated that 17 GWAS (18–34) have been published on prostate cancer as of 6 February 2012 (http://www.genome.gov/gwastudies/index.cfm). Most studies investigated subjects with European ancestry background except two studies, which reported on Asians (32) and African Americans (25). Thomas et al. (33) observed that the homozygous minor allele of a non-synonymous SNP (rs4072111) that changes a serine to proline in IL-16 was significantly (P 5 1.19 10 5) associated with an increased risk of aggressive cancer. Another study using a screening cohort and biopsy-proven controls observed significant associations (P 5 6.0 10 7 to 3.0 10 10) between aggressive prostate cancer and three intergenic SNPs (rs11199874, rs10749408 and rs10788165) that span a 590-kb region on chromosome 10q26 that encompasses FGFR2, an angiogenesis gene (28). Only one GWAS has so far observed a prostate cancer susceptibility SNP [rs2121875; odds ratio (OR) 5 1.05, 95% confidence interval (CI) 5 1.02–1.08; P 5 4 x 10 8] and it was found in the intron of FGF10, which is not directly involved in angiogenesis (26). Penney (29) observed associations with mortality for SNPs in IL-18 (rs360729, P 5 2.1 10 4; rs243908, P 5 3.0 10 4) and IL-11 (rs12709950, P 5 5.3 10 4) in their stage one scan, but none of them was replicated in stage 2. So far GWAS have directly or indirectly identified very few SNPs in angiogenesis genes and this limited evidence suggests that SNPs in the angiogenesis pathway may modify disease risk and also the risk of developing an aggressive disease. Candidate gene studies Several candidate gene studies have been conducted on angiogenesis genes and prostate cancer risk or progression. However, the majority of the studies are small (n , 800, 62.5%) to medium (n 5 800–2000, 21.9%) sized, and only a few (15.6%) are large studies (n 2000). Moreover, only a few
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genes or variants in the angiogenesis pathway have been studied. The most commonly studied angiogenesis genes are VEGF, MMPs, ILs, NOS, FGF, TGF-b and TNF-a and COL18A1 (endostatin). Table I–III summarizes the candidate genetic association studies conducted so far on angiogenesis genes. The genes are broadly categorized as main proangiogenesis (VEGF and FGF - Table I), other pro-angiogenesis (TGF-b, TNF-a, NOS, EGF, HIF-1a and ACE -Table II), pro-/anti- and antiangiogenesis (MMPs and ILs and COL18A1 - Table III). MMPs and ILs are categorized as pro-/anti-angiogenesis because certain family members are pro-angiogenesis, whereas others are anti-angiogenesis. Pro-angiogenesis genes Vascular endothelial growth factor. VEGF is the most important regulator of angiogenesis and plays a critical role in both the development and metastasis of tumors. It has a mitogenic effect on endothelial cells and promotes their migration and invasion and also facilitates metastasis by increasing vascular permeability to tumor cells (48). It is one of a family of six protein isoforms expressed in different tissues including the prostate. The expression of VEGF is positively associated with microvessel density, tumor stage, Gleason score and disease-specific survival in prostate cancer patients (49). Furthermore, plasma VEGF is higher in patients with localized prostate cancer than in healthy controls (50). VEGF is highly polymorphic and SNPs, particularly at 1154 (A/G), 634 (G/C) and 460 (C/T) in the promoter region, shown to affect its expression (51) have been studied in relation to prostate cancer risk and progression. The AA genotype at 1154 has been associated with low expression of VEGF and two previous independent studies have shown that carriers of the A allele have a reduced risk (OR 5 0.27–0.45) of prostate cancer (35,36). Though this finding is intriguing, both studies were relatively small and in one of the studies (35), almost half of the controls (124 of 263) were females. In a large study, Jacobs et al. (37) did not observe an association for this variant (per A allele or comparing GG to AA) or other variants in
SNPs SNPs in in angiogenesis and prostate cancer
Table I. Summary of epidemiologic studies of polymorphisms in main pro-angiogenesis genes and prostate cancer risk and progression Gene
SNP rsID
Alias
Case/control
Country
Outcome
OR/HR (95% CI)a/P-value
Reference
VEGF
rs1570360
�1154
UK
