Abstract
Neoplastic growth was often regarded as an autonomous process driven by uncontrolled expansion of malignant cell population. This view is now being transformed as it becomes apparent that basically normal regulatory and metabolic mechanisms comprising subcellular processes as well as homo- and heterotypic cell interactions are extensively used by growing tumours throughout all stages of their development. Therefore the role of normal genetic variation emerges as a major factor determining different aspects of neoplastic growth and eventually outcome of the disease. This review is focused on polymorphisms in the genes encoding products acting at post-initiation stages of tumour development. Its four main sections are devoted to gene polymorphisms affecting: i) growth control at the cellular level (cell proliferation, differentiation and death); ii.) factors involved in tumour invasion and metastasis (immune and inflammatory responses, extracellular matrix remodelling, angiogenesis and cell adhesion); iii) action of hormones and vitamines on growing tumours; iv) outcome of cancer therapy (cancer pharmacogenetics). Although active research in this field has been started only recently, some directions (e.g. cancer pharmacogenetics) already demonstrate impressive achievements. At the same time the reliability of results reported by many groups remains questionable mostly due to insufficient statistical power of the studies and often random choice of polymorphisms. It is evident that large studies based upon combined analysis of groups of genes within relevant regulatory and metabolic pathways have a much higher potential value in terms of unravelling prognostically important individual polymorphism profiles.

Keywords: Gene variants; Neoplasia; Metastasis; Survival; Pharmacogenomics

1. Introduction
Cancer constitutes one of the most important medico-biological problems remaining generally unsolved at the beginning of the new century. Although involvement of numerous genetic factors in the pathogenesis of neoplasia is well proven, understanding of the complex molecular mechanisms underlying neoplastic growth is still disappointingly incomplete. Intense investigation of cancer-related genetic alterations at the somatic cell level has shed some light on the sequence of molecular events leading to malignant transformation of somatic cells and clonal neoplastic growth. It is now believed that most (and probably all) types of cancer share a relatively small number of molecular, biochemical and cellular traits - acquired capabilities [1]. Hanahan and Weinberg suggested the following six alterations relevant for malignancy: self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis [1]. Although this scheme may not be perfect, the highlighting of one crucial common feature of all these alterations is particularly important. Indeed, neoplastic growth should not be regarded as a cell- autonomous process intrinsic to the cancer cell. There is no doubt that cancer development strongly depends upon changes in interactions between malignant cells and their normal neighbours [1]. Furthermore, even at the level of cancer cell, acquired genetic changes affect only a minuscule fraction of its genome. Tumour tissue grows as an abnormal analogue of the tissue of its origin, being influenced and often governed by interplay of multiple basically normal physiologic processes and corresponding regulatory mechanisms. In neoplasia these mechanisms are not necessarily damaged, but deregulated or taken out of their physiological context, so that their otherwise beneficial role can be totally distorted. It is well known that both cancer initiation risk and later neoplastic events (tumour growth, invasion, metastatic spread, response to therapeutic interventions and, finally, survival) are strongly affected by factors predetermined by individual's genetic background. The presence of millions of polymorphic gene variants in the human genome [2,3] provides extensive genetic (and eventually phenotypic) variation affecting both normal physiological mechanisms and cancer pathogenesis.

Tumour development goes through several consecutive stages involving complex sequences of interactions between cancer-specific phenomena (initiating mutagenesis by genotoxic carcinogens, cell transformation followed by expansion of transformed clones and eventially tumour growth, progression, invasion and metastasis) and respective protective and modulating mechanisms (see Fig. 1). It is important to stress that from the moment of cancer initiation target cells (mutant, then transformed, then malignant) are surrounded by their normal counterparts as well as by various perfectly normal cells of different types providing multiple homo- and heterotypic cell interactions. Thus, before invasion occurs, there is a good probability of spontaneous favourable outcome (prevention of initiation, successful DNA repair, elimination of transformed cells, stabilisation of the process at its early stages), however there are very few reliably reported cases of spontaneous regression of advanced invasive tumours [4]. One notable characteristic of the advanced stages of neoplasia is progressing failure of protective mechanisms in resisting tumour growth and spread (Fig. 1g). Consequently, it is obvious that understanding the role of genetic variation affecting these diverse protective/modulating systems is crucial for unravelling presently largely mysterious differences in "tumour behaviour", prognosis and response to therapeutic interventions.

