Prostate cancer: from the pathophysiologic implications of some genetic risk factors to translation in personalized cancer treatments

REVIEW

Prostate cancer: from the pathophysiologic implications ofsome genetic risk factors to translation in personalizedcancer treatmentsCR Balistreri1, G Candore1, D Lio1 and G Carruba2

Several pathologies affect human prostate, such as prostate cancer (PC), which is the most common non-skin malignant cancer inWestern male populations. A complex interaction between genetic and environmental factors (i.e. infectious agents, dietarycarcinogens) and hormonal imbalances has been reported to have a fundamental role in PC pathophysiology by evoking chronicinflammation. Thus, chronic inflammation drives prostate carcinogenesis and neoplastic progression. No adequate biomarkers existuntil now to guide PC prognosis and treatment. Accordingly, the research has particularly focused its attention on genetic variantsin genes, codifying molecules of signaling innate immune/inflammatory and steroid metabolism pathways, which are able tomodify the PC genetic susceptibility and clinical disease outcome. Single-nucleotide polymorphisms (SNPs) may operate incombination to create a ‘risk profile’. Combinations of several inflammatory and sex steroid hormone pathway SNPs are found in PCpatients. Thus, their combinations might be used as promising biomarkers in a pre- and post-treatment clinical PC setting. Indeed,their identification may hold promise for the realization of a personalized PC medicine. Many of these aspects are summarized inthis report through the elucidation of literature data and the results of our studies.

Cancer Gene Therapy advance online publication, 10 January 2014; doi:10.1038/cgt.2013.77

Keywords: prostate cancer; sex steroid and inflammatory network; SNPs; risk profile; genetic biomarkers; personalized PC medicine

INTRODUCTIONHost genetic factors may have a critical role in the pathophysiol-ogy of many human cancers.1 An interesting model is prostatecancer (PC). PC is the most frequently diagnosed non-skin canceramong men in economically developed countries and one of theleading causes of cancer-related death.1 Worldwide, over 660 000new cases are diagnosed each year, accounting for 10% of all newcancers in male subjects.2,3 In Europe, PC is the most commoncancer diagnosed in men, followed by lung and colorectal cancers,and the third leading cause of death in men preceded by lung andcolorectal cancers.2–4 Furthermore, its incidence increases rapidlyin European men over 50 years of age.2,3 Thus, it is becoming aserious health risk because of increased incidence in elderlypeople of Western countries. However, its diagnosis and treatmentare still very difficult, as PC can take decades to progress to aclinically manifest disease. Evidence on its clinical featuresproposes PC as a latent and clinical cancer characterized bymultifocal histologic patterns. Primary tumors often containmultiple, independent histologic foci, which are often geneticallydistinct.1 However, PC seems to arise from selective and individualclones during its progression.

The PC phenotypic heterogeneity is potentially relevant forunderstanding the distinction between latent and clinical disease.It is also integral to comprehending the strong correlationbetween PC development/progression and age-related chronicinflammation. In addition, this phenotypic PC feature has alsopaved the way for research into its complex pathophysiology, aswell as into the weight of interactions between genetic factors,

the host life exposure to environmental factors (i.e. infectiousagents and dietary carcinogens) and sex hormonal imbalances inPC onset and progression. This might facilitate the identification ofpotential molecular targets as PC biomarkers for early recognitionof individuals at disease risk and for development of newtherapeutic treatments. On the other hand, currently there is anoverall consensus to consider serum prostate-specific antigen(PSA) as a nonspecific marker to diagnose PC. Over the past twodecades, PSA has been considered a valuable tool for PCsurveillance. However, the age-adjusted mortality rates due toPC have remained fairly constant. Furthermore, increased serumPSA levels have frequently been observed in several other diseasestates of the prostate gland than cancer.5–7 As a result, intenseresearch is being conducted to identify circulating tissue andgenetic biomarkers as promising tools for PC diagnosis, stagingand prognosis and for development of appropriate andpersonalized therapeutic treatments. Promising data from animaland human genetic studies have been obtained, leading tocompelling evidence of a strong genetic role in PC development.Of special note are the findings obtained by case–control and twinstudies, segregation analyses and genome-wide investigations,underlining a strong genetic susceptibility for PC and its clinicaleffects.7–9 They have identified numerous candidate genes, andparticularly their genetic variants, associated with PC risk. Co-temporally, they propose interactions, either additively orepistatically, among PC risk-related genes (and among theirgenetic variants). Interestingly, among the several genetic variantsidentified to be associated with PC risk, common single-nucleotide

1Department of Pathobiology and Medical and Forensic Biotechnologies, University of Palermo, Palermo, Italy and 2Experimental Oncology, Department of Oncology, ARNAS-Civico, Palermo, Italy. Correspondence: Dr CR Balistreri, Department of Pathobiology and Medical and Forensic Biotechnologies, University of Palermo, Corso Tukory 211, Palermo90134, Italy.E-mail: [email protected] 4 July 2013; revised 16 September 2013; accepted 19 September 2013

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polymorphisms (SNPs) of a series of low penetrance alleles, the‘genetic modifier alleles’, appear likely to have an important role inPC susceptibility. They include a very long list and a large genenumber codifying different signaling pathways, including thoseinvolved in androgen action, DNA repair, carcinogen and sexsteroid hormone metabolism and inflammation.7 In addition,there is a general consensus on the potentiality of specificcombinations of these variants, in appropriate environmentalsituations, in profoundly affecting the risk of PC development andprogression.