rs1570360
�1154
rs2010963
�634
rs3025039
þ936
rs1570360
�1154
rs3025039
þ936
rs699947
�2578
Risk (GG versus AA) Survival (AA versus GG) Risk (GG versus AA) Advanced stage (GG versus AA) Risk (GG versus GC/CC) Advanced stage (GG versus GC/CC) Risk (CC versus TT) Advanced stage (CC versus TT) Risk (per A allele) Aggressivef (per A allele) Risk (per T allele) Aggressivef (per T allele) Risk (per A allele) Aggressivef (per A allele) Risk (per T allele) Aggressivef (per T allele) Risk (per A allele) Aggressivef (per A allele) Risk (frequency of A allele) Risk (frequency of T allele) Risk (frequency of T allele) Risk (frequency of C allele) Risk (frequency of T allele) Risk (frequency of T allele) Risk (frequency of A allele) Risk (per T allele) Advanced stage High grade Risk (TT versus CC) Advanced stage (TT versus CC) High grade (TT versus CC) Recurrence (TT versus TC/CC) Survival (TT versus TC þ CC) Risk (CC versus TT) Advanced stage (CC versus CT/TT) High grade (CC versus CT/TT) Risk (CC versus TT) Progression (CC versus CT/TT) Risk (AA versus CC) Risk (GG versus AA) Risk (TT versus TA/AA) Risk (GG versus AA) Risk (CC versus TT) Recurrence (GlyGly versus ArgGly/ArgArg) Risk (AA versus GG) Advanced stage (AA versus GG) High grade (AA versus GG)
0.45 (0.24–0.86) 0.49 (0.19–1.26) 0.27 (0.08–0.83) 0.002e 1.95 (1.04–3.65) 0.03e 1.82 (0.13–51.93) .0.05e 1.02 (0.90–1.15) 1.06 (0.90–1.24) 0.98 (0.83–1.15) 0.91 (0.73–1.14) 0.96 (0.86–1.08) 1.05 (0.90–1.22) 0.96 (0.82–1.12) 1.04 (0.85–1.27) 0.92 (0.81–1.04) 0.85 (0.71–1.00) 0.60e 0.95e 0.92e 0.36e 0.39e 0.15e 0.53e 2.2 (1.3–3.8) 0.76e 0.88e 0.98 (0.72–1.04) 1.04 (0.67–1.61) 1.16 (0.75–1.79) 2.46 (1.23–4.93) 2.98 (1.36–6.49) 1.28 (0.51–3.20) 2.23 (1.01–4.93) 2.23 (0.70–6.28) 0.72 (0.12–4.30) 3.12 (1.23–7.92) 1.44 (0.52–3.99) 0.98 (0.38–2.53) 0.54 (0.28–1.05) 1.44 (0.77–2.71) 0.73 (0.38–1.40) 0.02e 6.26 (3.15–12.43) 5.55 (3.02–10.21) 1.76 (0.96–1.02)
(35)
VEGF
238/263b 238c 101/100 30/71d 101/100 30/71d 101/100 30/71d 1158/1172 458/1172 1163 1163 1165/1177 460/1177 1142/1161 450/1161 1138/1158 446/1158 702/702 702/702 702/702 702/702 702/702 702/702 702/702 96/119 53/43d 58/38d 270/252 113/157d 163/105g 95c 99c 133/157 26/157 52/157 193/666 20/666 193/666 193/666 193/666 193/666 193/666 244c 492/179 167/325 197/228
Risk (GG versus AA) Risk (GG versus GA) Risk (AA versus GG) Risk (AA versus GG) Risk (GG versus AA) Risk (GG versus AA) Risk (Arg versus Gly) Risk (Arg versus Gly) Advanced stage (Arg versus Gly) Risk (Arg versus Gly) Risk (Arg versus Gly) Risk (Arg versus Gly)
1.05 (0.74–1.49) 0.77 (0.31–1.93) 0.92 (0.67–1.25) 2.46 (0.81–9.28) 1.03 (0.81–1.32) 0.60 (0.23–1.50) 1.17 (1.07–1.29) 1.17 (1.07–1.29) 1.18 (0.96–1.44) 1.21 (1.00–1.47) 1.24 (1.02–1.51) 1.15 (0.73–1.82)
VEGF
rs25648
VEGF
rs2010963
�634
rs699947
�2578 �2489 �460 �634 �7 þ936 þ1612 �460
rs833061 rs2010963 rs25648 rs3025039 VEGF
rs833061
VEGF
rs833061
�460
VEGF
rs833061
�460
VEGF
rs3025040 rs699947
þ2482 þ2578
VEGFR
rs2305948 rs1870377 rs1531289 rs7692791 rs351855 rs2011077
þ889 þ1416 IVS25–92 IVS6þ54
FGFR FGFR FGFR
rs1966265 rs376618 rs7708357 FGFR FGFR
rs351855 rs351855
G388R G388R
1189/1254 147/80 1238/1245 145/80 1258/1254 146/78 2618/1992 2618/2305 1542/677 1935/1787 492/344 191/174
Tunisia
USA
Austria
Taiwan Japan
Turkey USA USA
USA Japan USA White Black White Black White Black Meta-analysis Meta-analysis Caucasian Asian African
(36)
(37)
(38)
(39) (40)
(41) (42) (42)
(43) (44) (45)
(46) (47)
Note: The table includes results for meta-analysis (where at least one exists), but not results for the individual studies included in the meta-analysis. a HR, hazard ratio. b Controls included females. c Cases only. d Localized/advanced. e P-value. f A combination of stage and grade. g Low grade/high grade.
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Table II. Summary of epidemiologic studies of polymorphisms in other pro-angiogenesis genes and prostate cancer risk and progression Gene
SNP rsID
Alias
Case/control
Country
Outcome
OR/HR (95% CI)a/P-value
Reference
TGF-b1
rs16949649
�509
492/492 157/157 133/133
USA
Risk (CC versus TT) Advanced stage (CC versus TT) High grade (CC versus TT)
1.23 (0.80–1.87) 2.36 (1.03–5.43) 1.34 (0.60–3.00)
(69)
TGFb1
rs16949649
�509
