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Interleukin-10 Gene Polymorphisms and Cancer

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Interleukin-10 (IL-10) is a multifunctional cytokine with both immunosuppressive and anti-angiogenic functions. In consequence, IL-10 can have both tumor-promoting and tumor-inhibiting properties. Raised levels of serum and peri-tumoral IL-10 production have been reported in many malignancies, which have been interpreted in support of a role for IL-10 in tumor escape from the immune response. However, gene transfection studies in a number of malignancies argue more convincingly for an anti-tumor function of IL-10, possibly via inhibition of pathways of angiogenesis.

A large number of polymorphisms (primarily single nucleotide polymorphisms (SNPs)) have been identified in the IL-10 gene promoter. Convincing evidence that certain of these polymorphisms are associated with differential expression of IL-10 in vitro and in some cases in vivo have been obtained. While a large number of investigations of possible associations between IL-10 genotypes and immune mediated disease have been performed, the literature with regard to IL-10 polymorphisms and cancer is as yet small, but growing. These published studies include both solid tumors and hematological malignancies and common and less common diseases. In this chapter, the results from 15 studies in 10 different malignancies are reviewed. In 12 of these studies, positive associations between IL-10 genotype or haplotype and disease susceptibility and/or progression were reported. In some of these cancers (for example, cutaneous malignant melanoma, prostate cancer, breast cancer, non cardia gastric cancer and nonHodgkin's lymphoma) genotypes associated with low IL-10 expression were a risk factor for disease or disease progression, while in others (for example, cervical cancer, cardia gastric cancer, post-transplant squamous cell carcinoma of the skin and multiple myeloma), genotypes associated with high IL-10 expression were a risk factor).

All results reviewed should be regarded as preliminary, due to the small sample sizes of almost all of the studies and the limited numbers of IL-10 polymorphisms examined. In addition, few of the studies have examined levels of IL-10 production in vivo in the subjects genotyped. However, the preliminary data obtained thus far indicate that much larger studies are required in a number of cancers, in order to confirm initial results, extend studies to include more detailed genotype/haplotype analysis and to combine genotype and gene expression studies in the same subjects. Such studies will contribute significantly to our understanding of the biological role of IL-10 in tumor development, with implications for cytokine therapy in cancer.

Introduction

As considered in more detail elsewhere in this volume, Interleukin-10 (IL-10) is a key regulator of immune responses and was originally described as cytokine synthesis inhibitory factor,1 being produced by Th2 cells and inhibiting cytokine production by Th1 cells. Later studies showed that the actions of IL-10 on inhibition of pro-inflammatory cytokine production by both T and NK cells were indirect, acting via inhibition of accessory cell function.2-5 In addition, it was soon shown that IL-10 inhibits a broad range of activated monocyte/macrophage functions, including monokine synthesis, nitric oxide production, major histocompatibility complex (MHC) class II and CD80/CD86 costimulatory molecule expression.6-11 In vitro and in vivo studies revealed pleiotropic activities of IL-10 on B and T cells and, taken together, that a critical function of IL-10 is to suppress multiple immune responses through individual actions on T cells, B cells, antigen presenting cells and other cell types, and to skew the immune response from Th1 to Th2 (reviewed in detail in ref. 12). In malignancy, this might suggest a priori, that IL-10 might promote tumor development, by acting to suppress anti-tumor immune responses, where these occur. However, a number of other findings suggest that the biological properties of IL-10 are more complex than this and IL-10 may have immunostimulatory or immunosuppressive effects, depending upon the assay used, cell types involved and other concomitant immune events,13 therefore the actions of IL-10 on tumor development may be more complex. In particular, animal models suggest that IL-10 can induce NK cell activation and so facilitate anti-tumor responses, leading to tumor cell destruction. 14,15 Evidence for both tumor promoting and anti-tumor functions of IL-10 is briefly reviewed below.

IL-10 and Cancer

There are a number of reports describing elevated levels of IL-10 expression in patients with particular cancers, including malignant melanoma,16-19ovarian cancer20 and other carcinomas, 21-24 lymphoma and myeloma.25,26 These elevated levels have been reported both in the serum and/or tumor lesions. Furthermore, a negative correlation between circulating levels of IL-10 and prognosis has been reported in patients with solid tumors, including lung cancer,22 renal carcinoma24 and gastrointestinal tumors27 and hematological malignancies.28-29 A simplistic interpretation of these data would be that elevated IL-10 levels are associated with suppression of anti-tumor immune responses. However, elevated IL-10 expression can occur for a number of reasons. Production by tumor and other cells may indeed result in suppression of anti-tumor immune responses, but IL-10 may also act as a tumor growth factor, as evidenced by the action of exogenous IL-10 on human melanoma cells lines.30 In addition, IL-10 can also be produced by activated cells involved in anti-tumor immune responses and so may be indicative of a potent anti-tumor immune response. Indeed, it should be noted that elevated IL-10 levels do not correlate with prognosis in all studies31 and in some cases favorable prognosis has been associated with elevated IL-10 expression.32

More convincing data come from studies of IL-10 gene therapy in animal models of tumor growth and establishment, which consistently demonstrate an anti-tumor role for IL-10. In a colon carcinoma mouse model, transfection of tumor cells with IL-10 reduces the malignant potential of the tumor cells and induces a predominant Th2-mediated tumor rejection response. 33 Similarly, IL-10 transfected cell lines derived from mouse mammary adenocarcinoma, 34 ovarian carcinoma,35 malignant melanoma,36 Burkitt's lymphoma,37,38 prostate39 and colon cancers33 show significant inhibition of tumor growth. In support of this, systemic administration of IL-10 has inhibited tumor metastasis in various murine models, including melanomas,14,40 sarcomas and colorectal carcinomas.40

The mechanisms behind these antitumor effects are still incompletely understood. Many researchers attribute the antitumor effects of IL-10 to its effects on NK cell activation,14,15 although actions on T cells,40 macrophages41 and nitric oxide42 have also been implicated. In addition, IL-10 enhances the susceptibility of target cells to NK cell lysis by reducing cell surface MHC expression.43,44 However, an increasing body of evidence suggests that IL-10 exerts an antitumor effect by inhibition of angiogenesis. For example, in vitro studies of prostate tumor cells show that IL-10 stimulates tissue inhibitors of metalloproteinases (TIMPs) and inhibits matrix metalloproteinase (MMP) expression, so affecting induction of angiogenesis.45,46 Similarly, IL-10 gene transfection studies in malignant melanoma have shown that inhibition of tumor growth by inhibition of angiogenesis is accompanied by downregulation of synthesis of vascular endothelial growth factor (VEGF)—one of the most potent angiogenic factors—along with IL-1βtumor necrosis factor-αTNFα IL-6 and MMP-9 (all known to have angiogenic properties) in tumor-associated macrophages.17 In addition, in Burkitt's lymphoma, a lymphoid malignancy, introduction of human or viral IL-10 genes into tumors in SCID mice revealed an inhibition of VEGF-induced neovascularisation of the tumors.37

Accordingly, while the mechanisms remain unclear, there is a considerable and growing body of evidence for the antitumor properties of IL-10 and this may result at least in part from inhibition of angiogenesis, possibly by inhibition of production of angiogenic cytokines, growth factors and MMPs and stimulation of production of inhibitors of angiogenesis. Based on this, several investigators have suggested therapeutic use of IL-10 in cancer patients,14,15,17,40,47 but at present no clinical trials have been performed.

An alternative strategy to determine the role of IL-10 in the development of particular malignancies is via genetic approaches. In recent years a considerable number of genetic polymorphisms have been identified within the IL-10 gene, particularly within the promoter region of the gene. Certain of these polymorphisms have been shown to be associated with differential levels of IL-10 expression. A considerable number of studies have been performed to determine whether IL-10 polymorphisms are associated with susceptibility to a large number of immune-mediated diseases (reviewed in refs. 48 and 49) and a small number of investigations have been performed in solid tumors and hematological malignancies and this literature is briefly reviewed below.