Many of these aspects are summarized in this report by givingparticular emphasis to describing the role of genetic variants ininflammatory and steroid hormone metabolism genes and theirpathways. In particular, the data discussed in this review are basedon expert opinion derived on the findings from studies on aging,age-related diseases and inflammation.

INFLAMMATION AND PCIt is now well ascertained that chronic inflammation contributes toseveral forms of human cancer. Cancers often arise as the endstage of inflammation in adults. Approximately 20% of adultcancers, from those affecting the liver, esophagus, stomach tothose of the large intestine and prostate, are, indeed, attributableto chronic inflammatory conditions caused by infectious agents,chronic non-infectious, inflammatory diseases and/or otherenvironmental factors. Thus, chronic inflammation is nowregarded as an ‘enabling feature’ of human cancer. It seems toinfluence the cancer pathogenesis by (i) causing cell and DNAdamage, (ii) triggering restorative cell proliferation to replacedamaged cells and (iii) creating a tissue-rich microenvironment incytokines, chemokines and growth factors that can enhance cellreplication, angiogenesis and tissue repair.7,10 In addition, there isa complex interplay among host immune cells during neoplasticdevelopment, having both the ability to promote cancer and tolimit or eliminate it.11,12 Inflammatory/immune cells and solublefactors have indeed been observed in all tissues and organs withtumors (i.e. liver, gastrointestinal tract, prostate, thyroid gland,pancreas, urinary bladder, pleura and others).13 Furthermore, thesigns of ‘smoldering’ inflammation (i.e. tissue remodeling,angiogenesis and other wound healing-like features) are alsocommonly used by pathologists as morphologic cues of invasivecancer.14 Recent evidence demonstrates that these stromalprocesses have a fundamental role in cancer development andprogression, and, at least in some cases, may predict the clinicalbehavior of a cancer better than the characteristics of theneoplastic cells themselves.11,12 However, the critical role ofinflammatory cells in cancers has been recognized only recently.In addition, oncogenes seem to be involved in targetingproinflammatory pathways directly or indirectly. For example,Ras activates the transcription of the inflammatory cytokineinterleukin-8 (IL-8),15 whereas c-myc and bcl-2 inhibit apoptosisleading to necrotic tumor cell death and release of damage-associated molecular pattern molecules.16 In both circumstances,the resulting host response is inflammation, which promotestumor invasion and growth.10 Furthermore, several pathwayslinking inflammation and cancer have been identified: an intrinsicone, driven by genetic events that cause neoplasia, and anextrinsic one, driven by inflammatory conditions that predisposeto cancer.10 Key orchestrators at the intersection between intrinsicand extrinsic pathways include transcription factors, particularlynuclear factor-kB (NF-kB). NF-kB is a cytoplasmatic sensorconstituted by a protein complex (Rel family proteins: RelA/p65,c-Rel and RelB and NF-kB components: p50/p105 and p52/p100)and inhibited commonly by binding to IkB proteins (IkBa, IkBb,IkBg, IkBd, IkBe, IkBz and Bcl3). It modulates the inflammatoryresponse by mediating the gene expression of a large array ofproinflammatory genes, and consequently the release of soluble

mediators (cytokines, chemokines) and cellular components (e.g.tumor-associated macrophages), promoting cancerogenesis.17

NF-kB assists in the proliferation and survival of malignant cells,promotes angiogenesis and metastasis, subverts adaptiveimmunity and alters responses to hormones and chemothera-peutic agents. Emerging evidence suggests that its continualactivation and the consequent persistent inflammation promotegenetic instability.17 Thus, cancer-related inflammation representsa target for innovative diagnostic and therapeutic strategies.18 Asa result, particular attention is being focused on potential stimuliinvolved in prostatic inflammation and in identifying PC immunebiology, inflammatory pathways and inflammatory mediatorsimplicated in PC risk and development. On the other hand, thisrecent interest is based on the current hypothesis on prostatecarcinogenesis excellently evidenced by De Marzo et al.19 Thishypothesis sustains that genetic factors and the exposure toenvironmental factors, such as infectious agents (i.e. sexuallytransmitted organisms such as Neisseria gonorrhoeae, Chlamydiatrachomatis, Trichomonas vaginalis and Treponema pallidum, andnon-sexually transmitted bacteria such as Propionibacterium acnesand those known to cause acute and chronic bacterial prostatitis,primarily Gram-negative organisms such as Escherichia coli, andviruses such as Papillomavirus, Human Herpes simplex type-2,Cytomegalovirus), dietary carcinogens, hormonal imbalances,physical trauma and urine reflux cause injury of the prostateand lead to the development of recurrent and chronic inflam-mation.19 Chronic inflammation results in the formation of typicalrisk factor lesions in epithelial prostate cells, called ‘proliferativeinflammatory atrophy’ (PIA). These lesions occur predominantly atthe periphery of the prostate gland, where PC typically arises.19,20