Risk (CC versus TT) High grade (CC versus TT) Prognosis (CC versus TT) Risk (CC versus TT) High grade (CC versus TT) Prognosis (CC versus TT) Risk (CC versus TT) High grade (CC versus TT) Prognosis (CC versus TT) Risk (CC versus TT) High grade (CC versus TT) Prognosis (CC versus CT) Risk (CC/CT versus TT)
1.04 (0.76–1.42) 0.48 (0.27–0.85) 0.49 (0.24–1.00) 1.06 (0.71–1.59) 0.31 (0.15–0.68) 0.30 (0.10–0.89) 1.21 (0.71–2.06) 0.93 (0.37–2.33) 0.96 (0.32–2.87) 1.15 (0.58–2.31) 1.62 (0.40–6.63) 1.74 (0.23–13.41) 1.24 (1.02–1.52)
Aggressived (CC versus TT) Aggressived (CC versus TT) Aggressived (CC versus TT) Aggressived (CC versus TT) Risk (AA versus GG) Risk (TT versus CC) High grade (TT versus TC/CC) Metastasis (TT versus TC/CC) Risk (CC versus AA) High grade (TT versus TC/CC) Metastasis (TT versus TC/CC) Risk (CC versus TT) High grade (TC/CC versus TT) Metastasis (TC/CC versus TT)
0.75 (0.32–1.74) NCe 0.90 (0.36–2.25) 1.40 (0.13–15.75) 0.89 (0.67–1.17) 2.01 (1.16–3.42) 1.82 (1.07–3.07) 1.82 (1.07–3.07) 0.93 (0.45–1.89) .0.05g 1.89 (1.10–3.25) 0.87 (0.15–4.94) .0.05g .0.05g
Risk (CC versus TT) Aggressived (CC versus CT/TT) Non-aggressive (CC versus CT/TT) Risk (CC versus TT) Risk (CC versus TT) Risk (GT versus TT) Aggressived (GG versus GT/TT) Non-aggressive (GG versus GT/TT) Risk (GT versus TT) Risk (GT versus TT) Risk Aggressived (AA versus AG/GG) Non-aggressive (AA versus AG/GG) Risk (AA versus GG) Risk (AA versus GG) Risk (per T allele) Aggressived Risk (per C allele) Aggressived Risk (per T allele) Aggressived
0.98 (0.66–1.46) 1.13 (0.91–1.39) 1.02 (0.85–1.24) 0.97 (0.65–1.45) 1.21 (0.13–11.7) 1.25 (1.06–1.46) 1.26 (1.03–1.55) 1.20 (0.99–1.43) 1.20 (1.01–1.42) 1.64 (1.02–2.66) 0.77 (0.61–0.97) 0.71 (0.58–0.87) 0.83 (0.69–1.01) 0.79 (0.63–1.01) 0.59 (0.22–1.62) 1.11 (0.96–1.29) 1.03 (0.84–1.25) NCe 0.90 (0.76–1.07) 0.95 (0.82–1.10) 0.96 (0.86–1.07)
Risk (AA versus GG) Aggressived (AA versus GG) Non-aggressive (AA versus GG) Risk (AA versus GG) Risk (AA versus GG) Risk (GT/TT versus GG) Progression Risk (per allele) Aggressived (per allele) Risk (AA versus AG þ GG) High grade (AA versus AG þ GG) Metastasis (AA versus AG þ GG) Survival (AA versus AG þ GG) Risk (CC versus TT) Aggressived (per allele) Metastasis
1.33 (1.07–1.64) 1.48 (1.11–1.95) 1.21 (0.93–1.56) 1.28 (1.02–1.61) 1.85 (0.93–3.68) 1.59 (0.96–2.63) 0.63 (0.29–1.39) 0.98 (0.87–1.10) 0.98 (0.84–1.15) 1.94 (0.99–3.79) 3.37 (1.47–7.73) 2.61 (1.03–6.60) 0.018i 0.41 (0.21–0.82) 0.53 (0.22–1.29) 0.024i
TGF-b1 TNF-a
TNF-a TNF-a
rs1800470
þ29
rs1799724
�857
rs361525
�238
rs1800629 rs1799964
�308 �1031
rs1800630
�863
rs1799724
�857
NOS2A
S608L rs2297518
rs9282801
rs944722
NOS2A
rs2297518
S608L
NOS3
rs2070744
�786T/C
rs1799983
D298E
rs1007311
E298D
NOS3
NOS3
rs1007311
E298D
EGF
rs4444903
þ61
EGF
rs4444903
þ61
HIF-1a
rs11549465
þ1772
HIF-1a
rs11549465
þ1772
41262
653/1476 233/289 111/379 440/829 145/195 67/249 165/408 73/70 39/96 48/239 15/24 5/34 2605/3129 75/418 71/407 12/56 75/438 12/56 4238/4403 197/256 140/57f 87/110 197/256 140/57f 87/110 197/256 140/57f 87/110 1252/1254 536/1254 715/1254 1149/1373 103/93 1353/1787 536/1787 716/1787 1150/1393 103/394 1237/1750 530/1750 706/1750 1137/1365 100/385 1166/1178 459/1178 NCe 527/553 1420/1446 556/1446 1247/1772 532/1772 714/1772 1144/1377 102/395 125/153 74/153 1163/1178 458/1178 123/152 67/152 36/152 123h 1420/1450 455/1450 196/196
USA All NHWb HWc Black Meta-analysis USA White Black White Black Meta-analysis India
USA All White Black All White Black All White Black USA USA
USA All White Black Portugal USA Portugal
USA USA
(70)
(75) (86)
(79) (82)
(57)
(37) (37)
(57)
(59) (37) (88)
(37) (90)
SNPs SNPs in in angiogenesis and prostate cancer
Table II. Continued Gene
SNP rsID
ACE ACE
rs4646994 rs4646994
Alias
Case/control
Country
Outcome
OR/HR (95% CI)a/P-value
Reference
324 189/290 108/80f 33/143g
Meta-analysis China
Risk (DD versus II) Risk (DD versus ID/II) Advanced stage (DD versus ID/II) High grade (DD versus ID/II)
0.77 (0.64–0.92) 0.32 (0.20–0.51) 2.21 (1.17–4.19) 1.07 (0.46–2.50)
(94) (98)
Note: The table includes results for meta-analysis (where at least one exists), but not results for the individual studies included in the meta-analysis. a HR, hazard ratio. b Non-Hispanic White. c Hispanic White. d A combination of stage and grade. e Not calculated in the manuscript due to small numbers. f Localized/advanced. g Low grade/high grade. h Cases only. i P-value.