Until recently studies on gene polymorphisms in cancer have been focused mainly on relation to cancer risk modulation due to action of xenobiotic-metabolising enzymes determining interaction of external carcinogens with their DNA targets (Fig. 1a). Polymorphisms in genes encoding Phase I and Phase II enzymes (metabolic polymorphisms) have been extensively reviewed from this point of view [5-9] as well as genes encoding DNA repair enzymes [10-12]. For this reason studies on gene polymorphisms affecting cancer initiation are not considered in this article, which is devoted to later stages of carcinogenesis. At the same time some metabolic and DNA repair-related polymorphisms are going to be discussed in the contest of pharmacogenetics with regard to cancer chemotherapy.

Figure 1 schematically shows several types of protective/controlling mechanisms responding to tumour growth. Although domains of action of these mechanisms often overlap (some hormones can be regarded as growth-controlling factors, angiogenesis and immune responses are closely related to inflammation etc.), this scheme is going to be used throughout the review as a logical framework.

Legend	a. Initiation phase	b. Initiation phase (late)	c. Promotion phase (early)
d. Promotion phase (late)	e. Progression phase (early)	f. Progression phase	g. Progression phase (late)

Figure 1. Stages of tumour development and involved protective and modulating mechanisms affected by common gene polymorphisms. Only those protective/modulating mechanisms, which are believed to be involved at the corresponding stages (phases) of tumour development, are shown.

2. Gene polymorphisms affecting growth control at the cellular level (cell proliferation, differentiation and death)
Uncontrolled cell proliferation is generally accepted as the hallmark of cancer [1,13,14]. Genetic damage, which causes somatic mutations and leads to malignant transformation implying the loss of cell multiplication and death control, is believed to be the main triggering mechanism of neoplasia [13]. Nevertheless, most growth-controlling pathways in cancer cells are (at least initially) largely intact, their complex biomachinery being a subject of physiological diversity depending on the presence of intrinsic polymorphic gene variants. This section of the review considers the existing evidence linking polymorphisms in genes encoding some key factors of these systems with cancer progression and prognosis.

Alterations in genes encoding regulatory proteins of two major interconnected signalling pathways controlled by RB and p53 are reported for many tumours [15], however understanding of the role of individual genetic background as a factor in deregulation of cell proliferation, differentiation and death control is only starting to emerge. Nevertheless, it is obvious that early stages of cancer progression (see Figure 1) almost exclusively depend on these mechanisms. In real clinical conditions tumours are never detected immediately after initiation. Very often the diagnosis is made when malignant progression is well under way, and invasion has already started, therefore it is not surprising that many authors investigating polymorphisms in genes encoding factors of growth-controlling pathways interpret their findings in terms of cancer risk rather than progression modulation. Some of these studies will be mentioned in this review, however later stages of tumour development and prognostic value of relevant gene variants are considered in more detail. Table 1 summarises information regarding the role of polymorphisms in the genes encoding factors involved in the RB and p53 growth control pathways.

Table 1. Gene polymorphisms affecting factors involved in the regulation of cell proliferation, differentiation and death at the cellular level.

Although human retinoblastoma (Rb1) gene has been intensively studied for both germ-line and somatic mutations, little is known of its polymorphic variants. It can be partially explained by the size and complexity of the Rb1 gene [37]. The only report associating one of its polymorphisms with neoplasia suggests a relationship between a 799bp deletion in intron 2 of the Rb1 and glioma development risk [38]. Fortunately, information regarding other genes of the Rb pathway is more abundant. Cyclin D1 and p16^INK4a are known to affect phosphorylation of the retinoblastoma (RB) protein controlling late G1 phase checkpoint of the cell cycle [13]. Cyclin D1 gene polymorphisms have recently been actively investigated. Special attention has been paid to a splicing-affecting SNP (single nucleotide polymorphism) G(870)A resulting in the synthesis of functionally different splice variants of the protein [39]. Initial studies indicated that (870)A/A homozygotes appeared to have an increased risk of cancer of several sites [40,17,25,41]. Likewise, the A-allele was repeatedly shown to be associated with higher tumour grade, increased risk of invasion, shorter survival and poorer prognosis in general (see Table 1). However, there are at least two reports associating the (870)G/G genotype with poorer prognosis for laryngeal and pharyngeal [19] and hepatocellular [21] tumours. Whether these results reflect insufficient size of the two latter studies or yet unknown tissue-specific differences remains to be elucidated. The role of another reported SNP in the 3' UTR of this gene, G(1722)C, is still unclear, however there is one report linking the (1722)C/C homozygocity with poor prognosis for head and neck cancer [25]. Another intriguing polymorphic locus extremely important for growth regulation is CDKN2A, which encodes alternatively spliced p16^INK4a and p14^ARF. These proteins are among key factors in the RB and p53 growth-controlling pathways respectively [15]. Two common SNPs in the 3'-UTR of CDKN2A gene (see Table 1) have been shown to be prognostic for metastatic malignant melanoma [26] and bladder cancer [27]. The (500)G and (540)T variants have been associated with poorer prognosis. The (540)T allele has earlier been shown to be related to higher risk of developing sporadic primary melanoma [42].