Many of the PIA areas may show morphologic transitions inprostatic intraepithelial neoplasia (PIN) lesions considered putativePC precursors by De Marzo et al.19 (Figure 1). These morphologictransitions from PIA to PIN and PC have been confirmed by recentdata from other research groups. Among these, the findingsof Wang et al.21 are remarkable. By examining serial sections ofwhole-mount prostates from 50 cases, they observed that 17%of PIN lesions were found to be in the morphologic process ofmerging with PIA in 70% of the prostates examined. Furthermore,instances of PIA directly merging with cancer were identified in

Smouldering Inflammation

Hormonalimbalance Genetic

factors

Dietarycarcinogens

Infectiousagents

Lesions in epithelial prostatecells, called as “proliferativeinflammatory atrophy” (PIA)

Prostatic intraepithelialneoplasia(PIN)

Prostate Cancer

Figure 1. The complex pathophysiology of prostate cancer (PC)seems to be the result of an intricate interplay between geneticfactors, host life exposure to environmental factors (i.e., infectiousagents, dietary carcinogens) and hormonal imbalances. As a result,smoldering inflammation arises. It determines typical risk factorlesions preferentially in epithelial prostate cells, called ‘proliferativeinflammatory atrophy’ (PIA). Many of these lesions may showmorphologic transitions in prostatic intraepithelial neoplasia (PIN)lesions. PIN lesions, considered putative PC precursors, evolve withthe onset of PC.

SNPs of candidate genes in personalized cancer treatmentsCR Balistreri et al

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28% of the cases. The authors affirmed that merging lesions wereclosely adjacent to areas with chronic inflammation, suggesting itsfundamental role in this process. Further evidence on PIA as adirect precursor of PIN and/or cancer arises from several geneticdata, suggesting the presence in PIA lesions of some of thehallmark gene expression changes (i.e. downregulation of p27 andoverexpression of cyclooxygenase 2 (COX-2 also known as PTGS2))observed in PIN and PC.21

In addition, an increasing number of recent histologic investiga-tions confirm that PC tissues are commonly characterized bychronic inflammation. Lymphocytes, macrophages and, less fre-quently, other plasma cells and eosinophils were commonlyobserved in the tissue samples.19,20,22 In particular, they showedincreased infiltration of CD45þ cells in PIA lesions (all leukocytesexpress CD45 and non-leukocytes do not) with 70–80% of CD3þ Tlymphocytes and10–15% of CD19þ or CD20þ B cells. Macro-phage numbers also seemed increased in PIA lesions. Inphenotypical terms, a reversed CD8:CD4 ratio seems to characterizethe T cells. In terms of T-cell receptors, 90% of the cells appear to be‘standard’ ab T cells and 1% appear to be gd T cells. Class II majorhistocompatability antigen indicating the T cells ‘activated’ byantigen signaling has been observed to be expressed onapproximately 40% of the CD3þ T cells. Many of these T cellsshow CD45RO, indicating ‘antigen-experienced’ T cells. None of theT cells in the normal prostate epithelium show evidence ofactivation or of being antigen-experienced T cells. In addition,CD4þ T-cell responses in PIA, PIN and PC samples, divided intoseveral different types and classified according to their cytokineprofile (i.e. T helper type 1 (Th1) cells produce interferon-g andtumor necrosis factor-a (TNFa), whereas Th2 cells produce IL-4, IL-5and IL-13), have been defined as complex. In benign prostatehyperplasia and PC tissues, both Th0 (T cells that do not express anyof the indicated cytokines) and Th1 cells have been observed.19,20

However, some features of a Th2 response have also beendetected.19,20 In addition, regulatory T cells, able to suppressadaptive T-cell responses and autoimmunity, characterized by theexpression of CD25 and FOXP3, their typical transcription factor andsecretion of transforming growth factor-b (TGF-b), have also beenidentified in PIA, PIN and PC.19,20 Recently, Miller et al.23 evidencedCD4þ and CD25þ T cells, with properties of regulatory T cellsincluding the expression of the FOXP3 protein, in increasednumbers in clinically localized PC tissues compard with normalprostate tissues. Th17 cells, a new subset of CD4 effector T cells,which develop through distinct cytokine signals (especially IL-23)with respect to those involved in Th1 and Th2 responses, andrelease IL-17 cytokine, have also been identified in PIA, PIN and PCtissue samples.20 In particular, it has been evidenced that activatedT cells in benign prostate hyperplasia and PC tissues express highlevels of IL-17.20

However, further investigations are needed to fully elucidate thephenotypic and biologic properties of all T-cell subsets in prostatetissues. This may allow one to understand the significance ofclonotypical cell-mediated immunity in prostate carcinogenesis.Methods such as the quantitative image analysis of immunohisto-chemically stained inflammatory cell subsets and flow cytometry forthese subsets using tissues isolated from histologically defined areasmight be crucial to obtain such data.