the promoter (rs699947), 3# untranslated region (rs3025039) or exon 1 (rs25648 and rs2010963) with risk or advanced disease, albeit rs2010963 was associated with a borderline statistically (P 5 0.05) reduced risk of advanced disease. An increased risk of prostate cancer and an aggressive phenotype for homozygous and heterozygous carriers of the C allele at VEGF �634 (GC þ CC) have been reported in a small study (36). However, in a medium-sized study (702 cases and 702 controls) that examined seven SNPs in the promoter, coding or untranslated regions of VEGF, none of the SNPs (all P � 0.15), including �634, was associated with the risk for prostate cancer (38). Furthermore, this study did not find an association at any of the SNPs with stage, histological grade, prostate-specific antigen level at the time of diagnosis, age at diagnosis or VEGF plasma level (38). Studies on VEGF �460 polymorphism have also produced inconsistent results. One small study observed that the T allele of VEGF �460 polymorphism was associated with an increased risk of prostate cancer, but not with clinical stage (P 5 0.76) or grade (P 5 0.88) (39). Two subsequent small studies did not confirm this finding (40,41), but an association between this SNP with biochemical recurrence after radical prostatectomy and survival was observed in one of the studies (40). Other SNPs in the promoter region of VEGF or in the VEGF receptor are not associated with prostate cancer (38,42). Investigation of VEGF variants with risk or progression of prostate cancer has been largely limited to SNPs in the promoter region and the results have been inconsistent. The role of VEGF variants in prostate cancer therefore remains inconclusive. Nitric oxide synthase. Nitric oxide (NO) has a dual yet opposing role in carcinogenesis. It promotes carcinogenesis through induction of angiogenesis, whereas it inhibits carcinogenesis through induction of cell death (52). NOS is the enzyme that synthesizes NO in the cell. It has multiple isoforms: neuronal NOS (NOS1), inducible NOS (NOS2) and endothelial NOS (NOS3) (53). NOS2 (gene for NOS2 is NOS2A) is over expressed in prostate tumor tissues (54,55) and NOS3 protects prostate cancer cells from apoptosis (56). A large nested case–control study in the screening arm of the Prostate Lung Colon and Ovary (PLCO) cohort screening Trial found that polymorphisms in NOS2A (rs9282801 and rs944722) and NOS3 (rs1007311) were generally associated with aggressive cancer (stage III–IV or Gleason score �7) (57). The authors attempted to confirm their results in Cancer Genetic Markers of Susceptibility (CGEMS), which included �72% of the subjects in the PLCO study. Only one SNP (NOS2A rs2297518) overlapped between the PLCO and CGEMs studies and this SNP was not associated with prostate cancer in both studies. One NOS2A SNP (rs944722) that showed an association in the PLCO study was in high linkage disequilibrium (r2 5 0.96) with an SNP (rs2274894) in CGEMS that showed association in the same direction as that of rs944722, albeit marginally statistically significant (P 5 0.10). In this study, one SNP in NOS2A (rs9282801) showed
a statistical interaction (Pinteraction 5 0.01) with antioxidant vitamin intake and was associated with aggressive prostate cancer among subjects with a high antioxidant intake (OR 5 1.61, 95% CI 5 1.18–2.19), but not among subjects with low antioxidant intake (OR 5 1.06, 95% CI 5 0.76–1.48). This potential interaction is intriguing because of the potential role of NO as a reactive oxygen species scavenger that protects tumors from reactive oxygen speciesinduced apoptosis (58) and therefore warrants further investigation. A 27-bp repeat polymorphism in intron 4 of NOS3 was associated with prostate cancer risk and a non-synonymous codon 298 polymorphism of this gene was associated with advanced prostate cancer and bone metastasis in a small (N 5 278) case–control study (59). In a larger study, Jacobs et al. (37) did not observe an association between NOS2 and NOS3 polymorphisms and prostate cancer risk or advanced disease. Therefore, evidence for an association between NOS polymorphisms and prostate cancer remains inconclusive. Fibroblast growth factor receptor. Fibroblast growth factors (FGFs), along with VEGF, are key players in tumor angiogenesis and their inhibition represses tumor growth. Aberrant expression of multiple FGF family members and their cognate receptors are found in multiple cancers, including prostate cancer (60). Normal prostate stromal cells produce several FGFs, whereas prostate epithelial cells express corresponding FGF receptors (FGFR). The FGF/FGFR family members act as mediators of communication between the epithelium and the stroma (reviewed in (61)). FGFR4 is the only member of the FGF/ FGFR family that has been investigated in several studies to examine association of its genetic variants with prostate cancer risk and progression. The most studied polymorphism contains either glycine (Gly) or arginine (Arg) at codon 388 [FGFR4 Gly388Arg (G388R) or rs351855] in the transmembrane domain of the receptor. This polymorphism has been associated with tumor aggressiveness or patients’ survival in several cancers (62,63). However, results for studies of prostate cancer risk have been inconsistent with some studies reporting an association (43,44) or no association (45,64). Two metaanalyses of the same four studies concluded that the Arg(388) allele of FGFR4 Gly388Arg is associated with a modest increased risk (OR 5 1.17, 95% CI 5 1.07–1.29) of prostate cancer (46,47) for all ethnicities combined. One of the meta-analysis (47) found that the increased risk was more prominent in Caucasians (OR 5 1.21, 95% CI 5 1.00–1.47) and Asians (OR 5 1.24, 95% CI 5 1.02–1.51), but not African-Americans (OR 5 1.15, 95% CI 5 0.73–1.82). Furthermore, prostate cancer patients with the Arg/Arg genotype had an increased risk of advanced and metastatic disease compared with those with Gly/Gly þ Gly/Arg genotypes (47). One study that was part of the meta-analysis found an association between this SNP and biochemical recurrence (43). An intron 11 SNP (rs2011077) in FGFR was associated with increased risk of prostate cancer and advanced stage disease (44), but other SNPs (rs1966265, rs376618 and rs7708357) have shown no association with risk (45).