Several groups reported that polymorphisms in p21^Cip1 gene, product of which belongs to the family of cyclin-dependent kinase inhibitors, are affecting risk of endometrial [28], oesophageal [43], cervical [44] and oral cavity [45] tumours. Obviously, the role of the gene, product of which is deeply involved in cell proliferation and death control, can be exerted only in post-initiation stages of tumour growth, i.e. during pre-diagnostic promotion and progression. Results of two studies have also demonstrated the association of the codon 31 SNP in p21^Cip1 with endometrial cancer grade [28] and prognostically important progesterone receptor status of breast tumours [29].

Formidable efforts have been applied to the investigation of the central element of apoptosis regulation, the p53 gene [14,15]. In addition to multiple somatic mutations described for this gene, a polymorphism at its codon 72 (Arg/Pro) has attracted considerable attention. It has recently been reported that the Arg72 variant of p53 induces apoptosis markedly better than the Pro72 allele [46]. Indeed, the Pro72 has been shown to be associated with an increased risk of lung cancer in several studies [47-49], however reports regarding tumours of other sites lack consistency. Nevertheless, two communications on the relationship between this polymorphism and cancer prognosis (breast, lung) also indicate that the Pro72 variant could be regarded as prognostically unfavourable (see Table 1). Apoptotic pathway depends on a number of other proteins including CD95 (FAS), which has also been found to be encoded by a polymorphic gene [50]. Recent reports show that SNPs in its promoter region can affect risk of developing lung cancer [51] and acute myeloid leukaemia [52], however possible impact of these polymorphisms at later stages of neoplasia remains to be investigated.

Another growth-regulating factor of special importance is c-myc, which is implicated in various physiological processes. It is known that deregulated expression of c-myc can result in the loss of control upon proliferation (through cyclin D2 and cyslin-dependent kinase 4 or alternatively through CDKN2B and CDKN1A), differentiation (through MYC/MAX/MAD network) and apoptosis (through p14^ARF- p53 or other pathways) [53]. Information on the effects of polymorphisms in the myc family genes in neoplastic growth is limited by studies of a common EcoRI polymorphism in the L-myc gene. Several groups have shown the association of the S-allele of the gene with cancer risk and progression/prognosis [31-34] (see also Table 1).

Most of the genes considered in this section are widely expressed in different types of cells. However, there may be situations of organ-specific mechanisms that may be relevant only for some neoplastic diseases. It has recently been reported that a polymorphism in the P2X7 receptor gene strongly affects survival in chronic lymphocytic leukaemia patients [36]. The receptor is specific for the cells of haematopoietic lineage (lymphocytes, macrophages, dendritic cells) and is believed to be involved in both proliferation control and apoptosis (due to extended ATP stimulation). If confirmed, this finding can serve a spectacular example of organ-specific effects of some gene polymorphisms in neoplasia.

Growth control at the cellular level is a key element of cancer progression, but the understanding of the importance of common polymorphic variants of multiple regulatory genes is only starting to emerge. Analysis of the existing literature allows highlighting a few especially intriguing polymorphisms defining variants of cyclin D1, CDKN2A, p53 genes. It should, however, be admitted that the whole area remains largely obscure and rapid progress can be expected with the availability of the human genome sequence and more complete polymorphism maps.

3. Gene polymorphisms affecting factors involved in tumour invasion/metastasis (immune and inflammatory responses, extracellular matrix remodelling, angiogenesis and cell adhesion)
Cell interactions at the interface between growing tumour and underlying tissues can be regarded as the key mechanism driving tumour invasion. Complexity of this process is determined by the multiplicity of contributing cell types and biological mechanisms, which combine elements of immune response, inflammation-like reactions, extracellular matrix remodelling, angiogenesis (neovascularisation with both blood and lymphatic vessels) and altered cell adhesion [54-57]. One important feature of the "borderline" between tumour and surrounding tissues is the abundance of various biologically active molecules produced by both normal cells of different types and malignant cells. The latter function of cancer cells appears to be an example of the use by abnormal cells of basically normal mechanisms in order to provide further growth advantage to the developing neoplasm. Polymorphic genes encode most of the biologically active factors acting at the tumour/host interface, so normal genetic variation should be regarded as one of the key invasion-modulating mechanisms. Balasubramanian et al., discussing in their recent review [58] the role of gene polymorphisms in tumour angiogenesis, covered a very wide range of contributing factors including some indirectly involved mechanisms. There is no need in reiterating this discussion here, thus this section of the present article is focused mostly on recent findings relevant to tumour progression and prognosis. Results of the key original studies in the field are presented in Table 2.