IL-10 Gene Polymorphisms

The IL-10 gene is comprised of 5 exons, spans approximately 5.2 kB and is located on chromosome 1, at 1q31-1q32.50 Due to the critical role of IL-10 in regulating immune responses in health and immune-mediated diseases, a number of groups have pursued intensive studies to identify naturally occurring gene polymorphisms in the IL-10 gene and flanking regions. To date, at least 49 IL-10-associated polymorphisms have been reported in the literature and these are summarised in Table 1. An even larger number of polymorphisms are recorded in single nucleotide polymorphism (SNP) databases (e.g., the Wellcome Trust Sanger Institute/ European Bioinformatics Institute SNP database: Ensembl Genome Browser).

Table 1. IL-10 gene polymorphisims.

Table 1

IL-10 gene polymorphisims.

From Table 1 it can be seen that of the 49 polymorphisms listed, 46 are SNPs, 2 are microsatellite polymorphisms and 1 is a small (3 bp) deletion. Twenty-eight polymorphisms occur in the promoter region of the gene, 20 polymorphisms are noncoding intronic or synonymous substitutions and only 1 polymorphism results in a change in amino acid sequence. The promoter polymorphisms have been subject to the most scrutiny, particularly with regard to possible influences upon gene transcription and expression. For example, the IL-10 -1082 SNP and -1082, -819, -592 haplotype have been reported to be associated with differential IL-10 expression in vitro, with the -1082 A, -819 T, -592 A haplotype associated with decreased IL-10 expression, compared with the - 1082 G, -819 C, -592 C haplotype.55 This is thought to reflect - at least in part - differential transcription factor binding associated with the -1082 SNP.60 In addition, IL-10 R and G microsatellite haplotypes have also been shown to be associated with differential levels of IL-10 expression in vitro.61 Some workers have suggested that as much as 75% of inter-individual variation in IL-10 expression may be due to genetic variation,62 although others believe that the contribution of individual SNPs—such as the best-described -1082 SNP—may be much less than this.60 Accordingly, the role of IL-10 polymorphism in determining susceptibility to and prognostic outcome in nonmalignant immune-mediated diseases has been the subject of intense interest and a plethora of case-control studies have demonstrated a number of positive associations in a diverse range of diseases, including asthma,63,64 systemic lupus erythematosus,52 reactive arthritis65 and outcome of clinical renal,66,67 heart68 and bone marrow transplantation.69 Similarly, other investigations have failed to implicate IL-10 promoter polymorphisms in susceptibility to various diseases including multiple sclerosis,70,71 while in other diseases results are conflicting e.g., rheumatoid arthritis.72,73 Summaries of studies of IL-10 (and other) cytokine polymorphisms and disease have been published by Bidwell et al48 and Haukim et al,49 both of which contain extensive bibliographies.

IL-10 Gene Polymorphisms and Cancer

The literature concerning IL-10 polymorphism in cancer is very recent and is therefore still relatively small, but growing rapidly, with all publications dating from 2001. Results from these studies are summarised in Table 2 and each disease is considered in more detail below. From a casual inspection of Table 2, it will be noted that while all except one study is of case-control design, several studies have also investigated associations between particular IL-10 polymorphisms and markers of disease prognosis. Of the 15 studies listed, 6 have studied the IL-10 -1082 SNP alone and 8 have studied the IL-10 -1082, -819, -592 SNPs and haplotypes in case-control studies (in one study, cases only) of the malignancy in question. The IL-10G and IL-10R microsatellites were examined in the remaining study. Therefore all studies published thus far have focussed upon those polymorphisms for which there is direct evidence for a causal association with differential IL-10 expression (IL-10 -1082), or polymorphisms and haplotypes which act as markers for differential IL-10 expression (IL-10G and IL-10R microsatellites and IL-10 -1082, -819, -592 haplotypes). As yet, no published studies have performed detailed IL-10 SNP analysis or haplotyping across the complete IL-10 promoter and/or gene sequence in any malignancy.

Table 2. IL-10 polymorphisms and cancer.

Table 2

IL-10 polymorphisms and cancer.

In the following consideration of the studies summarised in Table 2, cutaneous malignant melanoma (CMM), prostate (PC) and breast cancer (BC) are considered first, since angiogenesis is crucial for the development of these tumors89 and indeed the extent of angiogenesis correlates with the probability of metastasis and/or prognosis in these malignancies.90-96

Cutaneous Malignant Melanoma

CMM is the most serious cutaneous malignancy and is increasing in frequency among most Caucasian populations, where the most important risk factor is exposure to ultraviolet light.97Relatively little is known of the genetic factors that mediate susceptibility to and prognosis in sporadic CMM, although polymorphisms associated with the melanocortin-1 receptor (MCR1),98,99 CDKN2A,100 XRCC3 DNA repair gene101 and glutathione S-transferase Mu phenotype (GSTM1)102 may be associated with susceptibility to CMM. Polymorphisms associated with the Vitamin D receptor and the cytochrome P450 CYP2D6 genes have been implicated in modulating prognosis in this tumor.103,104 In addition, several lines of evidence suggest that CMM patients develop an immune response to their tumors105 (supported by variable HLA-DQB1 allellic associations with CMM susceptibility and prognosis106,107), although in individuals with CMM, this anti-tumor immune response is insufficient to abrogate tumor development.

Based on the above, and to distinguish whether high constitutive levels of IL-10 have a tumor-promoting or anti-tumor influence in CMM, we have shown that the IL-10 -1082 AA genotype, associated with low IL-10 expression in vitro is associated with both susceptibility to CMM (OR = 1.78) and is a risk factor for more advanced (OR = 2.24) , and poorer prognosis disease, as evidenced by tumor Breslow thickness (OR = 3.67).74 IL-10 -1082, -819, -592 haplotypes associated with low IL-10 expression (ACC/ACC, ACC/ATA and ATA/ATA) were also associated with greater tumor Breslow thickness (OR = 3.63), which is the single most important prognostic indicator in CMM.108 In addition, the IL-10 -1082 GG genotype and IL-10 -1082, -819, -592 GCC/GCC _high expression_ haplotype were associated with noninvasive tumor growth (ORs = 2.42 and 2.31 for noninvasive growth respectively). This study was performed in British Caucasian CMM cases and controls. Some support for these findings is provided by the small, independent study of Martinez-Escribano et al,75 who showed that in Italian CMM patients, the IL-10 -1082, -819, -592 ACC/ATA low expression haplotype was also associated with greater tumor Breslow thickness and was a risk factor for poorer survival. Finally, it should be noted that results from these genetic studies are in accordance with the effects of IL-10 gene transfection in animal models of malignant melanoma, which suggests that intratumor expression of IL-10 abrogates tumor development.36

Although the influence of IL-10 on CMM development is likely to be complex, these results support recent findings that IL-10 has an anti-tumor effect in CMM, possibly via inhibition of VEGF expression and angiogenesis.17 In agreement with this, we have also obtained evidence that gene polymorphisms associated with differential expression of other angiogenic cytokines (in particular, VEGF) may also play a role in predisposition to and tumor growth in CMM.109

Prostate Cancer

In Western Europe and the USA, PC is the most common cancer diagnosed in men and the second most common cause of death with a continuing increase in incidence.110 The evidence that PC has a genetic component is compelling from epidemiological and genetic studies; some high-risk genes have been identified, that when present may predispose a carrier to development of the disease111. Examples of PC susceptibility genes include HPC1 on chromosome 1q24-25,112 HPCX on Xq27-28,113 BRCA1 on 17q21 and BRCA2 on 13q12,114 CAPB at 1p36,115 PCAP on 1q42.2-43116 and most recently ELAC2/HPC2 on chromosome 17p.117 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 proportion 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, can mount inflammatory immune responses and these responses-as evidenced by density of tumor infiltrating lymphocyes-may be associated with prognosis in PC (reviewed in ref. 118). The immune system may therefore play a role in the pathogenesis of PC, via regulation of tumor growth, while evasion of the immune response may play a role in disease progression. In addition, due to the critical role of angiogenesis in PC development93, and based on our findings in CMM, we elected to determine whether polymorphisms in pro- and anti-inflammatory and pro-angiogenic cytokine genes were associated with susceptibility to and/or markers of prognosis in a case-control study of British Caucasian PC patients and population controls. Results indicated that the IL-10 -1082 AA _low expression_ genotype was significantly increased in incidence in the patient group (OR = 1.78), closely paralleling results in CMM.76 This is again suggestive that genetically determined low levels of IL-10 production may be a risk factor in PC, via down-regulation of VEGF synthesis or enhanced lysis of tumor cells by NK cells. Again, results from this genetic study are in accordance with findings from IL-10 gene transfection studies in this malignancy.39

Evidence for a role for polymorphism in pro-angiogenic genes was also provided by this study, which showed significant associations between genotypes associated with low VEGF and low IL-8 expression and protection from PC.