During PC development and progression, the role of innate/inflammatory immune cells is also crucial, as demonstrated byseveral recent histopathologic investigations. Paradoxically, it hasbeen demonstrated that activation of the innate immune response(particularly through the NF-kB pathway) through Toll-like receptor(TLR)4-mediated recognition of pathogen-associated molecularpatterns or damage-associated molecular pattern molecules canpromote tumor development. This results in a milieu rich withinflammatory mediators.20,24 Thus, inflammatory mediatorsreleased through the NF-kB-TLR4 pathway may contributethrough their physiologic functions to the development and

progression of cancer, such as PC. Specifically, IL-1, IL-6, IL-8 andTGF-b released by immune cells and tumor cells promoteangiogenesis, tumor growth and the differentiation of Th1, Th17and regulatory T cells.25 Accordingly, recent studies demonstratethat TLR4 and IL-1 receptor-associated kinase sequencepolymorphisms are important risk factors for PC.7,26 Other studiesevidence that the MyD88-dependent signaling pathway also havea critical role in the production of IL-6 and in both spontaneousand carcinogen-induced development of tumors.26,27

Taken together, these studies indicate that TLR4-mediatedinflammation induced from bacterial and viral infection or fromother endogenous and exogenous agents can promote thedevelopment of cancers, such as PC. Thus, the blockade ofsignaling pathways required for inflammation or the induction ofproinflammatory mediators might decrease the risk of tumorigen-esis. Several agonists have been developed as anticancer drugs.However, optimal antitumor immunity requires robust enhance-ment of the effector T-cell response induced by tumor-specificantigenic peptides and control or elimination of regulatory T cell-suppressive function. Accordingly, the combination of peptide-based vaccines with TLR agonists may greatly improve thetherapeutic potential of cancer vaccines.21,24

As discussed, a number of separate research lines support thestrong role of inflammation in prostatic carcinogenesis and tumorprogression. These lines involve epidemiologic, genetic, histo-pathologic, molecular pathology and animal studies. Of particularattention are the data suggesting the crucial role of geneticfactors and environmental factors (e.g., lifestyle or microbialinfection and underlying subclinical prostatitis) in the induction ofa chronic inflammation involved in prostate carcinogenesis.Among genetic factors, ‘genetic modifier alleles’ of inflammatorygenes show significant associations with PC risk, as described inthe next section.

GENETIC POLYMORPHISMS THAT MODULATE INFLAMMATIONAND PC ONSET AND PROGRESSION: THE ROLE OF ‘GENETICMODIFIER ALLELES’Study of the human genome has enabled the dissection ofcomplex human traits and has paved the way to understandingthe basic pathways of health and disease. Population-basedassociation studies have emerged as powerful tools for examininggenes with a role in common multifactorial diseases that have astrong environmental component. These association studies oftenestimate the risk of developing a certain disease in carriers andnon-carriers of a particular genetic polymorphism. The largemajority of genetic variants studied are SNPs that occur with afrequency of 41% in the normal population (in contrast to‘mutations’ that occur with a frequency of o1%). It is estimatedthat approximately 3.5 million SNPs are present in the humanindividual genome.28 Naturally, most of these SNPs do not occurin coding sequences, and even those that do are not associatedwith any alteration in the amino-acid sequence and are thereforeof no functional consequence. There has been an exponentialincrease in the number of published genetic association studies.Quite often, a report of a single genetic marker is published withgreat promise only to be followed by several negative studies thatfail to reproduce the original observation. There is no doubt thatthe strategy of genetic association studies could be a powerfultool for dissecting human diseases, provided that certainprinciples are observed to minimize the chances of false-positiveand -negative reports.29

The emerging theme of the recent genetic association studies isthe analysis of modifier genes. Interest in modifier genes isgrowing rapidly because of their ability to modify qualitatively andquantitatively the phenotype of another gene. Modifier geneshave been shown to affect penetrance, dominance modification,progression, expressivity, pleiotropy and age of onset of


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monogenic and multigenic traits and diseases. Acting in aqualitative manner, a modifier may be required for a primarygene to express a phenotype. However, it appears that modifiersact more commonly in a quantitative manner. Modifiers may oftenunderlie quantitative trait loci such that the summation of positiveand negative modifier effects may greatly influence the resultingphenotype. This quantitative model explains how a disease allelemay cause significantly different phenotypes. Each individual in anoutbred human population possesses a unique complement ofmodifiers that influence the primary disease allele to producevariable phenotypic results.30

A neglected class of modifiers are protective alleles that cansuppress disease in otherwise susceptible individuals. Takentogether, these modifier genes and protective alleles provideimportant glimpses into the molecular and cellular basis for thefunctional networks that provide robustness and homeostasis incomplex biologic systems.31 Furthermore, understanding themolecular and cellular basis by which modifier genes exert theirinfluence might also provide insights into the identification ofphysiologic pathways as novel targets for therapeutic interventionsin human diseases.

As briefly mentioned in the introduction, several modifier allelesin a large gene number of signaling pathways, including thoseinvolved in androgen action, DNA repair, carcinogen and sexsteroid hormone metabolism and inflammation, have beenidentified to be associated with PC risk or to modulate it. Amongthese, some genetic modifier alleles of innate/inflammatory andsex hormone pathways have been examined in our studies and thedata obtained are discussed in the next paragraph (see Tables 1and 2).