Table 2. Gene polymorphisms affecting factors involved in immune response, inflammatory response, extracellular matrix remodelling, angiogenesis and cell adhesion.

An array of polymorphic cytokines/chemokines produced by both tumour and free stromal cells (especially macrophages) is largely responsible for the complex phenomena occurring at the tumour/host interface and leading to tumour invasion [55]. Tumour necrosis factor-alpha (TNF-alpha) is a highly multifunctional cytokine involved in immune and inflammatory responses and affecting angiogenesis and tumour growth [95]. Several promoter region SNPs and an intronic polymorphism in the corresponding gene (TNF-alpha) have been analysed in relation to progression and prognosis of malignancies of different sites (Table 2). The (-308)A allele was found to be associated with more serious prognosis in breast cancer [59], non-Hodgkin lymphoma [60,61] and childhood acute lymphoblastic leukaemia [63]. At the same time several studies failed to reveal any effects of TNF-alpha polymorphisms (Table 2). Reports regarding a closely related cytokine, lymphotoxin-alpha (LT-alpha or TNF-beta), indicate that an intron 1 SNP at position (+252) of its gene may be important. The presence of the (+252)A/A homozygocity has been shown to be prognostically favourable in patients with lung cancer [67], stomach cancer [68] and non-Hodgkin's lymphoma [60]. Structural and functional variation in other biologically active factors participating in complex interactions between growing tumour and underlying/surrounding connective tissue is now starting to attract a wide interest, however few available publications generate more questions than firm conclusions. Polymorphisms in several genes encoding interleukins have been suggested as prognostic markers (see Table 2), but most of these reports need confirmation. Nevertheless, "low expression" genotypes defined by promoter region SNPs in the IL-6 and IL-10 genes appear to be credibly associated with either improved (IL-6) or more serious (IL-10) prognosis in several types of tumours (see Table 2).

Relatively little information is available with regard to the genes encoding growth factors. Among them vascular endothelial growth factor (VEGF) presents special interest due to its role in tumour angiogenesis [97-99] and lymphangiogenesis [56]. The VEGF gene is highly polymorphic, and several SNPs located in its promoter [100] and 3'-untranslated region [101] have been shown to influence its transcription. Reports linking these polymorphisms with cancer risk are only starting to appear [62,102,103], and there is only one communication documenting association of one of the promoter region SNPs with growth characteristics of cutaneous malignant melanoma [77]. Nevertheless, further investigation of polymorphisms in this gene looks promising in terms of search for variants affecting tumour angiogenesis. Other factors directly involved in this process also deserve close attention. For instance, a recently described coding region SNP Asp(104)Asn in the gene encoding endostatin (strong angiogenesis inhibitor) appeared to be associated with prostate cancer risk, Asn(104)-bearing individuals being at significantly higher risk [104]. Endothelial nitric oxide synthase (e-NOS or NOS-3) generating nitric oxide possessing many physiological functions relevant for tumour invasion is also known to stimulate angiogenesis [105]. Polymorphisms in the eNOS gene have already been shown to be prognostically important for prostate and ovarian cancer (see Table 2).

Rapid tumour growth, invasion and metastasis are hardly possible without enhanced extracellular matrix degradation and remodelling. These processes depend on the concerted action of multiple enzymes, among which matrix metalloproteinases (MMPs) are believed to play a pivotal role [106]. Although information on the polymorphisms in the genes encoding different members of the MMP family is incomplete, several reports indicate important links. In particular, an insertion/deletion SNP 2G/1G(-1607) in the promoter region of the MMP-1 gene (encoding collagen-degrading MMP-1) has been found to be associated with tumour invasiveness in several studies. Its 2G variant presence correlated with more serious prognosis in ovarian [86], cervical [90], colorectal [88] cancers and malignant melanoma [87]. Variation among other members of this enzyme family is still poorly investigated. There is only one communication linking the 6A/5A(-1612) promoter polymorphism in the MMP-3 gene with metastatic breast cancer development [89], however these results obtained in a small group of patients require confirmation in larger studies.

Plasminogen activation system of extracellular proteolysis provides another pathway mediating extracellular matrix degradation [107,108]. It is well established that high levels of such components of this system as urokinase plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1) correlate with poor prognosis for tumours of many sites [107,108], however surprisingly little is known about prognostic importance of polymorphisms in the respective genes. Our recent study has indicated that the 4G variant of the 4G/5G (-675) insertion/deletion polymorphism in the PAI-1 gene is associated with metastatic colorectal tumours [91], but, again, the size of the study was not sufficient for making firm conclusions.

