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Influence of Cytokine Gene Polymorphisms on the Development of Prostate Cancer¹

Department of Histocompatibility and Immunogenetics, Southampton University Hospitals NHS Trust, Southampton SO16 6YD [S. L. M., P. R. E., W. M. H.]; Institute of Cancer Research, Royal Marsden Hospital NHS Trust, Sutton, Surrey SM2 5PT [S. E., D. P. D., A. D., C. S., R. A. E.]; University of Portsmouth, Portsmouth PO1 2RY [R. G.]; and CRC Genetic Epidemiology Unit, Strangeways Laboratories, Cambridge CB1 4RN [D. F. E.], United Kingdom

	ABSTRACT

Top ABSTRACT Introduction Patients and Methods Results and Discussion REFERENCES

 
Polymorphisms in the promoter regions of cytokine genes may influence prostate cancer (PC) development via regulation of the antitumor immune response and/or pathways of tumor angiogenesis. PC patients (247) and 263 controls were genotyped for interleukin (IL)-1ß-511, IL-8-251, IL-10-1082, tumor necrosis factor--308, and vascular endothelial growth factor (VEGF)-1154 single nucleotide polymorphisms. Patient control comparisons revealed that IL-8 TT and VEGF AA genotypes were decreased in patients compared with controls [23.9 versus 32.3%; P = 0.04, odds ratio (OR) = 0.66, 95% confidence interval (CI) 0.44–0.99 and 6.3 versus 12.9%; P = 0.01, OR = 0.45, 95% CI 0.24–0.86, respectively], whereas the IL-10 AA genotype was significantly increased in patients compared with controls (31.6 versus 20.6%; P = 0.01, OR = 1.78, 95% CI 1.14–2.77). Stratification according to prognostic indicators showed association between IL-8 genotype and log prostate-specific antigen level (P = 0.05). These results suggest that single nucleotide polymorphisms associated with differential production of IL-8, IL-10, and VEGF are risk factors for PC, possibly acting via their influence on angiogenesis.

	Introduction

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In Western Europe and the United States, PC⁴ is the most common cancer diagnosed in men and the second most common cause of death with a continuing increase in incidence (1) . The evidence that PC has a genetic component is compelling from epidemiological and genetic studies; some high-risk genes have been identified, which when present, may predispose a carrier to development of the disease (2) . Examples of PC susceptibility genes include HPC1 on chromosome 1q24-25 (3) , HPCX on Xq27-28 (4) , BRCA1 on 17q21 and BRCA2 on 13q12 (5) , CAPB at 1p36 (6) , PCAP on 1q42.2-43 (7) , and, most recently, ELAC2/HPC2 on chromosome 17p (8) . The association between these high penetrance genes and PC susceptibility highlights the complex and multigenic mode of inheritance of PC, yet more common, lower penetrance susceptibility polymorphisms in genes may be implicated in a higher portion of the sporadic PC disease burden and so have more relevance to public health. The prostate was originally thought to be an immunologically privileged site. However, there is now good evidence that the prostate has a lymphatic system and can mount inflammatory immune responses, and these responses, as evidenced by density of tumor-infiltrating lymphocytes, may be associated with prognosis in PC (reviewed in Ref. 9 ). The immune system may therefore play a role in the pathogenesis of PC, via regulation of tumor growth, whereas evasion of the immune response may play a role in disease progression. Cytokines (soluble chemical messengers) play a crucial role in regulating both humoral and cell-mediated immune responses. Promoter regions of a number of key pro and anti-inflammatory cytokine genes contain polymorphisms that directly influence cytokine production (10) . These promoter polymorphisms may lead to either high- or low-level production of a given cytokine, causing interindividual differences in immune responsiveness, which may influence antitumor immune responses in PC. In addition, particular cytokines (e.g., IL-8, IL-10, and VEGF) may also influence tumor development via their action on pathways of tumor angiogenesis. In this study, we aimed to determine whether polymorphisms associated with differential expression of IL-1ß, IL-8, IL-10, TNF-, and VEGF are associated with susceptibility to and prognosis in PC.

	Patients and Methods

Top ABSTRACT Introduction Patients and Methods Results and Discussion REFERENCES

 
Subjects.
Stored DNA samples from 247 Caucasian PC patients collected from one clinic were available via the Institute of Cancer Research, Royal Marsden NHS Trust, London, United Kingdom. The mean age of these patients at presentation was 68.1 years (age range 48–80 years). The method of DNA extraction used has been described previously (11) .

Controls.
The control group used in this project comprised genomic DNA samples from 263 Caucasian, cancer-free bone marrow and solid organ donors, collected via Southampton General Hospital Histocompatibility and Immunogenetics Department. The mean age of these controls (139 males and 124 females) was 39.2 years (age range 3–69 years). The DNA extraction technique used has been described previously (12) .

Clinical Data.
A full 9-year (1993 to present day) clinical follow-up study, including family history, tumor grade (Gleason score), tumor stage classification (Tumor-Node-Metastasis), PSA level at diagnosis, and survival was available.