In the following sections, we describe the role of geneticmodifier alleles modulating inflammation and PC risk. Threegenetic epidemiologic approaches (precisely the candidate geneapproach, pathway analysis, and genome-wide associationstudies) have been used to assess SNPs of proinflammatory genesand PC risk. In addition, the number of studies reporting on theassociation between one or multiple SNPs in inflammation-relatedpathways, and thus PC risk, has greatly increased.

Candidate gene approachThe candidate gene approach is a hypothesis-driven method thatis widely used. Sequence variants of several inflammatory geneshave been extensively explored to predict PC risk,7,19,32 even ifmost of these findings are inconsistent. However, some interestingdata have been obtained. Among these, an interesting association

has been recently observed by Licastro et al.33 between an SNP(GG genotype) in the promoter region of a-1-antichymotrypsinand increased risk for PC (age-adjusted odds ratio (OR)¼ 2.676;confidence interval (CI): 1.375–5.205). a-1-Antichymotrypsin is anacute-phase protein upregulated in response to inflammation. a-1-Antichymotrypsin is also a serine protease inhibitor, and mostcirculating PSA is bound to ACT.33

Another recent case–control study in the risk factors forprostate cancer study, by examining a cytokine-rich region at5q31.1 implicated as suggested previously in PC risk, observed amodest association between two alleles of IL-4 and PC risk and noassociation between IL-5 or IL-13.34 The associations with IL-4were not present in another large case–control study (theMelbourne Collaborative Cohort Study). However, the authorsevidence that one of the IL-4 alleles (rs2243250 genotype) led to adecrease in IL-4 activity, potentially pointing to an antitumorfunction of IL-4 in PC risk.34

A number of recent studies have also detected the potentialinteraction of SNPs between multiple different cytokines inconferring an increased PC risk. Among these, the study ofZabaleta et al.35 examined nine SNPs in three cytokines (IL-1B,IL-10 and TNF) in a case–control study of African-American versusCaucasian men. This study evidenced an increased combined riskof PC in African Americans carrying variants in IL-1B (IL1B-511CT/TT) and IL-10 (IL10-592CC) (OR¼ 2.56; 95% CI: 1.09–6.02). Similarly,in Caucasians, a higher risk for PC was associated with thecombinations of variants of IL-1B (IL1B-31TT/TC) and IL-10 (IL10-1082AA) (OR¼ 2.92; 95% CI: 1.13–7.55) as well as IL-10 (IL10-592AA) and TNF (TNF-238GG) (OR¼ 2.14; 95% CI: 1.05–4.38). Thissame group also examined 15 SNPs in five cytokine genes (IL-1B,IL-10, TNF-a, IL-6 and IL-8) in relation to risk of aggressive PC(Gleason sum 8 or PSA 420 ng ml� 1 or Gleason sum 7 and clinicalstages T3–T4) in African Americans and Caucasians.33 Using themultivariate adaptive regression spline regression analysis, thisstudy demonstrated an association between aggressive PC and anIL-8 (IL8-47CT) genotype (OR¼ 3.50; 95% CI: 1.13–10.88) as well asan increased risk with combined genotypes in IL-1B (IL1B-511CC)and IL-10 (IL10-1082GG) (OR¼ 3.38; 95% CI: 1.70–6.71) inCaucasian men. Unfortunately, the number of African-Americanmen in this study was not large enough for analysis. Interestingly,both studies showed an association between increased risk for PCor aggressive PC. Another recent study investigated 143 SNPs in16 inflammation-related genes (CXC ligand 12 (CXCL12), IL-4, IL-6,IL-6ST, prostaglandin-endoperoxide synthase 2 (PTGS2), signaltransducer and activator of transcription 3 (STAT3), TNFa, proteinkinase B (AKT1), CXCR4, IL-6R, IL-8, IL-10, NFkB, phosphatidylinositol

Table 1. Genes (accession number) and SNPs (accession number) associated with PC risk, and their innate/inflammatory pathways and biologiceffects

Genes SNPs Biologic effects Related pathways

TLR4(NM-138554.1)

þ 896A/G(Asp299Gly; rs4986790)þ 1196C/T(Thr 399Ile; rs4986791)

Determining a single amino-acid substitution in theextracellular receptor domain and, hence, a blunted innate/inflammatory response to both foreign pathogens andendogenously generated inflammatory ligands

TLR4 receptorpathway41,42,60,61

TLR2(NM 003264)

þ 2408 G/A(Arg753Gln; rs5743708)þ 2029C/T(Arg677Trp; no rs availabledesignation)

Determining a single amino-acid substitution in theextracellular receptor domain and, hence, a blunted innate/inflammatory response to both foreign pathogens andendogenously generated inflammatory ligands

TLR2 receptor pathway41,60,61

PTGS2(NM-000963)(COX-2 gene)

� 765G/C (rs20417) Located in the promoter region of this gene, it determines areduced gene expression and consequently a reducedproduction of COX-2 enzyme

Arachinoid acid–ecosanoidpathway41,60

5-Lo(NM000698)

� 1708 G/A(no rs available designation)

Located in the promoter region of this gene, it determinesan increased gene expression and consequently an elevatedproduction of 5-lypoxygenase enzyme

Arachinoid acid -ecosanoidpathway41,60

Abbreviations: PC, prostate cancer; SNP, single-nucleotide polymorphism; TLR, Toll-like receptor.