Alterations in cell adhesion and cell-cell interactions constitute another major pathogenetic mechanism essential for cancer invasion and metastasis. The majority of cell adhesion molecules can be assigned into three main families, the integrins, the immunoglobulin superfamily and the cadherins [57]. Although it is generally accepted that genes encoding these families of factors are highly variable, information on possible involvement of their polymorphisms in both cancer risk and prognosis modulation is scarce. There are only two reports linking integrin gene polymorphisms with cancer risk, the both regarding the integrinbeta3 gene [92,109]. One of these studies has also revealed associations between variants of the integrinalpha2 and integrinbeta3 genes and some prognostic characteristics of breast tumours (Table 2) [92]. Possible links between other polymorphic genes encoding cell adhesion molecules are very poorly investigated with one notable exception. A transcription-modulating promoter region SNP C(-160)A of the E-cadherin gene has been identified a few years ago [110], and several reports on the role of this polymorphism in cancer risk and prognosis have recently been published. Studies of urothelial (mainly urinary bladder) [111,93] and prostate [112] tumours have revealed a cancer-predisposing effect of the (-160)A variant. The (-160)A allele is known to be associated with a reduced transcriptional activity. At the same time investigation of the role of this SNP in gastric cancer development produced controversial results, different groups reporting risk-increasing effects of both the A(-160) [113] and the C(-160) [114,94] alleles, whereas combined analysis of several case-control studies has not revealed any significant association of either allele with stomach cancer risk [115]. In two small studies, where assessments of prognostic validity of the polymorphism have been done, different alleles have been found prognostically unfavourable for urinary bladder and gastric tumours (see Table 2).

Analysis of published articles regarding involvement of polymorphic genes encoding key factors mediating immune reactions, inflammation, angiogenesis, extracellular matrix degradation and cell adhesion/communication has shown obvious lack of reliable information. Relatively convincing results associating certain polymorphic variants with cancer progression and prognosis have been reported for only a handful of genes such as TNFalpha, lymphotoxin alpha, MMP-1 and, probably, e-NOS, however it has to be stressed that studies in this direction have been initiated only a few years ago. Although lack of credible results does not allow making serious conclusions, it appears to be important to notice that most of the pathogenetically important polymorphisms in this highly heterogenous group of genes affect regulatory (especially promoter) sequences. Therefore it can be suggested that gene expression changes rather than structural changes in the relevant protein products are likely to be involved in complex biological machinery driving cancer invasion and metastasis.

4. Gene polymorphisms affecting action of hormones/vitamins on growing tumours
The importance of hormones in cancer pathogenesis and therapy of the disease is especially evident in hormone-dependent tumours (breast, prostate, ovarian, endometrial cancers). Several groups of factors (hormone receptors, enzymes involved in hormone biosynthesis and metabolism) encoded by polymorphic genes have recently been shown to be associated with modulating risk of the development of tumours of these sites [116-118]. Much less is known about the role of these genes in determining tumour progression and prognosis. Almost all available reports regarding involvement of polymorphic gene variants at later stages of hormone-dependent tumour progression are listed in Table 3. It should be stressed that some genes of great interest in this context are only starting to attract scientific attention. For instance, many authors described associations of different polymorphisms throughout highly polymorphic estrogen receptor alpha (ERalpha) gene sequence with the risk of developing breast [143,144], endometrial [145,146], prostate [147] and kidney [148] cancer. Likewise, one recent report describes a synergistic effect of a variant of estrogen receptor beta (ERbeta) gene and sex steroid hormones on breast cancer risk [149]. Functionally important polymorpisms in progesterone receptor (PR) gene have also been implicated in modulating breast [150,151] and endometrial [152] cancer risk. However, possible effects of variants of these genes at later stages of cancer development are still unknown. It appears to be very likely that some of the estrogen and progesteron receptor gene polymorphisms will be identified as prognostically important. This suggestion is partially supported by studies of much better investigated androgen receptor-encoding (AR) gene. Shorter alleles of its exon 1 (GAG)n repeat polymorphism have been found to be associated with more serious prognosis for prostate, breast and ovarian tumours (see Table 3). Moreover, one publication indicates that another AR exon 1 repeat polymorphism may affect survival in breast cancer patients [123]. Several polymorphisms have been identified in the prostate specific antigen gene, which is functionally related to androgen action. It is, however, impossible to make any conclusion on the role of these polymorphic variants in cancer development. Studies of two linked SNPs in the promoter region of the PSA gene produced opposite results for breast [124] and prostate [125] cancer. Among other genes encoding hormone receptors only one lutheinizing hormone receptor (LHR) gene polymorphism was identified as a prognostic factor in breast cancer patients [126].