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Table III. Summary of epidemiologic studies of polymorphisms in pro-/anti- and anti-angiogenesis genes and prostate cancer risk and progression Gene
SNP rsID
Pro-/anti-angiogenesis MMP-1 rs1799750 MMP-2
Alias
Case/control Country
Outcome
OR/HR (95% CI)a/P-value Reference
�1602
283/251 158/251 210/251 1417/1450 556/1450 1414/1441 557/1441 1410/1439 554/1439 521/549 522/548 527/553 1415/1441 555/1441 525/550 101/109 55/106 71/106 247/263 238d
Risk (1G1G versus 1G2G/2G/2G) Advanced Stage (1G1G versus 1G2G/2G/2G) High Grade (1G1G versus 1G2G/2G2G) Risk (AA versus GG) Aggressiveb (AA versus GG) Risk (CC versus TT) Aggressiveb (CC versus TT) Risk (AA versus GG) Aggressiveb (AA versus GG) Aggressiveb (per minor allele) Aggressiveb (per minor allele) Aggressiveb (per minor allele) Risk (per minor allele) Aggressiveb (per minor allele) Aggressiveb (per minor allele) Risk (CC versus CT/TT) High grade (CC versus CT/TT) Advanced stage (CC versus CT/TT) Risk (CC versus TT) Survival (CC versus TT)
1.04 (0.62–1.74) 1.42 (0.70–2.89) 1.47 (0.62–3.50) 1.30 (1.04–1.64) 1.36 (1.00–1.86) 1.33 (1.06–1.67) 1.47 (1.08–2.00) 1.24 (0.97–1.58) 1.21 (0.86–1.70) 1.03 (0.86–1.22) 0.94 (0.79–1.12) 1.09 (0.88–1.34) 0.95 (0.75–1.20) 0.81 (0.58–1.13) 0.93 (0.73–1.18) 2.86 (1.28–6.45) 3.21 (1.29–8.06) 2.47 (1.02–6.00) .0.05c 0.77 (0.33–1.76)
Aggressiveb (CC versus TT) Aggressiveb (CC versus TT) Aggressiveb (TT versus CC) Aggressiveb (TT versus CC) Aggressiveb (CC versus TT) Aggressiveb (CC versus TT) Risk (CC versus TT) Advanced stage (CC versus TT) Early stage (CC versus TT) Risk (CC versus TT) Advanced stage (CC versus TT) Early stage (CC versus TT) Risk (CC versus TT)
0.99 (0.42–2.31) 6.55 (0.59–72.35) 1.25 (0.55–2.86) 6.64 (0.60–73.78) 3.11 (1.20–8.06) 3.07 (0.22–43.40) 0.80 (0.54–1.20) 1.03 (0.53–2.01) 0.74 (0.48 (1.16) 1.22 (0.70–2.12) 1.54 (0.64–3.68) 0.91 (0.69–1.21)
Aggressiveb (GG versus GA) Aggressiveb (GG versus GA) Aggressiveb (GG versus GA) Aggressiveb (GG versus GA) Aggressiveb (CC versus GG) Aggressiveb (CC versus GG) Risk (CC versus TT) Advanced stage (CC versus TT) Early stage (CC versus TT) Risk (CC versus GG) Risk (AA versus GG) Risk (CC versus CT) Risk (AA versus TT) Survival (TT versus AA)
1.19 (0.66–2.14) 1.19 (0.18–7.7) 1.08 (0.59–1.97) 1.71 (0.25–11.57) 0.77 (0.39–1.52) 0.38 (0.05–3.13) 1.18 (0.82–1.69) 1.00 (0.55–1.83) 1.21 (0.82–1.80) 0.87 (0.67–1.13) 0.92 (0.71–1.20) 1.17 (0.68–2.01) 0.66 (0.44–0.99) 1.26 (0.59–2.67)
Aggressiveb (GG versus TT) Aggressiveb (GG versus TT) Aggressiveb (CC versus TT) Aggressiveb (CC versus TT) Aggressiveb (TT versus AA) Aggressiveb (TT versus AA) Risk (GG versus CC) Advanced stage (GG versus CC) Early stage (GG versus CC) Finland Risk (TT versus AA) Meta-analysis Risk (G versus A) Risk (T versus C) Advanced stage (C versus T) Risk (A versus C) Advanced stage (C versus A) Meta-analysis Risk (G versus A) Risk (T versus C) Risk (A versus C) Taiwan Recurrence (AA versus AG/GG)
1.10 (0.57–2.13) 0.43 (0.05–3.65) 1.29 (0.14–11.67) 5.10 (0.32–81.48) 0.78 (0.39–1.56) 1.44 (0.10–19.95) 0.91 (0.65–1.29) 0.64 (0.36–1.13) 1.02 (0.70–1.48) 1.2 (0.8–1.8) 0.94 (0.83–1.06) 0.95 (0.83–1.09) 1.16 (1.04–1.31) 1.02 (0.96–1.08) 1.13 (1.01–1.26) 1.00 (0.91–1.10) 0.96 (0.85–1.08) 1.03 (0.96–1.11) 2.97 (1.07–8.23)
rs1477017 rs17301608 rs11639960
MMP-9
rs17576 rs3918256 rs2250889 rs3787268
R574P
MMP-9
rs2274756 rs3918242
R668Q �1562
IL-1
rs16944
�511
rs16944
�511
rs1143627
�31
rs1143634
þ3954
rs16944
�511
IL-1
IL-1
rs1143634
�31
rs1800797
70/383e 4/22e þ180 66/176e 12/79e �174 74/401e 15/57e �174 484/613 124/613 359/613 �236 1053/1053 IVS2 þ 180 1053/1053 Ex5 þ 132 1053/1053 �251 247/263 238d
IL-6 rs2069832 rs1800795 IL-6
rs1800795
IL-6
rs1800795 rs2069832 rs2069849 rs4073
IL-8
�598
IL-8 rs2227307
þ230 �47
rs4073
�251
IL-8
rs4073
�251
IL-8 IL-10
rs4073 rs1800896 rs1800871
�251 �1082 �819
rs1800872
�592
rs1800896 rs1800871 rs1800872 rs1800871
�1082 �819 �592 �819
IL-10 IL-10
61264
74/418e 13/58e 74/417e 13/57e 75/413e 13/58e 473/607 124/607 359/607 486/614 124/614 359/614 473/607
71/393e 12/55e 71/387e 13/56e 65/353e 11/48e 484/613 124/613 359/613 584/584 3385/4311 2827/3685 1076/708f 2243/2508 1424/1064f 4846/5244 2939/3899 3741/3507 116d
Japan USA
USA
Tunisia UK USA White Black White Black White Black USA
USA White Black White Black White Black USA Finland UK USA White Black White Black White Black USA
(104) (37)
(37)
(106) (35) (86)
(109)
(86)
(109) (81) (35) (86)
(109) (110) (117)
(118) (119)
SNPs SNPs in in angiogenesis and prostate cancer
Table III. Continued Gene
SNP rsID
IL-18
rs187237 rs1946518 Anti-angiogenesis COL18A1 rs1248337 COL18A1 rs1248337
Alias
Case/control Country
Outcome
OR/HR (95% CI)a/P-value Reference
�137 �607
265/280 265/280
China
Risk (GG versus CC) Risk (CC versus AA)
2.18 (1.03–4.60) 1.20 (0.74–1.96)
(120)
D104N D104N
1841/198
Brazil USA White Black USA
Risk (DN versus DD)
2.4 (1.4–4.2)
(126) (127)
253/190 136/162 COL18A1 rs1248337
D104N 147/678 223/678 129d
Progression (DN versus DD) Progression (DN versus DD) Risk (NN/DN versus DD) Advanced stage (NN/DN versus DD) High grade (NN/DN versus DD) Progression (NN/DN versus DD)
0.87 (0.51–1.49) 0.46 (0.05–4.47) 1.2 (0.9–1.6) 0.8 (0.5–1.4) 1.0 (0.7–1.5) 1.2 (0.7–1.8)
(129)
Note: The table includes results for meta-analysis (where at least one exists), but not results for the individual studies included in the meta-analysis. HR, hazard ratio. b A combination of stage and grade. c P-value. d Cases only. e High aggressive/low þ intermediate aggressive. f Localized/advanced. a