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3-kinase (PIK3)R1, PTGS1 and vascular endothelial growth factor(VEGF)) in a case–control study of African-American versusCaucasian men.34 Among these SNPs, genetic variants in IL-4, IL-6ST, PTGS2 and STAT3 genes were associated significantly andindependently with PC susceptibility. In addition, SNPs in AKT1,PIK3R1 and STAT3 were associated with aggressive PC.36

These studies collectively underline the potential importance ofthe interactions between inflammatory cytokines and inflamma-tion pathways in conferring PC risk.

Other inflammatory molecules seem to have a crucial role in PC.Among these, COX-2 (also known as PTGS2) is extensively studiedwith regard to PC. This enzyme is an inducible isoform of theenzymes that convert arachidonic acid to proinflammatoryprostaglandins. An overexpression of COX-2 in PC has beenobserved, particularly in PIA areas.7 Furthermore, several recentlypublished studies have demonstrated significant associations ofSNPs in the PTGS2 gene with PC risk.7,20,37 However, differentresults have been obtained.7,20,37 Nevertheless, COX-2 remains amolecule of particular interest in the link between inflammationand PC.

Of special note also are the data on the strong correlationbetween genetic variants of genes of the TLR4 pathway and PCsusceptibility in humans. In particular, a large number of recentcase–control studies performed in different populations of the

world have examined the role of TLR4 SNPs in PC.26 Accordingly, alarge study analyzed eight TLR4 SNPs in 1383 PC patients and 780age-matched controls from Sweden. It found that the sequencevariant (11381G/C; rs11536889) in the 30-untranslated region ofthe TLR4 gene increases PC risk by 4.9%.38 In another large study,performed on 700 patients and 700 controls from the UnitedStates, 16 TLR4 SNPs have been analyzed.39 Homozygosityfor the variant alleles of eight SNPs has been associated with astatistically significant lower PC risk (TLR4_1893, TLR4_2032,TLR4_2437, TLR4_7764, TLR4_11912, TLR4_16649, TLR4_17050and TLR4_17923), while the TLR4_15844 polymorphism corres-ponding to 11381G/C was not associated with PC risk.39 Thefindings of these previous studies were recently confirmed. Chenget al.,40 analyzing six TLR4 SNPs in 1012 men, demonstrated thatrs10759932 SNP was associated with a fourfold increased risk ofdisease.

Recently, we evaluated the role of þ 896A/G (Asp299Gly;rs4986790) and þ 1196 C/T (Thr399Ile; rs4986791) TLR4 SNPs inPC in the Sicilian population. A significant increase in þ 896Aproinflammatory allele frequency was observed in PC patientswhen compared with age-related controls and centenarians (asdescribed above), emphasizing the role of TLR4 in the pathophy-siology of this age-related cancer.41 To confirm our suggestions onthe biologic effects of þ 896A/G TLR4 SNP in the pathophysiology

Table 2. Genes (accession number) and SNPs (accession number) associated with PC risk, and their related sex hormone pathways and biologiceffects

Genes SNPs Biologic effects Related pathways

AR(OMIM313700)

þ 211G/A(G1733A), rs6152

Located within exon 1, the SNP consists of a G-to-A change in the thirdposition of codon 211. The A allele associated with a statistically significantnearly threefold increased risk of PC among African-American men (age o65years), likewise an excess proportion of this allele has been found among PCcases with an affected brother. European studies have also observed anassociation between A allele and high-grade disease

Androgen sex hormonereceptor pathway59,60

SRD5A2(NM000348)

A49T, rs9282858 A49T SNP substitutes threonine for alanine at codon 49; the T allele has beenreported to be the allele with higher enzyme activity. It has been associatedwith a higher risk of PC

Androgen sex hormonepathway (5-a-reductaseenzyme)59,60

V89L, rs523349 V89L SNP substitutes leucine for valine at codon 89; it has been reported toreduce almost 30% of adrostanediol glucuronide, a serum marker of 5-a-reductase activity among Asians. Among Caucasian men, a 10% insignificantlylower androstanediol glucuronide level has been observed in individuals withthe L/L genotype. Hence, V89L might reduce the risk for PC

CYP19(NM-031226)

C1558T, rs1062033 It is a silent SNP in exon 10, corresponding to the 30-untranslated region ofmRNA; it has been proposed as functionally relevant, because it is correlatedto the level of aromatase mRNA in tumor cells

Androgen sex hormonepathway (aromataseenzyme)59,60

39Trp/Arg, rs2236722 Located in the codon 39 Trp/Arg, it is significantly associated with PCArg264Cys, rs700519 Located in exon 7, it determines the C to T substitution in the position of

nucleotide 826, resulting in the substitution from Arg to CYs at codon 264. Ithas been associated with an increased risk of PC