Table 3. Gene polymorphisms affecting interactions of hormones/vitamins with growing tumours.

Multiple enzymes of several families control sex hormone biosynthesis and metabolism. Most of these enzymes are encoded by polymorphic genes, effects of variants of which on cancer risk have recently been reviewed in detail [116-118,153]. Again, there are few reports linking polymorphisms in these genes (SRD5A2, CYP17, CYP19, COMT) with cancer progression and prognosis (see Table 3), and making safe conclusions is impossible due to scarcity of the existing evidence. Among genes controlling sex hormone biosynthesis and metabolism, SRD5A2 variants, especially its Val(89)Leu polymorphism, are better investigated in relation to progression and prognosis of breast and prostate cancer. The Leu(89) homozygocity has been shown to be associated with more serious prognosis of breast cancer in two studies [129,130]. In contrast, results of the assessment of this SNP in relation to prostate cancer are highly controversial. There are conflicting reports indicating association of the both alleles of Val(89)Leu SRD5A2 polymorphism with poor prognosis in prostate cancer or no effect at all [127,128,131]. Polymorphisms of other genes encoding enzymes of sex hormone metabolism, albeit potentially important, are not sufficiently investigated (see Table 3).

There is a substantial body of evidence linking vitamin D with cancer risk reduction. Vitamin D action is controlled by its polymorphic receptor (VDR), which plays a major role in cancer risk modulation by the vitamin [154]. Among several known vitamin D receptor (VDR) gene polymorphisms, the synonymous codon 352 SNP, better known as TaqI polymorphism, has been tested in relation to tumour progression/prognosis in cancers of different sites. The association of the (352)T/T homozygocity with more aggressive tumours and unfauvorable prognosis is reported for breast [137], prostate [138] and renal [139] cancers. Although promising, these results should be treated with caution until they are confirmed in larger studies. Information regarding a few other VDR gene polymorphisms is limited (see Table 3).

Among other vitamins, folate is extensively investigated as a factor affecting colorectal cancer development. The key enzyme of folate metabolism, methylenetetrahydrofolate reductase (MTHFR), has been shown to be implicated as a risk factor owing to the presence of two SNPs in its gene (MTHFR) [155,156]. However, it appears that the role of this pathway at the later stages of cancer progression is determined by its involvement in the mechanism of action of some chemotherapeutic agents [157], thus folate metabolism-related gene polymorphisms are going to be considered in the next section of this review.

Briefly summarising available information regarding polymorphisms in genes encoding factors of hormone- and vitamin-dependent pathways of tumour growth control, the author has to conclude that, again, only "the tip of the iceberg" appears to be visible. Very few polymorphisms have been repeatedly and reproducibly shown to be prognostically important for some types of tumours. Only AR exon 1 (CAG)n and probably VDR TaqI polymorphisms can be assigned to this category. At the same time there are potentially important polymorphic genes, which are either completely uninvestigated (e.g. female sex hormone receptor genes) or poorly investigated in the contest of cancer progression and prognosis.

5. Gene polymorphisms affecting outcome of cancer therapy (Cancer pharmacogenetics)
The importance of gene variants encoding enzymes of the metabolic pathways interacting with anticancer drugs is now well understood, and a new area of cancer pharmacogenomics is gradually taking shape (see recent reviews [157-160]). The main endpoint of assessing genetic background in cancer patients (mostly those with advanced tumours) undergoing cytotoxic chemotherapy or radiotherapy is to provide information allowing to select therapeutic strategies rendering maximal damage to target tumour cells with minimal side effects and eventually leading to improved survival. For this reason some metabolic pathways and genes discussed here are not directly involved in neoplastic growth, being factors controlling xenobiotic metabolism. Polymorphic genes considered in this section (see Table 4) are mostly related to two major problems in cancer therapy: i) general response to anticancer drugs (toxicity and its modulation; ii) modulation of specific responses (sensitivity/resistance) of tumours to anticancer drugs defining the efficacy of therapeutic procedures.

Table 4. Gene polymorphisms affecting outcome of cancer therapy (Cancer pharmacogenetics).

Several recent reviews in the field describe pharmacogenetic aspects of the main groups of cytostatic agents in detail [157-160], therefore only a few most interesting examples of polymorphic genes affecting cancer therapy are discussed here, whereas information on other relevant genes is listed in Table 4.

Therapeutic agents used for containing neoplastic growth are selected to target specific biological mechanisms, so different metabolic pathways are important for different groups of anticancer drugs. For this reason the presence of some gene variants can be predictive of the efficacy of the use of a certain drug in a certain patient. The existence of alternative chemotherapeutic approaches for similar clinical situations makes it potentially possible to select or "tailor" chemotherapy schemes according to individual genetic background. Although studies in this direction have been started only recently, some tentative conclusions have already been made.