There are some data to suggest that FGFR4 388 polymorphism is associated with increased risk of prostate cancer and advanced disease, particularly in Caucasians and Asians (46,47), but limited data exist on other polymorphisms in this gene. Transforming growth factor beta. TGF-b is a family of potent regulators of cellular proliferation, differentiation and morphogenesis, as well as extracellular matrix formation, extracellular proteolysis, and inflammation. Alterations in gene expression, secretion and regulation of TGF-b may lead to a favorable environment for tumor development by angiogenesis stimulation and immune system suppression (65). Of the TGF-bs, TGF-b1 is highly expressed in prostate cancer and leads to tumor promotion and metastasis (66). Several polymorphisms in TGF-b1 gene have been identified, and two variants in strong linkage disequilibrium, C�509T and Tþ29C, are associated with increased serum levels (67,68). A nested case–control study within the Physicians Health Study observed that the T allele of TGF-b1 C-509T was associated with advanced disease, but not with risk or high-grade prostate cancer (69). However, in a larger study, the TT genotype of TGF-b1 C-509T was associated with decreased risk of high-grade prostate cancer and poor prognosis among non-Hispanic White men, but no association for Hispanic White men or Black men (70). The polymorphism at þ29 of TGF-b1 is non-synonymous and changes a leucine to a proline. A meta-analysis of different cancers, including five prostate cancer studies (69,71–74), stratified by cancer type concluded there was a modest increased risk (OR 5 1.24, 95% CI 5 1.02–1.52) of prostate cancer among carriers of the C allele of Tþ29C polymorphism (75). Interestingly, the frequency of the C allele differed among the six studies from 0.29 in Europeans in Brazil (71) to 0.54 among Europeans in Germany (74). Thus, findings to date for TGF-b1 C-509T are inconsistent, but TGF-b1 Tþ29C may be associated with a modest increased risk of prostate cancer. Tumor necrosis factor alpha. TNF-a is a multifunctional cytokine with a key role in angiogenesis. It facilitates angiogenesis by directly stimulating proliferation of endothelial cells or by indirectly regulating the expression of pro-angiogenic factors (76–78). A number of studies have been conducted to examine the association between TNF-a polymorphisms and prostate cancer risk. Wang et al. (79) recently performed a meta-analysis including 30 case–control studies with a total number of 16 507 cases and 19 749 controls to derive a precise estimation of the association between the most studied TNF-a polymorphism, TNF-a-308 A/G (rs1800629), and the risk of four common cancers, including prostate cancer. A subgroup analysis on prostate cancer that included six studies (80–85) consisting of 4238
cases and 4403 controls revealed that rs1800629 was not associated with prostate cancer risk (OR 5 0.89, 95% CI 5 0.67–1.17). Other polymorphisms in TNF-a, such as �1031T.C, �857 C.T and �238, that alter expression are less studied. Increased risk of prostate cancer has been reported for the CC genotype at �1031 and �1031 C and �857 T alleles are associated with higher tumor grade and an increased risk of tumor progression and metastasis (82). However, Zabaleta et al. (86) did not observe an association with aggressive (using a combination of Gleason score and clinical stage) disease for the �857 polymorphism. The association between TNF-a �308 variants and prostate cancer is null and the association with advanced disease for other variants is inconsistent. Other pro-angiogenesis genes. Epidermal growth factor (EGF) activates several pro-oncogenic intracellular pathways inducing proliferation, differentiation and tumorigenesis in epithelial cells by binding to the EGF receptor. Although EGF can have direct effects on tumor cells, it also promotes angiogenesis, predominantly through a mitogenic effect on endothelial cells (87). In a small study comparing prostate cancer patients treated with androgen blockade therapy (N 5 123) to healthy controls (N 5 152), an association was observed between a functional EGF SNP at þ61G/A (rs4444903) and high Gleason (�7) score, metastatic disease and survival (88). In a larger (1425 cases and 1453 controls) and more comprehensive (16 SNPs in EGF) study, Jacobs et al. (37) did not observe an association with EGF polymorphisms, including þ61G/A, and prostate cancer risk or advanced disease. The hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates the expression of genes involved in various cellular functions, including angiogenesis, in response to hypoxia (89). HIF-1 binds to DNA as a heterodimer consisting of HIF-1a and HIF-1b. Unlike HIF-1b which is ubiquitously expressed, HIF-1a expression is tightly regulated by oxygen tension (89). Two non-synonymous polymorphisms (C1772T and G1790A) in exon 12 within the oxygen-dependent degradation region of HIF-1a that may result in overexpression and enhanced stability of the protein has been described. In a small study of androgen-independent prostate cancer (AIPC) patients (N 5 196) and healthy controls (N 5 196), the C1772T polymorphism was associated with AIPC, but the frequency of the G1790A polymorphism was low (AIPC 5 3.1% and controls 5 1.5%) and no definitive conclusion could be reached (90). Li et al. (91) did not observe a direct association with prostate cancer risk for the two variants but observed that men with the CC genotype of HIF-1a C1772T and higher IGFBP-3 serum levels had a lower risk of aggressive prostate cancer. Recently, Foley et al. (92) observed that
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heterozygous carriers of the C1772T polymorphism of HIF-1a have an increased risk for clinically localized prostate cancer, though the CT genotype did not modulate HIF-1a protein expression in hypoxia in vitro. Jacobs et al. (37) did not observe an association between HIF-1 polymorphisms and prostate cancer risk or aggressive disease. Angiotensin II (Ang II) is a main effector in the renin–angiotensin system and plays a critical role in cell proliferation and angiogenesis (93). Angiotensin-converting enzyme (ACE) generates Ang II from its precursor. ACE is synthesized by the prostate and an insertion (I)/deletion (D) polymorphism in the ACE gene has been described, with the highest levels of circulating and tissue ACE activity found in carriers of the DD genotype (94). In a recent meta-analysis, including three studies (95–97), a lower risk of prostate cancer was observed for carriers of the II genotype compared with the DD genotype (94). A similar finding was recently observed among Han Chinese where the II genotype and I allele, compared with the DD genotype and D allele, were associated with a decreased risk of prostate cancer (98), suggesting that this genotype may influence the behavior of human prostate cancer. Pro-/anti-angiogenesis genes Matrix metalloproteinases. MMPs