ERa, ESR1 A351G, rs: 9340799T397C, rs: 2234693

351A/G (or XbaI) and 397T/C (or PvuII), most widely studied SNPs of ER1 gene,seem to be in linkage disequilibrium. They have been associated with higherrisk of PC. Concerning the XbaI SNP, higher circulating levels ofandrostenedione have been observed in A/A (or x/x genotype) Thepolymorphism IVS1-397 was described as a C-to-T change in the intron of ESR(located at position 397 before exon 2; http://genome.ucsc.edu). Thesubstitution of T generates a sequence, which can be cut by ESR1 IVS1-397 T/C(PvuII) (CAG/CTG—complementary strand). This SNP has been associated withestrogen-dependent diseases. The clinical data indicate that carriage of thisSNP has functional consequences by influencing ESR ligand binding and localestrogenic action

Estrogen sex hormone-a receptor pathway59,60

ERb, ESR2 G1082A(no rs availabledesignation)

It has been reported to be associated with increased estrogen dysfunction Estrogen sex hormone-b receptor pathway59,60

Abbreviations: ESR, estrogen receptor; PC, prostate cancer; SNP, single-nucleotide polymorphism; TLR, Toll-like receptor.


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of PC, we recently assessed the levels of IL-6,TNF-a, IL-10 andeicosanoids in lipopolysaccharide-stimulated whole-bloodsamples from 50 young healthy Sicilians, screened for thepresence of this SNP. Both proinflammatory cytokines andeicosanoids were significantly higher in carriers bearing theþ 896A TLR4 allele, whereas the anti-inflammatory IL-10 valueswere higher in carriers of the þ 896 G TLR4 allele.42 This suggeststhe ability of the þ 896 G TLR4 allele to mediate a better controlof inflammatory responses induced by chronic stimuli, likelydecreasing the effects of prostate carcinogens.

Of the other TLR4-related pathway genes, only some SNPs ofCD14 and NF-KB1 (encoding for the p50 subunit of NF-kB) geneshave been analyzed to evidence their ability to modulate PCrisk.43,44 In particular, the CD14 (� 260C4T) polymorphism,located near the Sp1 transcription factor binding site andknown to have a major influence on CD14 expression, has beendemonstrated to be associated with PC in old African-Americanmen in a study including 264 cases and 188 controls.43

Furthermore, a functional insertion/deletion polymorphism (e94insertion/deletion ATTG) in the promoter of the NF-KB1 gene hasalso been genotyped in a total of 117 PC patients and 143 controlsubjects. The frequency of the ATTG2 allele in PC patients wassignificantly higher than in controls (63.7% vs 54.5%; P¼ 0.035,OR¼ 1.461). Thus, the functional NF-KB1 promoter polymorphismseems to be associated with increased risk for PC.44

Further investigations are certainly needed to explain thebiologic mechanism of the TLR4 pathway in PC. However, it seemsplausible from the current literature data that modifying thegenetic sequence of the TLR4 gene could result in a high state ofTLR4 activation, favoring chronic inflammation and carcinogenesis.On the other hand, an overexpression of TLR4 and endogenousTLR4 ligands has been observed in PC cells.24 However, TLR4engagement by endotoxin and by endogenous ligands representsa notable contribution to the outcome of different cancertreatments, such as radiation or chemotherapy. Further researchon the role and mechanisms of TLR4 pathway activation in PC mayprovide novel antitumor vaccine adjuvants and TLR4 inhibitors thatcould prevent inflammation-induced PC carcinogenesis.

Pathway analysisThe pathway analysis approach, which is also hypothesis driven,relies on examining a more comprehensive set of genes involvedin a specific functional role—for example, inflammation, cell cycle,DNA repair and so on. However, this approach is being overtakenby advances in high-throughput genome technology and theadvent of genome-wide association studies. A case–control studyused the multiple-stage design to analyze association betweenSNPs of over a thousand inflammatory genes and the risk for PC.Three SNPs, rs7250623 on the CRLF1 gene, rs753733 on the FCER2gene (encoding the low-affinity receptor for immunoglobulin E(FceRII, CD23)) and rs2144493 on CIDEB (codifying cell death-inducing DFFA-like effector b) and LTB4R2 (encoding leukotrieneB4 receptor 2) genes, are associated with PC risk.45

Thus, pathway analysis enables us to investigate the subpath-way interactions. However, it limits the ability to detect the cross-talk between the inflammation pathway and other pathways.

Genome-wide association studyIn the post-genome era, a genome-wide association study hasbecome a powerful tool for analyzing the whole genome andidentifying SNPs related to the outcome of interest.