Breast Cancer

BC is by far the most common malignancy affecting Western women. A family history of BC is one of the most important and consistent risk factors, highlighting the role of inherited germline susceptibility genes. In the mid 1990s, two BC susceptibility genes, BRCA 1 (chromosome 17) and BRCA 2 (chromosome 13) were identified.119,120 Mutations that render these genes nonfunctional or absent are inherited in an autosomal dominant manner and confer a high disease risk. However, recent epidemiological studies suggest that BRCA 1 and BRCA 2 mutations only account for a few percent of BC cases.121 It is highly likely that a number of more prevalent, low penetrance genes contribute to BC susceptibility in a larger population of women and are therefore responsible for a greater proportion of the disease burden.121-123

Recent modelling of breast cancer inheritance in a population where BRCA1 and 2 gene carriers had been excluded from the cohort revealed a model of inheritance that is polygenic and provides an estimate that nearly 90% of all breast cancer cases will occur in an identifiable subset of perhaps half the general population.124 As yet, little is known about low penetrance susceptibility genes which contribute to BC susceptibility and only a few have been identified, including genes involved in carcinogen detoxification and oestrogen metabolism.125-127

There is accumulating evidence indicating the presence of peritumoral inflammatory infiltrate in BC, which may reflect-at least in part-an antitumor immune response, while angiogenesis is necessary for the development of BC and the extent of angiogenesis correlates with tumor development and patient survival.94-96 In addition, high levels of IL-10 mRNA are detectable in tumor lesions.128 Accordingly, we have performed a small study of 144 British Caucasian BC patients and 263 controls, for the same panel of SNPs in pro- and anti-inflammatory and pro-angiogenic cytokine genes as studied in PC, but have failed to demonstrate any associations with susceptibility to BC, for any of these SNPs, including IL-10 -1082, save for the TNFα308 GG, which was increased in frequency in the BC group, at a marginal level of significance.77 Conversely, in an independent study of 125 Italian BC patients and 100 controls, Giordani et al78 have reported a significant association between the IL-10 -1082 AA_low expression_ genotype and BC, analogous to our findings in CMM and PC, but have failed to demonstrate any association between the TNFα308 SNP and BC.

Therefore the limited data obtained to date with regard to IL-10 polymorphism and development of BC are equivocal, but suggest that a larger study of IL-10 -1082 and additional polymorphisms is merited in this very common cancer.

Cervical Cancer

Most high-grade cervical neoplasms have been shown to contain oncogenic human papilloma virus (HPV) DNA, although only a small proportion of such cases progress to cervical cancer. Factors-including genetic factors-leading to impaired immune responses to HPV may play a role in determining susceptibility to the development of cervical cancer. In support of this, a number of studies have implicated particular HLA polymorphisms (In particular, HLA-DQB1*03 alleles) in conferring susceptibility to squamous cell cervical carcinoma.129-132 In addition, variation in the secretion of several cytokines, including IL-10, have been reported in the blood and tissues of patients with cervical cancer,133-135 while angiogenesis is also necessary for the development of cervical neoplasia.136

Based on the above, two studies have sought to address whether IL-10 polymorphisms are associated with susceptibility to cervical cancer. In the first published study of 77 Zimbabwean women with histologically proven cancer of the uterine cervix and 69 age- and parity matched controls, the IL-10 -1082 GA genotype was found at a significantly increased frequency of 40.2% in the cases as compared with a frequency of 16% in the controls (P = 0.001). Since only one case and no controls were of IL-10 -1082 GG genotype, and the GA genotype is associated with higher IL-10 expression in vitro than the AA genotype, the authors of this study infer that a genetic predisposition to produce higher levels of IL-10 may play an important role in the pathogenesis of cervical cancer.79 This is consistent with IL-10 contributing to tumor escape from the immune response in the development of this malignancy, but the molecular function of IL-10 in the pathogenesis of HPV infection and cervical cancer may be multifactorial and the authors stress that results should not be interpreted in isolation from studies of other cytokine polymorphisms in this malignancy.79

The second published study examined the frequency of the IL-10 -1082, -819 and -592 polymorphisms in 144 Korean women with invasive cervical cancer and 179 ethnically matched noncancer controls. In this study, all individuals were homozygous for the -1082 AA genotype and only two haplotypes (-1082, -819, -592 ATA and ACC) were observed, neither of which were associated with invasive cervical cancer, nor with serum IL-10 concentration.80 Therefore, in Korean women the IL-10 genotypes studied do not appear to influence susceptibility to invasive cervical carcinoma, but due to the lack of IL-10 -1082 polymorphisms observed in this study group and hence lack of comparability with the Zimbabwean study outlined above, a role for IL-10 polymorphism in the development of cervical cancer cannot be ruled out by this study alone.

Gastric Cancer

Gastric carcinoma remains a common disease worldwide137 and cancers of the upper gastrointestinal tract comprise four distinct entities, namely squamous cell and adenocarcinoma of the esophagus, adenocarcinoma of the gastric cardia and adenocarcinoma of the distal (noncardia) stomach. Environmental and host-related factors interact in disease development, among which Helicobacter pylori infection and cigarette smoking are important environmental risks. Host immunogenetic factors have been shown to be associated with increased risk of gastric cancer and its precursors. In particular, El-Omar and colleagues have shown that functional polymorphisms in the pro-inflammatory IL-1β gene and its receptor antagonist (IL-1RN) are associated with increased risk of noncardia gastric tumors.138,139 These data indicate that genetic control of inflammation and response to Helicobacter pylori infection may be important in the development of upper gastrointestinal cancers in general. Accordingly, in a US-based study group, El-Omar and colleagues have also investigated the role of SNPs in the TNFα IL-1βIL-4, IL-6 and IL-10 genes and risk of development of upper gastrointestinal tract cancers, including esophageal and gastric cancers. Proinflammatory genotypes of TNFα(carriers of -308 A high expression allele) and IL-10 (carriers of the -1082, -819, -592 ATA low expression_ haplotype) were associated with a more than doubling risk of developing noncardia gastric cancers (OR for possession of IL-10 ATA haplotype = 2.5). Carriage of multiple proinflammatory polymorphisms of TNFαIL-1βIL-1RN and IL-10 conferred greater risk, with ORs of 2.8 for one, 5.4 for two and 27.3 for three or four high risk genotypes. In contrast, these polymorphisms were not consistently related to the risk of esophageal or gastric cardia cancers.83 The authors interpret these findings to suggest that a proinflammatory host genotype favors the development of a hypochlorydric, atrophic response to gastric infection with Helicobacter pylori which in turn predisposes to noncardia gastric adenocarcinoma, but not to cardia or esophageal tumors. However, an association of IL-10 _low expression_ genotypes with noncardia gastric adenocarcinoma is also consistent with anti-angiogenic functions of IL-10 and angiogenesis is known to be important in the development of gastric cancer.140

Two similar studies of IL-10 polymorphism in the development of gastric cancer in Taiwanese Chinese have been performed by Wu and colleagues.81,82 In opposition to the study of El-Omar and colleagues,83 the studies of Wu report that the IL-10 -1082, -819, -592 GCC high expression haplotype is associated with the development of gastric cancer taken as a single entity (OR = 2.67), and in particular with cardia cancer (OR = 3.21) and advanced stage of disease (OR = 2.29).82 These results are more consistent with genetically programmed high expression levels of IL-10 contributing to an anti-inflammatory immune response, contributing to tumor escape. However, due to the very different frequencies of IL-10 SNP alleles in the two study groups (US and Chinese), differing environmental factors and associations with different forms of gastric cancer (noncardia v cardia), it is difficult to compare the results from these two principal studies and-as yet-to extract unifying findings with regard to IL-10 polymorphisms and gastric cancer development.