One good example of potential importance of cancer pharmacogenomics is the determination of the role of thiopurine methyltransferase (TPMT) variants in both therapeutic efficacy and non-specific general toxicity of thiopurines widely used in treatment of leukaemias [158,159]. It is now known that several variants of the highly polymorphic TPMT gene encode less stable enzyme molecules that have low specific activity. The presence of these variants (TPMT*2, TPMT*3A, TPMT*3C, TPMT*7) is predictive of reduced enzyme activity, homozygotes and compound heterozygotes being TPMT-deficient [158,159,161-163]. In these individuals (and to some extent in heterozygotes as well) therapy with thiopurines at conventional doses is associated with severe haematopoietic toxicity. It has, however, been shown that thiopurines can be successfully used in TPMT-deficient patients at lower doses [158], thus screening prospective patients for TPMT variant alleles can help in determining treatment schemes and dosages for thiopurine chemotherapy. It is, however, likely that there may be other, yet unknown, genetic determinants of TPMT activity [159], and further research in this direction is required.

Another example of the clinical use of pharmacogenetics comes from studies on the effects of variants of hepatic UDP-glucuronosyltransferase 1A1 (UGT1A1) in treatment of advanced solid tumours with irinotecan. UGT1A1 glucuronidates SN-38, the active metabolite of irinotecan [159], thus impaired activity of the enzyme results in severe toxicity. The UGT1A1 gene has multiple polymorphisms throughout its sequence [200], and two variants have been shown to be associated with UGT1A1 deficiency. It has been demonstrated that carriers of the UGT1A1*28 allele defined by the presence of (TA)₇ instead of the wild-type (TA)₆ repeat sequence in the promoter region of the gene have a considerably reduced rate of SN-38 glucuronidation due to reduced UGT1A1 expression [158]. Likewise, reduced UGT1A1 activity may be caused by the presence of the UGT1A1*27 allele ( Pro(229)Gln due to C(686)A SNP ) [164]. Administration of irinotecan can cause severe neutropaenia and diarrhoea in the patients possessing these "low activity" UGT1A1 alleles, therefore pre-therapy genotyping can prove useful.

Numerous studies have been devoted to investigation of genetic factors affecting chemotherapy based upon the use of 5-fluorouracil (5-FU) and its analogues. The drug is inactivated in the liver by dehydropyrimidine dehydrogenase (DPD), another highly polymorphic enzyme with over 20 known functionally important mutations in its gene (DPYD) [159]. Among these variants, the DPYD*2A allele characterised by a splicing-affecting SNP in intron 14 has attracted attention because of its association with a reduced DPD activity and 5-FU toxicity [166-168]. It is, however, difficult to make a firm conclusion regarding predictive value of genotyping for this SNP since severe toxicity following 5-FU treatment was repeatedly observed in the absence of DPYD variant alleles [166]. Moreover, the presence of the DPYD*2A allele was reported in an individual with a normal DPD activity [201].

Polymorphic genes discussed so far are important primarily due to specific detoxifying action of their products and failure of some "low-activity" variants to protect from toxic effects of chemotherapeutic agents. Most of the mentioned variants exert strong "single-gene" effects, but are relatively uncommon (due to low frequencies some of them can be regarded as functionally important mutations rather than polymorphisms). More common gene variants are less likely to be associated with "single-gene" effects. Rather, they are usually involved in complex metabolic and regulatory pathways, affecting some steps, which are normally compensated through action of other components of these networks. One interesting example of such a system relevant for cancer chemotherapy is folate metabolism [160]. Fluoropyrimidines (5-FU and capecitabine) and methotrexate are components of many chemotherapeutic schemes. These drugs are known to inhibit folate metabolism acting at its different stages [160], thus polymorphisms in the group of genes encoding enzymes of this pathway attracted close attention as possible modulators of the drug action. Table 4 shows that investigations in this direction have mostly been focused on polymorphisms in the genes encoding methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) with some attention paid to methylenetetrahydrofolate dehydrogenase (MTHFD1) and reduced folate carrier (RFC1). Two studies have shown that the MTHFR allele (677)T was associated with an increased toxicity following methotrexate treatment of acute leukaemia [169] and ovarian cancer [170]. Likewise, (677)T/T homozygocity was found to predispose to methotrexate toxicity in patients undergoing bone marrow transplantation [202]. At the same time it has recently been reported that the presence of this allele was associated with higher response rates in patients with metastatic colorectal cancer treated with 5-FU. The latter report needs confirmation due to small study size, but it cannot be excluded that the same gene variant may exert opposite effects with regard to chemotherapeutic agents of different groups.