are a multifarious family of proteolytic enzymes involved in tumor growth, invasion and metastasis through the breakdown of extracellular matrix and release of proangiogenic factors (99). MMPs were initially recognized as proangiogenic, but recent evidence suggests that individual MMPs can exhibit pro- or anti-angiogenesis properties depending on the type and stage of development of a particular cancer (100,101). The family of mammalian MMPs includes 24 members, but only polymorphisms in MMP-1, -2 and -9 have been studied in relation to prostate cancer. An insertion/deletion SNP 2G/1G (�1602) in the promoter region of MMP-1 has been described (102,103). This polymorphic site usually has one guanine (1G) and the insertion of an additional guanine at the site (2G) enhances the expression of MMP-1 (102,103). The presence of the second G allele of the MMP-1 promoter polymorphism was not associated with susceptibility or progression of prostate cancer (104,105). Associations between three correlated intronic SNPs (rs1477017, rs17301608 and rs11639960) among 13 genotyped SNPs in MMP-2 and prostate cancer risk and advanced disease were reported in the Cancer Prevention Study II Nutrition Cohort (37). However, associations for two (rs17301608 and rs11639960) of the three SNPs were not confirmed in an independent dataset using cases from the CGEMS GWAS and controls from the PLCO study cohort. The other SNP was not genotyped in CGEMS. Sfar et al. (106) observed that subjects carrying at least one copy of the MMP-9 T allele of a functional genetic variant of MMP-9 (�1562 C/T, rs3918242) had an increased risk of developing a high-grade tumor and advanced disease, but preliminary results from a recent study did not detect an association between �1562 C/T (P 5 0.91) or other polymorphisms (Q279R and R574P) in MMP-9 and prostate cancer aggressiveness (107). However, the recent study was based on only 97 patients and only 32 showed a positive biopsy for prostate cancer. In a large study, Jacobs et al. (37) did not observe an association with prostate cancer risk or advanced disease for five SNPs (including R574P) in MMP-9. Therefore, the evidence to date suggests that MMP SNPs are not likely to be associated with prostate cancer risk or progression. Interleukins. Chronic inflammation is one of several factors associated with the development of prostate cancer. ILs are a group of cytokines and variants in cytokine genes have been associated with increased inflammation and cytokine production. Murphy et al. (17) observed that expression of IL-8 correlates with Gleason score, tumor stage and microvessel density. Lehrer et al. (108) reported an elevation of serum IL-8 in prostate cancer patients with bone metastases, when compared with men with localized prostate cancer. Few studies have been conducted on IL, except for IL-10, variants in the context of prostate cancer. One polymorphism (rs16944) in IL-1
81266
is associated with aggressive disease among Caucasians (86) and the interaction between IL-1 and IL-10 is associated with increased risk (OR 5 3.38, 95% CI 5 1.70–6.71) of prostate cancer among this group (83). Presently, no association with risk or survival has been observed for this variant or other IL-1 variants (35,109). IL-6 variants have not been associated with risk or aggressive disease (81,109). Association with IL-8 has been inconsistent with one study reporting a reduction in risk associated with the TT genotype of IL-8–251 (35), whereas other studies have reported no association with risk or aggressive disease for this polymorphism (86,110). IL-10 is the most studied IL in the context of IL variants and prostate cancer. IL-10 is a pleiotropic cytokine that inhibits tumorinduced angiogenesis and inflammation. The anti-angiogenesis effect of IL-10 reduces tumor growth, whereas its anti-inflammatory effect promotes tumorigenesis by enabling tumor cells to escape immune surveillance (111,112). Reduced levels of IL-10 expression have been associated with polymorphisms in its promoter region (IL-10 �1082, �819 and �592) and several studies have examined the association between these polymorphisms and prostate cancer. However, the results have been inconsistent with some studies reporting an increased (35,80,83,86,113–115), decreased (83) or no association (115,116) with risk or progression. To derive a more precise estimation of the association between IL-10 gene polymorphisms and prostate cancer, two meta-analyses have been recently performed. In one meta-analysis including 10 studies (4107 cases and 5274 controls), there were no significant associations between prostate cancer risk and IL-10 �1082 A.G (rs1800896), �819 C.T (rs1800871) or �592 C.A (rs1800872) polymorphisms and the results were similar for Asians and Caucasians (117). However, the meta-analysis suggested that rs1800871 and rs1800872 polymorphisms might be modestly associated with advanced disease and might therefore impact disease progression. Controls in some of the studies that are included in this meta-analysis deviated from Hardy–Weinberg and also had benign prostatic hyperplasia, which could potentially bias the summary estimate. A second larger meta-analysis including 5503 cases and 6078 controls from 12 studies (including 10 in the previous meta-analysis) also did not observe associations between IL-10 rs1800896, rs1800871 and rs1800872 polymorphisms and prostate cancer risk and the findings were similar for Asians and Caucasians (118). This finding provides additional evidence that these polymorphisms may not be associated with prostate cancer risk. To date, only one study has examined polymorphisms in ILs with biochemical recurrence of prostate cancer after radical prostatectomy (119). This study observed that the AA genotype of IL-10 rs1800871 was independently associated with a higher risk of prostate-specific antigen recurrence compared with the A/G þ G/G genotypes, suggesting that the IL-10 polymorphism may be a prognostic factor for prostate-specific antigen recurrence after radical prostatectomy (119). However, this study included only 116 cases and the finding needs to be replicated in an independent larger study. Analysis of two SNPs (�137 G/C and �607 C/A) in the IL-18 gene promoter in a Chinese population observed that �137 GC and CC genotypes and the �137C/�607A haplotype were associated with a significantly increased risk of prostate cancer compared with the �137 GG genotypes or the �137G/�607C haplotype (120). So far, the association between SNPs in ILs and prostate cancer risk is generally null, but the available evidence suggests that IL variants may be associated with advanced disease and potentially recurrence of the disease. Anti-angiogenesis gene COL18A1 (endostatin) Endostatin is a C-terminal cleavage product of the extracellular matrix protein collagen XVIII (COL18A1). It inhibits endothelial cell proliferation in vitro and tumor angiogenesis and growth in vivo (121). Endostatin is an important inhibitory molecule which mediates the sequential steps involved in angiogenesis. Higher serum levels of endostatin in animal models result in