Post-Transplant Squamous Cell Skin Cancer

Malignancies arise in 20 to 40% of transplant recipients within 20 years of receipt of graft.141 Skin carcinomas account for up to 50% of these cancers. Viruses, including HPVs, Epstein Barr virus and human herpes virus-8 are involved in the pathogenesis of post-transplant tumors, especially skin carcinomas, B-cell lymphomas and Kaposi's sarcoma. Impaired host immune defences, resulting from heavy immunosuppression are also associated with an increased risk of malignancy. Genetic risk factors are also suspected. Accordingly, genetic polymorphisms associated with differential levels of cytokine production may have an important effect on tumorigenesis after organ transplantation. In this context, IL-10 plymorphism is of particular interest, since, in addition to the biological functions of IL-10 discussed in some detail above, ultraviolet-induced DNA damage, a risk factor for skin cancer, also increases production of IL-10.142

For the above reasons, Alamartine et al,84 in a French-based study, investigated possible associations between the IL-10 -1082, -819 and -592 SNPs and the occurrence of post-transplant skin cancers in a series of 70 renal transplant recipients who developed post-transplant squamous (SCC) or basal cell carcinoma (BCC), 70 healthy controls and 70 age, sex and immunosuppression-matched renal recipients without cancer. Taken together, IL-10 -1082, -819, -592 haplotypes were differently distributed when comparing cancer patients with unaffected patients and with controls. Results showed that genotypes associated with low production of IL-10 (IL-10 -1082, -819, -592 GCC negative) were less frequent in cancer patients (23% v 47% in unaffected patients), but only in patients with SCC (12%) and not BCC (37%). In addition, genotypes associated with high IL-10 production (GCC homozygous) were more frequent in cancer patients (24% v 11%), but this difference was significant only when comparing all cancer patients, or patients with SCC, with controls. The frequency of GCC homozygosity was not increased when considering patients with BCC with unaffected patients. The predicted correlation between IL-10 genotype and in vitro secretion of IL-10 by mononuclear cells was also confirmed by the same study.

Therefore results from this study suggest that genetically programmed elevated IL-10 production may favor the development of carcinoma-especially SCC-in renal transplant patients, although, as for most of the studies reviewed in this chapter, this result requires independent confirmation or replication.

Hematological Malignancies

Multiple myeloma (MM) is a monoclonal B cell neoplasm, in which immunoglobulin producing malignant plasma cells accumulate in the bone marrow. It is unclear whether genetic factors influence susceptibility to MM or clinical course of the disease. However, IL-10 has been implicated in the growth and differentiation of normal B cells,143 has been shown to be a growth factor for MM cells144 and elevated levels of IL-10 have been reported in patients with MM.26 In addition, IL-10 has been implicated in the pathogenesis of other human B-cell malignancies.25 Accordingly, Zheng et al85 analysed the frequency of IL-10 G and R microsatellite alleles in a series of 73 Swedish Caucasian MM patients and 109 ethnically matched controls. Significantly increased frequencies of the IL-10 G 136/136 and IL-10 R 112/114 genotypes were seen in the MM patients, along with a decreased frequency of the IL-10 R 114/116 genotype. In addition, increased production of IL-10 was detected in the supernatants of lipopolysaccharide-stimulated peripheral blood mononuclear cells from MM patients carrying one or two IL-10 G 136 alleles, compared with other IL-10 genotypes. These results suggest that genetically determined elevated levels of IL-10 production may may a role in the development of MM.

The Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders, with some subtypes rarely transforming to acute leukemia.145 There is increasing evidence for an inflammatory component in the pathogenesis of MDS and an autoimmune mechanism is suggested by response to immunosuppression in some MDS patients.146 Despite this, Gowans et al86 failed to find any association between HLA class I and II, TNFαLTαnd IL-10 polymorphisms with either susceptibility to or disease progression in MDS or secondary acute myeloid leukemia (AML) in a series of 150 UK MDS/AML patients and up to 1000 controls, depending upon polymorphism investigated. Accordingly, this single study provides no evidence for a role for the IL-10 -1082, -819 and -592 SNPs in determining susceptibility to or disease progression in MDS and AML. Conversely, a study by Lauten et al88 showed an association between the IL-10 -1082 GG genotype and a protective effect from poor predisone response in a series of 135 German childhood acute lymphoblastic leukemia (ALL) patients, where prednisone response has high predictive power of survival in childhood ALL.147 These preliminary data suggest that genetically programmed high levels of IL-10 production may be associated with treatment outcome in childhood ALL, although large prospective studies will be needed to confirm this.

Finally, Cunningham et al,87 in an Australian-based study, have reported significant associations between the IL-10 -1082 AA genotype and aggressive nonHodgkin's lymphoma (NHL) (OR = 1.97) and between the -1082, -819, -592 ATA and ACC haplotypes and aggressive lymphoma (OR = 1.65). No association was found between IL-10 genotypes and Hodgkin's disease or less aggressive forms of lymphoma. Results in NHL are in apparent conflict with reports that serum IL-10 level is an important prognostic indicator in this disease, with high levels of viral IL-10 correlating with poor prognosis.28,148 However, the genetic results may be interpreted in several ways. The authors consider that a genetically determined _relative lack_of IL-10 may allow lymphoma to arise or progress under the influence of other pro-lymphoma cytokines, or that in patients with aggressive disease, IL-10 genotypes alone may not be an accurate predictor of of IL-10 production in vivo.

Summary

As a multifunctional cytokine with both immunosuppressive and anti-angiogenic functions, IL-10 has both tumor-promoting and tumor-inhibiting properties. In addition, when considering both serum and peritumoral levels of IL-10 production in individual malignancies, interpretation of apparently raised levels of IL-10 requires caution and should not be considered in isolation from source of production and levels of other biologically relevant cytokines. However, gene transfection studies in a number of malignancies argue more convincingly for an anti-tumor function of IL-10, possibly via inhibition of pathways of angiogenesis.

Much endeavor has been directed towards identification of polymorphisms in the IL-10 gene and a large number of polymorphisms-primarily SNPs-have been identified in the IL-10 gene promoter. Convincing evidence that certain of these polymorphisms-in particular the IL-10 -1082 SNP and associated IL-10 -1082, -819 and -592 haplotype-are associated with differential expression of IL-10 in vitro and in some cases in vivo have been obtained. While a large number of investigations of possible associations between IL-10 genotypes and immune mediated disease have been performed, the literature with regard to IL-10 polymorphisms and cancer is as yet small, but growing. These published studies include both solid tumors and hematological malignancies and common and less common diseases. As yet, most of these studies comprise small, single center case-control investigations, which may be prone to sampling bias and type 1 errors. In addition, in most of the 10 malignancies reviewed in this chapter, only from one to a maximum of three studies have been performed in each disease, in a range of human populations and ethnic groups. Despite this, it is perhaps striking that in 12 of the 15 studies reviewed in this chapter, positive associations between IL-10 genotype or haplotype and disease susceptibility and/or progression were detected-albeit with relatively modest Odds Ratios and probabilities. In some of these cancers (for example, cutaneous malignant melanoma, prostate cancer, breast cancer, non cardia gastric cancer and nonHodgkin's lymphoma) genotypes associated with low IL-10 expression were a risk factor for disease or disease progression, while in others (for example, cervical cancer and cardia gastric cancer, post-transplant squamous cell carcinoma of the skin and multiple myeloma), genotypes associated with high IL-10 expression were a risk factor.

At this stage, all of the above findings should be regarded as highly preliminary, due to the small sample sizes of almost all of the studies and the limited numbers of IL-10 polymorphisms examined. In addition, few of the studies have examined levels of IL-10 production in vivo in the subjects genotyped. However, the preliminary data obtained thus far indicate that much larger studies are required in a number of common and relatively common cancers, in order to confirm initial results, extend studies to include more detailed genotype/haplotype analysis and to combine genotype and gene expression studies in the same subjects. In this way, our understanding of the biological role of IL-10 in tumor development will be greatly aided, with implications for cytokine therapy in cancer.