Another key enzyme of folate metabolism is thymidylate synthase (TS), one of the main targets of fluoropyrimidines inhibiting its activity [203]. The TS gene has an enhancer element in its 5'-untranslated region, and this element contains polymorphic 28-bp repeats. The presence of a triple repeat (TSER*3 allele) causes 2-4-fold increase in gene expression and was shown to be an indicator of poor prognosis in patients treated with fluoropyrimidines (see Table 4). It is important to note that at least one study has demonstrated combined adverse effects of this allele and polymorphic variants of MTHFR and Methylenetetrahydrofolate dehydrogenase (MTHFD1) genes [172]. These observations are perfectly in line with the idea of approaching combinations of key polymorphic genes within metabolic/regulatory pathways instead of analysing single gene variants [156,160]. Folate metabolism system is a good candidate for this comprehensive approach, however development of serious studies of this type remains a challenging target for future research.

Table 4 also includes information regarding some genes encoding enzymes of xenobiotic metabolism, polymorphisms of which are believed to affect cancer initiation as well. There are multiple studies on several members of the glutathione-S-transferase (GST) family in relation to responses to different chemotherapy schemes, but results of these studies are often contradictory, and further research is needed to establish the role of different GST variants in cancer pharmacogenetics. Similarly, only single reports are available on polymorphic genes encoding other xenobiotic-metabolising enzymes (CYP1A1, NQO1, SULT1A1). Among other genes listed in Table 4, multi-drug resistance P-glycoprotein (MDR-1) gene has recently attracted attention following two independent reports providing evidence supporting prognostic significance of its C(3435)T polymorphism [192,193]. Finally, there are several communications demonstrating associations of several polymorphisms in DNA repair genes (XRCC1, ERCC1, hMSH2) with adverse responses and outcome in platinum-based chemotherapy and radiotherapy. XRCC1 and hMSH2 gene polymorphisms have also been shown to affect risk of developing therapy-related secondary acute myeloid leukaemia (t-AML).

Although most of the studies cited in this section were based upon analysis of small groups of patients, the progress in pharmacogenetics (and now pharmacogenomics) of cancer looks impressive. It can be partially explained by availability of much stricter selection criteria for candidate genes, which are determined through careful analysis of metabolic and regulatory pathways affected by certain drugs. Hence, there are good reasons to be optimistic about wider application of pre-therapy genetic screening allowing individualisation of chemotherapy schemes and dosages in the near future.

6. Conclusions
The main point of this review was to stress the importance of common ("normal") gene variants at different stages of neoplasia. Even obviously incomplete landscape provided by presently available literature allows concluding that numerous gene variants frequently found in human populations may influence different stages of the neoplastic growth. These variants act through their products involved in various regulatory systems and metabolic chains at different levels of biological organisation. Proliferation, differentiation and death of transformed and even malignant cells can be affected by pre-existing polymorphisms in genes exerting regulation of these basic processes. Likewise, genetic background emerges as a key factor in setting "rules of the game" for multiple homo- and heterotopic cell interactions defining tumour growth and spread. It looks very likely that combinations of common polymorphic gene variants define complex patterns of inflammation-like reactions, extracellular matrix remodelling and angiogenesis requiring collaboration of non-malignant cells of different types with growing tumours. Finally, it is already proven that polymorphisms in some genes involved in xenobiotic metabolism and DNA repair can dramatically change efficacy, toxic effects and outcome of cancer therapy.

Although the importance of the field is beyond doubt, it should be emphasised that the existing information is still very scarce and fragmentary. Some directions, like cancer pharmacogenetics, are more advanced , whereas other areas remain obscure. One major example of the latter is the problem of the relationship between genetic background and energy balance in cancer. Cachexia remains a lethal complication in many advanced cases of malignant tumours, but its possible genetic determinants remain virtually unknown. Recent progress in defining gene variants involved in energy balance regulation [156] should accelerate investigation of this urgent problem.

Impressive recent progress in decoding the human genome has provided information about hundreds of thousands of potentially important gene polymorphisms. In this situation careful selection of polymorphisms to be analysed in relation to a certain pathogenetic component becomes a critical element defining success of a research approach. For this reason combined investigation of groups of functionally important gene variants within regulatory or metabolic cascades appears to be the most acceptable compromise given usual restrictions imposed by study size, funding etc. in most cases.

Investigation of common gene polymorphisms with regard to cancer progression and prognosis is still going through its initial stages. Its ultimate goal is, however, clear. Although this direction is not going to resolve the problem of cancer per se, the main hope is to reach a much higher level of understanding the forces driving the process of malignant growth. This understanding would allow predicting its future course in each individual case and developing individually adopted means of its elimination or containment.

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