SNPs SNPs in in angiogenesis and prostate cancer
regression of solid tumors (122–124). Furthermore, the lower incidence of tumors in Down syndrome patients who have higher serum levels of endostatin provides further evidence for the tumor suppressive role of endostatin (125). A non-synonymous polymorphism in the endostatin gene (COL18A1) occurs at codon 104, which results in the change of aspartic acid to asparagine (D104N, rs1248337). Though this polymorphism does not appear to affect expression, structural modeling suggests it may impair binding to other molecules that could decrease its potential to inhibit angiogenesis (126). The D104N polymorphism has been associated with increased risk, but not aggressiveness, of prostate cancer, among Caucasians and Blacks in Brazil (126). However, the study had only 61 and 11 classified Caucasian and Black cases, respectively, and only one unclassified participant aged �65 years was homozygous for the N allele in the study. Macpherson et al. (127) did not observe an association with this polymorphism and AIPC or survival. In another study, endostatin D104N polymorphism was not associated with aggressiveness or disease-free survival (128). In a recent larger prospective study (544 incident cases and 678 matched controls) within the Physicians’ Health Study, no overall association was observed between carriage of the N allele of endostatin D104N and prostate cancer risk or cancer-specific mortality (129). However, an analysis stratified by body mass index (BMI) revealed that among men homozygous for the D allele, overweight and obese (BMI �25 kg/m2) men had a twofold increased risk of prostate cancer, prostate cancer death or metastasis. In contrast, healthy weight (BMI ,25 kg/m2) men who had at least one copy of the N allele had a higher prostate cancer risk and a worse prognosis. These findings suggest that BMI may interact with this polymorphism in prostate cancer development and progression. The evidence to date suggests that endostatin is not associated with prostate cancer risk or progression but may interact with BMI to impact risk and outcome. However, this interaction has been examined in only one study and future studies are warranted to confirm this finding. Multiple angiogenesis genes and gene–gene interactions Few studies have examined multiple angiogenesis genes or the interaction between angiogenesis genes and prostate cancer risk or progression. A recent study evaluated the association between prostate cancer and variants in IL-10, TGF-b1, VEGF, their receptors and the joint modifying effects of these variants in a case–control study consisting of African American men (42). The study did not observe main effects for any of the SNPs but observed that the presence of VEGF 2482T combined with VEGFR IVS 6 þ 54 loci was associated (P 5 0.04) with the risk of prostate cancer. A combined effect of EGF þ 61G.A and TGF-b1 þ 869T.C functional polymorphisms have been shown to be associated with risk (P 5 0.004) and time to androgen independence (P 5 0.039) in prostate cancer (130). In a similar study, the combination of VEGF �1154G/A; VEGF �634G/C; MMP9 �1562C/T and TSP1 �8831A/G yielded a significant gene dosage effect for increasing numbers of potential high-risk genotypes, where individuals with one and three high-risk genotypes had increasingly elevated risks of prostate cancer (131). Jacobs et al. examined associations between SNPs in nine angiogenesis-related candidate genes (EGF, LTA, HIF1A, HIF1AN, MMP2, MMP9, NOS2A, NOS3 and VEGF) and risk of overall and advanced prostate cancer. They observed initial associations at SNPs in only HIF1A and MMP2, but almost all the associations did not replicate in an independent dataset (37). These preliminary findings suggest that interaction of angiogenesis gene polymorphisms may be associated with prostate cancer but replication in larger studies is needed. Conclusions Strong biological evidence exists for the involvement of angiogenesis in prostate cancer development and progression. However, the evidence that links polymorphic variants in key genes within this
pathway with prostate cancer progression and prognosis is limited to just a few genes. For most of the variants, the data are inconsistent. Although the exact basis for the inconsistent results is unknown, potential explanations include differences in study design, populations and relatively small sample sizes. More importantly, investigation of few SNPs in candidate genes may not be an optimal approach for an association study. Most of the studied SNPs are in promoter regions and have been studied because of their potential effect on expression. Since gene expression may be affected by either SNPs in the promoter regions or DNA methylation, it is conceivable that DNA methylation may be involved in the complex angiogenesis pathway. Therefore, future studies should incorporate the methylation status of genes in the angiogenesis pathway in relation to prostate cancer risk and progression. Funding This research was supported in part by a cancer prevention fellowship (EKA) supported by the National Cancer Institute grant (R25TCA147832; PI: Egan, K) and (R01CA128813; PI: Park, JY). Acknowledgements We are grateful to Donald Buchanan and Veronica Nemeth for excellent graphic design of manuscript. Conflict of Interest Statement: None declared.
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