References

1.
Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse helper T cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989;170:2081–2095. [PMC free article: PMC2189521] [PubMed: 2531194]
2.
Malefyt de Waal R, Haanen J, Spits H. et al. IL-10 and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes by downregulation of class II MHC expression. J Exp Med. 1991;174:915–924. [PMC free article: PMC2118975] [PubMed: 1655948]
3.
Fiorentino DF, Zlotnik A, Viera P. et al. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J Immunol. 1991;146:3444–3451. [PubMed: 1827484]
4.
Ding L, Shevach EM. IL-10 inhibits mitogen-induced T cell proliferation by selectively inhibiting macrophage costimulatory function. J Immunol. 1992;148:3133–3139. [PubMed: 1578140]
5.
Hsu D-H, Moore KW, Spits H. Differential effects of Interleukin-4 and -10 on Interleukin-2-induced interferon-γ synthesis and lymphokine-activated killer activity. Int Immunol. 1992;4:563–569. [PubMed: 1627494]
6.
Malefyt de Waal R, Abrams J, Bennett B. et al. IL-10 inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991;174:1209–1220. [PMC free article: PMC2119001] [PubMed: 1940799]
7.
Fiorentino DF, Zlotnik A, Mossman TR. et al. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991;147:3815–3822. [PubMed: 1940369]
8.
Ding L, Linsley PS, Huang L-Y. et al. IL-10 inhibits macrophage costimulatory activity by selectively inhibiting the up-regulation of B7 expression. J Immunol. 1993;151:1224–1234. [PubMed: 7687627]
9.
Gazzinelli RT, Oswald IP, James SL. et al. IL-10 inhibits parasite killing and nitric oxide production by IFN-γ-activated macrophages. J Immunol. 1992;148:1792–1796. [PubMed: 1541819]
10.
Oswald IP, Gazzinelli RT, Sher A. et al. IL-10 synergises with IL-4 and TGF-beta to inhibit macrophage cytotoxic activity. J Immunol. 1992;148:3578–3582. [PubMed: 1588047]
11.
Ralph P, Nakoinz I, Sampson-Johannes A. et al. IL-10, T lymphocyte inhibitor of human blood cell production of IL-1 and tumor necrosis factor. J Immunol. 1992;148:808–814. [PubMed: 1730874]
12.
Moore KW, Malefyt de Waal R, Coffman RL. et al. Interleukin-10 and the Interleukin-10 receptor. Ann Rev Immunol. 2001;19:683–765. [PubMed: 11244051]
13.
Ding YZ, Fu S, Zamarin D. et al. Interleukin-10. In: Thomson AW, Lotze MT, eds. The Cytokine Handbook. 4th ed. London: Academic Press. 2003:603–625.
14.
Zheng LM, Ojcius DM, Garaud F. et al. Interleukin-10 inhibits tumor metastasis through an NK cell-dependent mechanism. J Exp Med. 1996;184:579–584. [PMC free article: PMC2192723] [PubMed: 8760811]
15.
Kundu N, Beaty TL, Jackson MJ. et al. Antimetastatic and antitumor activities of IL-10 in a murine model of breast cancer. J Natl Cancer Inst. 1996;88:536–541. [PubMed: 8606382]
16.
Dummer W, Becker JC, Schwaaf A. et al. Elevated serum levels of Interleukin-10 in patients with metastatic malignant melanoma. Melanoma Res. 1995;5:67–68. [PubMed: 7734958]
17.
Huang S, Ullrich SE, Bar-Eli M. Regulation of tumor growth and metastasis by Interleukin-10: The melanoma experience. J Interferon Cytokine Res. 1999;19:697–703. [PubMed: 10454339]
18.
Kruger-Krasagakes S, Krasagakis K, Garbe C. et al. Expression of Interleukin-10 in human melanoma. Br J Cancer. 1994;70:1182–1185. [PMC free article: PMC2033698] [PubMed: 7981073]
19.
Sato T, McCue P, Masuoka K. et al. Interleukin-10 production by human melanoma. Clin Cancer Res. 1996;2:1383–1390. [PubMed: 9816311]
20.
Gotlieb WH, Abrams JS, Watson JM. et al. Presence of Interleukin-10 (IL-10) in the ascites of patients with ovarian and other intra-abdominal cancers. Cytokine. 1992;4:385–390. [PubMed: 1421000]
21.
Fortis C, Foppoli M, Gianotti L. et al. Increased Interleukin-10 serum levels in patients with solid tumors. Cancer Lett. 1996;104:1–5. [PubMed: 8640735]
22.
De VitaF, Orditura M, Galizia G. et al. Serum Interleukin-10 levels as a prognostic factor in advanced nonsmall cell lung cancer patients. Chest. 2000;117:365–373. [PubMed: 10669676]
23.
Fujieda S, Sunaga H, Tsuzuki H. et al. IL-10 expression is associated with the expression of platelet-derived endothelial cell growth factor and prognosis in oral and oropharyngeal carcinoma. Cancer Lett. 1999;136:1–9. [PubMed: 10211932]
24.
Wittke F, Hoffmann R, Buer J. et al. Interleukin-10 (IL-10): An immunosuppressive factor and independent predictor in patients with metastatic renal cell carcinoma. Br J Cancer. 1999;79:1182–1184. [PMC free article: PMC2362244] [PubMed: 10098756]
25.
Khatri VP, Caligiuri MA. A review of the association between Interleukin-10 and human B-cell malignancies. Cancer Immunol Immunother. 1998;46:239–244. [PubMed: 9690451]
26.
Klein B, Lu ZY, Gu ZJ. et al. Interleukin-10 and Gp130 cytokines in human multiple myeloma. Leuk Lymphoma. 1999;34:63–70. [PubMed: 10350333]
27.
De VitaF, Orditura M, Galizia G. et al. Serum Interleukin-10 levels in patients with advanced gastrointestinal malignancies. Cancer. 1999;86:1936–1943. [PubMed: 10570416]
28.
Blay JY, Burdin N, Rousset F. et al. Serum Interleukin-10 in non-Hodgkin's lymphoma: A prognostic factor. Blood. 1993;82:2169–2174. [PubMed: 8400266]
29.
Bohlen H, Kessler M, Sextro M. et al. Poor clinical outcome of patients with Hodgkin's disease and elevated Interleukin-10 serum levels. Clinical significance of Interleukin-10 serum levels for Hodgkin's disease. Ann Hematol. 2000;79:110–113. [PubMed: 10803931]
30.
Yue FY, Dummer R, Geertsen R. et al. Interleukin-10 is a growth factor for human melanoma cells and down-regulates HLA class-I, HLA class-II and ICAM-1 molecules. Int J Cancer. 1997;71:630–637. [PubMed: 9178819]
31.
Cortes JE, Talpaz M, Cabanillas F. et al. Serum levels of Interleukin-10 in patients with diffuse large cell lymphoma: Lack of correlation with prognosis. Blood. 1995;85:2516–2520. [PubMed: 7537119]
32.
Sjoberg J, Aguilar-Santelises M, Sjogren AM. et al. Interleukin-10 mRNA expression in B-cell chronic lymphocytic leukaemia inversely correlates with progression of disease. Br J Haematol. 1996;92:393–400. [PubMed: 8603006]
33.
Adris S, Klein S, Jasnis M. et al. IL-10 expression by CT26 colon carcinoma cells inhibits their malignant phenotype and induces a T cell-mediated tumor rejection in the context of a systemic Th2 response. Gene Ther. 1999;6:1705–1712. [PubMed: 10516719]
34.
Giovarelli M, Musiani P, Modesti A. et al. Local release of IL-10 by transfected mouse mammary adenocarcinoma cells does not suppress but enhances antitumor reaction and elicits a strong cytotoxic lymphocyte and antibody-dependent immune memory. J Immunol. 1995;155:3112–3123. [PubMed: 7673726]
35.
Richter G, Kruger-Krasagakes S, Hein G. et al. Interleukin-10 transfected into Chinese hamster ovary cells prevents tumor growth and macrophage infiltration. Cancer Res. 1993;53:4134–4137. [PubMed: 8364905]
36.
Gerard CM, Bruyns C, Delvaux A. et al. Loss of tumorigenicity and increased immunogenicity induced by interleukin-10 gene transfer in B16 melanoma cells. Hum Gene Ther. 1996;7:23–31. [PubMed: 8825865]
37.
Cervenak L, Morbidelli L, Donati D. et al. Abolished angiogenicity and tumorigenicity of Burkitt lymphoma by Interleukin-10. Blood. 2000;96:2568–1273. [PubMed: 11001913]