Genotyping Methodology.
IL-1ß-511 (CT), IL-8-251 (AT), IL-10-1082 (AG), TNF--308 (AG), and VEGF-1154 (AG) SNPs were genotyped by the amplification refractory mutation system-PCR technique using one reaction per allele of each SNP (13) . All PCR reactions were performed in 10-µl reaction volumes, and final reagent concentrations were: AS reaction buffer (Abgene, Epsom, United Kingdom), 200 µM each deoxynucleotide triphosphate, 12% (w/v) sucrose, 200 µM cresol red, 1 µM each specific/common primer, 0.2 µM each internal control primer (see Table 1 for sequences), 0.25 units of Thermoprime^PLUS DNA polymerase (Abgene), and 50–100 ng/µl DNA. MgCl₂ concentrations were optimized for each SNP (Table 1) . PCR reactions were performed using a Tetrad DNA engine (MJ Research, Inc., Watertown, MA), a 9600 Thermal Cycler (PE Biosystems, Foster City, CA), or an MWG primus 96 plus Thermal Cycler (MWG Biotech United Kingdom, Ltd., Milton Keynes, United Kingdom), according to the following thermocycler conditions: 1 min at 96°C, 10 cycles of 96°C for 15 s, T_a for each SNP for 50 s (Table 1) , 72°C for 40 s, then 20 cycles of 96°C for 10 s, 60°C for 50 s, and 72°C for 40 s. PCR products were loaded directly onto 2% agarose gels (containing 0.5% mg/ml ethidium bromide), electrophoresed, and visualized by photography under UV transillumination.

	Results and Discussion

Top ABSTRACT Introduction Patients and Methods Results and Discussion REFERENCES

 
In this preliminary study, a panel of five cytokine SNPs were studied, namely IL-1ß-511, IL-8-251, IL-10-1082, TNF--308, and VEGF-1154. These SNPs were selected, because all have been reported to influence expression of their respective cytokine in vitro (10 , 14 , 15) and represent proinflammatory (IL-1ß and TNF-) and immunosuppressive (IL-10) cytokines and cytokines which influence the process of angiogenesis (IL-8, VEGF, and IL-10). All samples were genotyped for each SNP according to DNA availability (ranging from 238 to 247 PC cases and from 220 to 263 controls genotyped, depending on SNP). Patient and control genotype distributions fitted Hardy-Weinberg equilibrium at the P = 0.05 level. The case control results show that the three SNPs, IL-8-251, IL-10-1082, and VEGF-1154, all with angiogenic properties, were significantly associated with PC susceptibility (Table 2) . VEGF is a potent stimulator of angiogenesis, necessary for successful microvasculature development and important for metastasis, survival, and spread of the tumor. Patients (238) and 263 controls were completely genotyped in this study, and the results showed that VEGF (-1154) AA genotype (low producer of VEGF; Ref. 15 ) was significantly decreased in the patient group when compared with controls (6.3 versus 12.9%; P = 0.01). This result is in agreement with publications that state that many PC patients have been shown to produce VEGF at higher concentrations than in normal prostate tissue (16) . Accordingly, VEGF low producers genotypes may confer protection for PC, whereas high producers may have a promoting effect on PC progression and successful survival of the tumor.

Conversely, other studies have suggested that high IL-10 levels are tumor promoting and that elevated serum IL-10 levels have been observed in patients with various solid tumors (22) . These imply that IL-10 may influence tumor escape from the immune response based on its immunosuppressive functions, through suppression of Th1 type cytokine production, especially IL-2. However, the present immunogenetic study does not support an immunosuppressive role of IL-10 in tumor development in PC.

The IL-8 (-251) TT genotype (low producer of IL-8; Ref. 14 ) was decreased significantly in PC patients when compared with controls. Patients (238) and 235 controls were fully genotyped, and the results showed that the TT genotype, associated with low IL-8 production, was decreased significantly among the PC patients (23.9 versus 32.3%) compared with controls (P = 0.04). IL-8 has a known function in the regulation of angiogenesis and tumor growth in PC. A recent report showed that neutralizing antibodies to IL-8 inhibited angiogenic activity in a human PC cell line/murine model and reduced tumorigenicity in vivo, implicating IL-8 as an important modulator of PC growth (23) . In support of this, results from this study suggest that genetically determined low levels of IL-8 product may be protective in PC. IL-1ß-511 and TNF--308 genotypes showed no significant associations with PC in this case control study (Table 2) , suggesting that these genotypes may not play a role in PC susceptibility and progression.

The cytokine SNP genotypes were compared within the PC patient series and stratified according to the three key prognostic indicators (Table 3) and overall and disease-free survival (Table 4) to determine whether cytokine genotypes influence prognosis in PC. The data in Table 3 show a significant correlation and also a possible influence of IL-8 (AA, high producer) genotype on increased log PSA level measured before removal of tumor (P = 0.05). No significant associations between cytokine genotype and tumor stage, grade, disease-free survival, or overall survival were seen, although a number of nonsignificant trends were observed (Tables 3 and 4 ). These results suggest that a more definitive investigation is required in a larger subject group.

In conclusion, the most significant findings from this exploratory study (the first study of cytokine SNPs in PC) indicate that although the influence of cytokine SNPs on PC is likely to be complex, and influences on antitumor immune responses cannot be ruled out by this study, cytokine genotypes associated with the angiogenic pathway (IL-10, VEGF, and IL-8) may have a significant effect on disease development. A definitive study of SNPs influencing this pathway is indicated by these preliminary results to confirm their association with PC susceptibility and investigate possible associations with prognosis.

	ACKNOWLEDGMENTS

 
We thank the patients and control individuals for taking part in this study. We also thank Margaret Stevens who provided administrative support.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the NHS Executive South East, United Kingdom, The Cancer Research Campaign, United Kingdom, and The Prostate Cancer Charitable Trust.

² A list of collaborators are available on request.

³ To whom requests for reprints should be addressed, at Histocompatibility and Immunogenetics Laboratory, Tenovus Building, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, United Kingdom. E-mail: wmh1{at}soton.ac.uk

⁴ The abbreviations used are: PC, prostate cancer; TNF, tumor necrosis factor; IL, interleukin; VEGF, vascular endothelial growth factor; PSA, prostate-specific antigen; CI, confidence interval; NHS, National Health Service; SNP, single nucleotide polymorphism.

Received 2/16/02. Accepted 4/25/02.

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