38.
Mucke S, Draube A, Polack A. et al. Suppression of the tumorigenic growth of Burkitt's lymphoma cells in immunodeficient mice by cytokine gene transfer using EBV-derived episomal expression vectors. Int J Cancer. 2000;86:s301–306. [PubMed: 10760815]
39.
Stearns ME, Wang M. Antimetastatic and antitumor activities of Interleukin 10 in transfected human prostate PC-3 ML clones: Orthotopic growth in severe combined immunodeficiency mice. Clin Cancer Res. 1998;4:2257–2263. [PubMed: 9748147]
40.
Berman RM, Suzuki T, Tahara H. et al. Systemic administration of cellular IL-10 induces an effective, specific, and long-lived immune response against established tumors in mice. J Immunol. 1996;157:231–238. [PubMed: 8683120]
41.
Di CarloE, Coletti A, Modesti A. et al. Local release on Interleukin-10 by transfected mouse adenocarcinoma cells exhibit pro- and anti-inflammatory activity and results in a delayed tumor rejection. Eur Cytokine Netw. 1998;9:61–68. [PubMed: 9613679]
42.
Kundu D, Dorsey R, Jackson MJ. et al. Interleukin-10 gene transfer inhibits murine mammary tumors and elevates nitric oxide. Int J Cancer. 1998;76:713–719. [PubMed: 9610731]
43.
Petersson M, Charo J, Salazar-Onfray F. et al. Constitutive IL-10 production accounts for the high NK sensitivity, low MHC class I expression and poor transporter associated with antigen processing (TAP)-1/2 function in the prototype NK target YAK-1. J Immunol. 1998;161:2099–2105. [PubMed: 9725200]
44.
Salazar-Onfray F, Petersson M, Franksson L. et al. IL-10 converts mouse lymphoma cells to a CTL-resistant, NK-sensitive phenotype with low but peptide-inducible MHC class I expression. J Immunol. 1995;154:6291–6298. [PubMed: 7759867]
45.
Stearns ME, Fudge K, Garcia F. et al. IL-10 inhibition of human prostate PC-3 ML cell metastases in SCID mice: IL-10 stimulation of TIMP-1 and inhibition of MMP-2/MMP-9 expression. Invasion Metastasis. 1997;17:62–74. [PubMed: 9561025]
46.
Stearns ME, Rhim J, Wang M. Interleukin 10 (IL-10) inhibition of primary human prostate cell-induced angiogenesis: IL-10 stimulation of tissue inhibitor of metalloproteinase-1 and inhibition of matrix metalloproteinase (MMP)2/MMP-9 secretion. Clin Cancer Res. 1999;5:189–196. [PubMed: 9918218]
47.
Kaufman HL, Rao JB, Irvine KR. Interleukin-10 enhances the therapeutic effectiveness of a recombinant poxvirus-based vaccine in an experimental murine tumor model. J Immunother. 1999;22:489–496. [PMC free article: PMC2562555] [PubMed: 10570747]
48.
Bidwell J, Keen L, Gallagher G. et al. Cytokine gene polymorphism in human disease: On-line databases. Genes and Immun. 1999;1:3–19. [PubMed: 11197303]
49.
Haukim N, Bidwell JL, Smith AJP. et al. Cytokine gene polymorphism in human disease: On-line databases, Supplement 2. Genes and Immun. 2002;3:313–330. [PubMed: 12209358]
50.
Eskdale J, Kube D, Tesch H. et al. Mapping of the human IL-10 gene and further characterisation of the 5' flanking sequence. Immunogenetics. 1997;46:120–128. [PubMed: 9162098]
51.
Kube D, Rieth H, Eskdale J. et al. Structural characterisation of the distal 5' flanking region of the human Interleukin-10 gene. Genes and Immun. 2001;2:181–190. [PubMed: 11477472]
52.
Gibson AW, Edberg JC, Wu J. et al. Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus. J Immunol. 2001;166:3915–3922. [PubMed: 11238636]
53.
D'Alfonso S, Rampi M, Rolando V. et al. New polymorphisms in the IL-10 promoter region. Genes and Immun. 2000;1:231–233. [PubMed: 11196718]
54.
Tountas NA, Cominelli F. Identification and initial characterisation of two polymorphisms in the human Interleukin-10 promoter. Eur Cytokine Netw. 1996;7:578.
55.
Turner DM, Williams DM, Sankaran D. et al. An investigation of polymorphism in the Interleukin-10 gene promoter. Eur J Immunogenetics. 1997;24:18. [PubMed: 9043871]
56.
Eskdale J, Kube D, Gallagher G. A second dinucleotide polymorphic repeat in the 5' flanking region of the human IL10 gene. Immunogenetics. 1996;45:82–83. [PubMed: 8881045]
57.
Eskdale J, Gallagher G. A polymorphic dinucleotide repeat in the human IL-10 promoter. Immunogenetics. 1995;52:444–445. [PubMed: 7590988]
58.
Donger C, Georges J-L, Nicaud V. et al. New polymorphisms in the Interleukin-10 gene - relationships to myocardial infarction. Eur J Clin Invest. 2001;31:9–14. [PubMed: 11168433]
59.
Lazarus R, Klimecki WT, Palmer LJ. et al. Single nucleotide polymorphisms in the Interleukin-10 gene: Differences in frequencies, linkage disequilibrium patterns and haplotypes in three United States ethnic groups. Genomics. 2002;80:223–228. [PubMed: 12160736]
60.
Reuss E, Fimmers R, Kruger A. et al. Differential regulation of Interleukin-10 production by genetic and environmental factors: A twin study Genes and Immun. 2002. 3:407–413. [PubMed: 12424622]
61.
Eskdale J, Gallagher G, Verweij CL. et al. Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc Natl Acad Sci USA. 1998;95:9465–9470. [PMC free article: PMC21361] [PubMed: 9689103]
62.
Westendorp RG, Langermans JA, Huizinga TW. et al. Genetic influence on cytokone production and fatal meningococcal disease. Lancet. 1997;349:170–173. [PubMed: 9111542]
63.
Borish L, Aarons A, Rumbyrt J. et al. Interleukin-10 regulation in normal subjects and patients with asthma. J Allergy Clin Immunol. 1996;97:1288–1296. [PubMed: 8648025]
64.
Lim S, Crawley E, Woo P. et al. Haplotype associated with low Interleukin 10 production in patients with severe asthma. Lancet. 1998;352:113. [PubMed: 9672280]
65.
Kaluza W, Leirisalo-Repo M, Marker-Hermann E. et al. IL-10.G microsatellites mark promoter Haplotypes associated with protection against the development of reactive arthritis in Finnish patients. Arthritis Rheum. 2001;44:1209–1214. [PubMed: 11352256]
66.
Poole KL, Gibbs PJ, Evans PR. et al. Influence of patient and donor cytokine genotypes on renal allograft rejection: Evidence from a single centre study. Transplant Immunol. 2001;8:259–265. [PubMed: 11316069]
67.
Pelletier R, Pravica V, Perrey C. et al. Evidence for a genetic predisposition towards acute rejection after kidney and simultaneous kidney-pancreas transplantation. Transplantation. 2000;70:674–680. [PubMed: 10972228]
68.
Awad MR, Webber S, Boyle G. et al. The effect of cytokine gene polymorphisms on pediatric heart allograft outcome. J Heart Lung Transplant. 2001;20:625–630. [PubMed: 11404167]
69.
Middleton PG, Taylor PR, Jackson G. et al. Cytokine gene polymorphisms associating with severe acute graft-versus-host disease in HLA-identical siblings. Blood. 1998;92:3943–3948. [PubMed: 9808588]
70.
He B, Xu C, Yang B. et al. Linkage and association analysis of genes encoding cytokines and myelin proteins in multiple sclerosis. J Neuroimmunol. 1998;86:13–19. [PubMed: 9655468]
71.
Maurer M, Kruse N, Giess R. et al. Genetic variation at position -1082 of the Interleukin 10 (IL10) promotor and the outcome of multiple sclerosis. J Neuroimmunol. 2000;104:98–100. [PubMed: 10683520]
72.
Eskdale J, McNicholl J, Wordsworth P. et al. Interleukin-10 microsatellite polymorphisms and IL-10 locus alleles in rheumatoid arthritis susceptibility. Lancet. 1998;352:1282–1283. [PubMed: 9788463]
73.
Coakley G, Mok CC, Hajeer AH. et al. Interleukin-10 promoter polymorphisms in rheumatoid arthritis and Felty's syndrome. Br J Rheumatol. 1998;37:988–991. [PubMed: 9783765]
74.
Howell WM, Turner SJ, Bateman AC. et al. IL-10 promoter polymorphisms influence tumor development in cutaneous malignant melanoma. Genes and Immun. 2001;2:25–31. [PubMed: 11294564]
75.
Martinez-Escribano JA, Moya-Quiles MR, Muro M. et al. Interleukin-10, Interleukin-6 and interferon-γ gene polymorphisms in melanoma patients. Melanoma Res. 2002;12:465–469. [PubMed: 12394188]
76.
McCarron SL, Edwards S, Evans PR. et al. Influence of cytokine gene polymorphisms on the development of prostate cancer. Cancer Res. 2002;62:3369–3372. [PubMed: 12067976]
77.
Howell WM, Smith KC, Fussell HM. et al. Influence of cytokine gene polymorphisms on susceptibility to and prognosis in breast cancer. Genes Immun. 2003;4(Suppl 1):S35–10.
78.
Giordani L, Bruzzi P, Lasalandra C. et al. Association of breast cancer and polymorphisms of interleukin-10 and tumor necrosis factor-alpha genes. Clin chem. 2003;49:1664–1667. [PubMed: 14500594]
79.
Stanczuk GA, Sibanda EN, Perrey C. et al. Cancer of the uterine cervix may be significantly associated with a gene polymorphism coding for increased IL-10 production. Int J Cancer. 2001;94:792–794. [PubMed: 11745479]
80.
Roh JW, Kim MH, Seo SS. et al. Interleukin-10 promoter polymorphisms and cervical cancer risk in Korean women. Cancer Lett. 2002;184:57–63. [PubMed: 12104048]
81.
Wu M-S, Wu C-Y, Chen C-J. et al. Interleukin-10 genotypes associate with the risk of gastric carcinoma in Taiwanese Chinese. Int J Cancer. 2003;104:617–623. [PubMed: 12594817]
82.
Wu M-S, Huang S-P, Chang Y-T. et al. Tumor necrosis factor-α and Interleukin-10 promoter polymorphisms in Epstein-Barr virus-associated gastric carcinoma. J Infect Dis. 2002;185:106–109. [PubMed: 11756988]
83.
El-Omar EM, Rabkin CS, Gammon MD. et al. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology. 2003;124:1193–1201. [PubMed: 12730860]
84.
Alamartine E, Berthoux E, Mariat C. et al. Interleukin-10 promoter polymorphisms and susceptibility to skin squamous cell carcinoma after renal transplantation. J Invest Dermatol. 2003;120:99–103. [PubMed: 12535204]
85.
Zheng C, Huang D, Liu L. et al. Interleukin-10 gene promoter polymorphisms in multiple myeloma. Int J Cancer. 2001;95:184–188. [PubMed: 11307152]
86.
Gowans D, O'Sullivan A, Rollison S. et al. Allele and Haplotype frequency at human leucocyte antigen class I/II and immunomodulatory cytokine loci in patients with myelodysplasia and acute myeloid leukaemia: In search of an autoimmune aetiology. Br J Haematol. 2002;117:541–545. [PubMed: 12028020]
87.
Cunningham LM, Chapman C, Dunstan R. et al. Polymorphisms in the Interleukin 10 gene promoter are associated with susceptibility to aggressive non-Hodgkin's lymphoma. Leukemia & Lymphoma. 2003;44:251–255. [PubMed: 12688341]
88.
Lauten M, Matthias T, Stanulla M. et al. Association of initial response to prednisone treatment in childhood acute leukaemia and polymorphism within the tumor necrosis factor and the Interleukin-10 gene. Leukemia. 2002;16:1437–1442. [PubMed: 12145682]
89.
Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other diseases. Nat Med. 1995;1:27–31. [PubMed: 7584949]
90.
Srivastava A, Laidler P, Hughes LE. et al. Neovascularisation in human cutaneous melanoma: A quantitative morphological and Doppler ultrasound study. Eur J Cancer Clin Oncol. 1986;22:1205–1209. [PubMed: 2434333]
91.
Srivastava A, Laidler P, Davies R. et al. The prognostic significance of tumor vascularity in intermediate-thickness (0.76-4.0 mm thick) skin melanoma. Am J Pathol. 1988;133:419–423. [PMC free article: PMC1880778] [PubMed: 3189515]
92.
Herlyn M, Clark WH, Rodeck U. et al. Biology of tumor progression in human melanocytes. Lab Invest. 1987;56:461–474. [PubMed: 3553733]
93.
Weidner N, Carroll PR, Flax J. et al. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol. 1993;143:401–409. [PMC free article: PMC1887042] [PubMed: 7688183]
94.
Weidner N, Semple JP, Welch WR. et al. Tumor angiogenesis and metastasis - correlation in invasive breast carcinoma. N Engl J Med. 1991;324:1–8. [PubMed: 1701519]
95.
Bosari S, Lee AKC, DeLellis RA. et al. Microvessel quantitation and prognosis in invasive breast cancer. Hum Pathol. 1992;23:755–761. [PubMed: 1377162]
96.
Horak E, Leek R, Klenk N. et al. Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer. Lancet. 1992;340:1120–1124. [PubMed: 1279332]
97.
Cress RD, Holly EA. Incidence of cutaneous melanoma among nonHispanic whites, Hispanics, Asians and blacks: An analysis of California cancer registry data, 1988-93. Cancer Causes Control. 1997;8:246–252. [PubMed: 9134249]
98.
Valverde P, Healy E, Sikkink S. et al. The Asp84Glu variant of the melanocortin-1 receptor is associated with melanoma. Hum Mol Genet. 1996;5:1663–1666. [PubMed: 8894704]
99.
Kennedy C, ter HuurneJ, Berkhout J. et al. Melanocortin 1 receptor (MCR1) gene variants are associated with an increased risk for cutaneous melanoma which is largely independent of skin type and hair color. J Invest Dermatol. 2001;117:294–300. [PubMed: 11511307]
100.
Kumar R, Smeds J, Berggren P. et al. A single nucleotide polymorphism in the 3' untranslated region of the CDKN2A gene is common in sporadic primary melanomas, but mutations in the CDK2NB, CDK2NC, CDK4 and P53 genes are rare. Int J Cancer. 2001;95:388–393. [PubMed: 11668523]
101.
Winsey SL, Haldar NA, Marsh HP. et al. A variant within the DNA repair gene XRCC3 is associated with the development of melanoma skin cancer. Cancer Res. 2000;60:5612–5616. [PubMed: 11059748]
102.
Lafuente A, Molina R, Palou J. et al. Phenotype of glutathione S-transferase Mu (GSTM1) and susceptibility to malignant melanoma. Br J Cancer. 1995;72:324–326. [PMC free article: PMC2033998] [PubMed: 7640212]
103.
Hutchinson PE, Osborne JE, Lear JT. et al. Vitamin D receptor polymorphisms are associated with altered prognosis in patients with malignant melanoma. Clin Cancer Res. 2000;6:498–504. [PubMed: 10690530]
104.
Strange RC, Ellison T, Ichii-Jones F. et al. Cytochrome P450 CYP2D6 genotypes: Association with hair colour, Breslow thickness and melanocyte stimulating hormone receptor alleles in patients with malignant melanoma. Pharmacogenetics. 1999;9:269–276. [PubMed: 10471058]
105.
Wolfel T, Hauer M, Klehmann E. et al. Analysis of antigens recognised on human melanoma cells by A2-restricted cytolytic T lymphocytes (CTL) Int J Cancer. 1993;55:237–244. [PubMed: 7690346]
106.
Lee JE, Reveille JD, Ross MI. et al. HLA-DQB1*0301 association with increased cutaneous melanoma risk. Int J Cancer. 1994;59:510–513. [PubMed: 7960221]
107.
Bateman AC, Turner SJ, Theaker JM. et al. HLA-DQB1*0303 and *0301 alleles influence susceptibility to and prognosis in cutaneous malignant melanoma in the British caucasian population. Tissue Antigens. 1998;52:67–73. [PubMed: 9714476]
108.
Mackie R, Hunter JA, Aitchison TC. et al. Cutaneous malignant melanoma, Scotland, 1979-1983. The Scottish Melanoma Group. Lancet. 1992;339:971–975.
109.
Howell WM, Bateman AC, Turner SJ. et al. Influence of vascular endothelial growth factor single nucleotide polymorphisms on tumor development in cutaneous malignant melanoma. Genes and Immun. 2002;3:229–232. [PubMed: 12058259]
110.
Hegarty NJ, Fitzpatrick JM, Richie JP. et al. Future prospects in prostate cancer. The Prostate. 1999;40:261–268. [PubMed: 10420155]
111.
Saingh R, Eeles RA, Durocher F. et al. High risk genes predisposing to prostate cancer development - do they exist? Prostate Cancer Prostatic Dis. 2000;3:241–247. [PubMed: 12497071]
112.
Smith JR, Freije D, Carpten JD. et al. Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science. 1996;274:1371–1374. [PubMed: 8910276]
113.
Xu J, Meyers D, Freije D. et al. Evidence for a prostate cancer susceptibility locus on the X chromosome. Nat Genet. 1998;20:175–179. [PubMed: 9771711]
114.
Ford D, Easton DF, Bishop DT. et al. Risk of cancer in BRCA1 mutation carriers. Lancet. 1994;343:692–695. [PubMed: 7907678]
115.
Gibbs M, Stanford JL, McIndoe RA. et al. Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36. Am J Hum Genet. 1999;64:776–787. [PMC free article: PMC1377795] [PubMed: 10053012]
116.
Berthon P, Valeri A, Cohen-Akenine A. et al. Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2-43. Am J Hum Genet. 1998;62:1416–1424. [PMC free article: PMC1377158] [PubMed: 9585607]
117.
Tavtigian SV, Simard J, Teng DH. et al. A strong candidate prostate cancer susceptibility gene at chromosome 17p. Nat Genet. 2001;27:172–180. [PubMed: 11175785]
118.
Hrouda D, Perry M, Dalgleish AG. Gene therapy for prostate cancer. Semin Oncol. 1999;26:455–471. [PubMed: 10482188]
119.
Miki Y, Swensen J, Shattuck-Eidens D. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266:66–71. [PubMed: 7545954]
120.
Wooster R, Bignell G, Lancaster J. et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995;378:789–792. [PubMed: 8524414]
121.
Blackwood MA, Weber BL. BRCA1 and BRCA2: From molecular genetics to clinical medicine. J Clin Oncol. 1998;16:1969–1977. [PubMed: 9586917]
122.
Nathanson K, Weber BL. “Other” breast cancer susceptibility genes: Searching for more holy grail. Hum Mol Genet. 2001;10:715–720. [PubMed: 11257104]
123.
Wooster R, Weber BL. Breast and ovarian cancer. New Eng J Med. 2003;348:2339–2347. [PubMed: 12788999]
124.
Pharoah PD, Antoniou A, Bobrow M. et al. Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet. 2002;31:33–36. [PubMed: 11984562]
125.
Charrier J, Maugard CM, LeMevel B. et al. Allelotype influence at glutathione S-transferase M1 locus on breast cancer susceptibility. Br J Cancer. 1999;79:346–353. [PMC free article: PMC2362188] [PubMed: 9888479]
126.
Bergman-Jungestrom M, Gentile M, Lundin A, Wingren S. The South East Breast Cancer Group. et al. Association between CYP17 gene polymorphism and risk of breast cancer in young women. Int J Cancer. 1999;84:350–353. [PubMed: 10404084]
127.
Dunning AM, Healey CS, Pharaoh PDP. et al. A systematic review of genetic polymorphisms and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 1999;8:843–854. [PubMed: 10548311]
128.
Venetsanakos E, Beckman I, Bradley J. et al. High incidence of Interleukin-10 mRNA but not Interleukin-2 mRNA detected in human tumors. Br J Cancer. 1997;75:1826–1830. [PMC free article: PMC2223600] [PubMed: 9192989]
129.
Wank R, Thomssen C. High risk of squamous cell carcinoma of the cervix for women with HLA-DQw3. Nature. 1991;352:723–725. [PubMed: 1876187]
130.
Mehal WZ, Lo Y-MD, Herrington CS. et al. Role of human papillomavirus in determining the HLA associated risk of cervical carcinogenesis. J Clin Pathol. 1994;47:1077–1081. [PMC free article: PMC502196] [PubMed: 7876378]
131.
Apple RJ, Erlich HA, Klitz W. et al. HLA DR-DQ associations with cervical carcinoma show papillomavirus-type specificity. Nat Genet. 1994;6:157–163. [PubMed: 8162070]
132.
Nawa A, Nishiyama Y, Kobayashi T. et al. Association of human leukocyte antigen-B1*03 with cervical cancer in Japanese women aged 35 years and younger. Cancer. 1995;75:518–521. [PubMed: 7812922]
133.
Jacobs N, Giannini SL, Doyen A. et al. Inverse modulation of IL-10 and IL-12 in the blood of women with preneoplastic lesions of the uterine cervix. Clin Exp Immunol. 1998;111:219–224. [PMC free article: PMC1904851] [PubMed: 9472685]
134.
Giannini SL, Al-Saleh H, Piron N. et al. Cytokine expression in squamous intraepithelial lesions of the uterine cervix: Implications for the generation of local immunosuppression. Clin Exp Immunol. 1998;113:183–189. [PMC free article: PMC1905041] [PubMed: 9717966]
135.
De GruijlTD, Bontkes HJ, van den Muysenberg AJC. et al. Differences in cytokine mRNA profiles between premalignant and malignant lesions of the uterine cervix. Eur J Cancer. 1999;35:490–497. [PubMed: 10448305]
136.
Van TrappenPO, Ryan A, Carroll M. et al. A model for coexpression pattern analysis of genes implicated in angiogenesis and tumor cell invasion in cervical cancer. Br J Cancer. 2002;87:537–544. [PMC free article: PMC2376148] [PubMed: 12189553]
137.
Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of 25 major cancers in 1990. Int J Cancer. 1999;80:827–841. [PubMed: 10074914]
138.
El-Omar EM, Carrington M, Chow WH. et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000;404:398–402. [PubMed: 10746728]
139.
Furuta T, El-Omar EM, Xiao F. et al. Interleukin 1β polymorphisms increase risk of hypochlorhydria and atrophic gastritis and reduce risk of duodenal ulcer recurrence in Japan. Gastroenterology. 2002;123:92–105. [PubMed: 12105837]
140.
Yu HG, Li JY, Yang YN. Increased abundance of cyclooxygenase-2 correlates with vascular endothelial growth factor-A abundance and tumor angiogenesis in gastric cancer. Cancer Lett. 2003;195:43–51. [PubMed: 12767510]
141.
London NJ, Farmery SM, Will EJ. et al. Risk of neoplasia in renal transplant patients. Lancet. 1995;346:403–406. [PubMed: 7623570]
142.
Nishigori C, Yarosh DB, Ullrich SE. et al. Evidence that DNA damage triggers Interleukin-10 cytokine production in UV-irradiated murine keratinocytes. Proc Natl Acad Sci USA. 1996;93:10354–10359. [PMC free article: PMC38388] [PubMed: 8816804]
143.
Emilie D. Production and roles of IL-6, IL-10, and IL-13 in B-lymphocyte, malignancies and in B-lymphocyte hyperactivity of HIV infection and autoimmunity. Methods. 1997;11:133–142. [PubMed: 8990099]
144.
Lu ZY, Gu ZJ, Xhang XG. et al. Interleukin-10 induces Interleukin-11 responsiveness in human myeloma cell lines. FEBS Lett. 1995;377:515–518. [PubMed: 8549788]
145.
Germing U, Gattermann N, Aivado M. et al. Two types of acquired idiopathic sideroblastic anaemia (AISA): A time tested distinction. Br J Haematol. 2000;108:724–728. [PubMed: 10792275]
146.
Jonasova A, Neuwirtova R, Cermak J. et al. Cyclosporin A therapy in hypoplastic MDS patients and certain refractory anaemias without hypoplastic bone marrow. Br J Haematol. 1998;100:304–309. [PubMed: 9488617]
147.
Dordelmann M, Reiter A, Borkhardt A. et al. Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukaemia. Blood. 1999;94:1209–1217. [PubMed: 10438708]
148.
Cortes J, Kurzrock R. Interleukin-10 in non-Hodgkin's lymphoma. Leukemia & Lymphoma. 1997;26:251–259. [PubMed: 9322887]
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