Several genome-wide association studies in diverse ethnicgroups have recently identified more than 40 germline variants ofvarious genes or chromosomal loci that are significantly asso-ciated with PC susceptibility, including multiple 8q24 loci,prostate-specific genes, metabolic- and hormone-related genesand many regions where no coding gene is annotated. However,

there are only a few variants or genes for which biologicsignificance or functions have been elucidated so far. The greatestchallenge related to genome-wide association studies-associatedloci in prostate genomics is to understand the functionalconsequences of these PC-associated loci and their involvementin PC biology and carcinogenesis. There have been attempts todetermine PC risk estimations by combining multiple PC-associated variants for clinical tests, and these can identify a veryminor population with a high risk for PC. However, they cannotdistinguish the risk for aggressive PC from that for non-aggressivePC. Further identification of PC-susceptibility loci in largergenome-wide association study cohorts and biologic insightsgained from such functional analyses have the potential totranslate into clinical benefits, including the development ofreliable biomarkers, risk estimation and effective strategies forscreening and prevention of PC.32

SEX STEROID HORMONE-RELATED PATHWAYS IN PCSex steroid hormones are assumed to have a critical role in thecomplex pathophysiology of human PC.7,46–49 Androgens areprimarily responsible for the development and function of thehuman prostate gland as well as for the maintenance ofhomeostasis of prostate tissues in adulthood. The major prostaticandrogen is testosterone and its derivative di-hydrotestosterone(DHT), produced locally through the 5a-reductase enzyme. Most oftheir effects are mediated by binding to androgen receptors (AR).Androgens also represent well-established risk factors fordevelopment and progression of benign and malignant disordersof the prostate gland.46

Current evidence also suggests a crucial role of estrogens inboth normal and diseased human prostate.47–49 In particular, ithypothesizes that a combined action of androgens and estrogensand their balance seems to be remarkable in maintaining prostatehealth and tissue homeostasis. An alteration of this balance hasbeen evidenced to be involved in the development of bothbenign and malignant diseases, including PC.47,48

In aging men, circulating levels of estradiol are unchanged orincreased, as opposed to the decline of plasmatic testosterone.Estrogen production is maintained through aromatization ofadrenal androgens driven by the aromatase enzyme, especiallyin peripheral adipose tissue.47 In normal prostate gland, thearomatase enzyme is expressed within the stroma, while themalignant prostate shows an aberrant aromatase expression inthe epithelial compartment.46 This has been associated with anincreased risk for PC.48

This condition is further complicated by the differentialexpression and activity of the two estrogen receptors (ER), aand b.46,47 A sustained activation of ERa may eventually lead to anaberrant proliferation, inflammation and to the development ofpremalignant lesions. In contrast, ERb receptors haveantiproliferative effects and exert a protective role againstprostate carcinogenesis.46,47,49,50

Despite the above evidence, many epidemiologic studieshave failed to show a significant association between circulatingsex steroids and PC risk.51–53 Indeed, several problems relatedto measurement of plasma steroids, both androgens andestrogens, should be considered to explain this large inconsist-ency in data. However, the ethnic variability and the heterogeneityof the genetic background among the individuals may well have amajor impact. In particular, SNPs of genes involved in bothmetabolism and action of steroid hormones seem to be primarilyimplicated.

In the following paragraph, we describe the recent data on therole of genetic modifier alleles in sex hormone pathways in PC risk,by considering the candidate gene approach, pathway analysisand genome-wide association studies.


6


FOCUS ON THE ROLE OF GENETIC VARIANTS OF THE SEXHORMONE PATHWAYCandidate gene approachThe major chunk of literature on genetic studies on PC cancer hasapplied a candidate gene approach and examined geneticvariations involved in sex hormone pathways. This strategy isbased on pathophysiologic observations, such as varying rates ofprostate tissue proliferation in response to changes in plasma orintraprostatic sex hormone levels, caused by genetic variations. TheAR gene, the steroid a-reductase type 2 gene (SRDAR2, whichconverts testosterone to dihydrotestosterone in the prostategland), the cytochrome P450c17 and P450c19 genes (CYP17 andCYP19, respectively, which are involved in the synthesis anddegradation of sex hormones) and the ERa and ERb genes (ESR1and ESR2, respectively) have all been studied extensively.Significant associations between some SNPs of these genes andPC risk have been observed.54–58 However, most studies have beensmall and results have varied between men from different ethnicbackgrounds. We have recently analyzed the association betweenPC and nine functional SNPs of the AR, SRD5A2, CYP19, ERS1 andERS2 genes involved in sex hormone pathways (see Table 2). Ourresults suggested the potential association of seven out of nineSNPs with PC.59–61

Genome-wide association studiesAs a result of developments in genotyping and data analysis overthe past few years, genome-wide association studies havediscovered new genetic variants and loci associated with PCincidence.62

Pathologic implications of genetic variants of sex hormonepathwayHowever, the mechanisms underpinning the putative role of PCrisk-associated genetic factors in the development and/orprogression of PC during the aging process remain unknown.Further studies are needed to confirm these data to get insightinto relevant mechanisms, with special emphasis on the localmetabolism and action of androgens or estrogens. It should benoted that circulating sex steroids cannot be consideredrepresentative of their intraprostatic levels, which strictly dependon the expression and activity of key enzymes governing localmetabolism and biotransformation.49 In this respect, the appraisalof steroid enzymes (such as aromatase and 5-a-reductase) andreceptors (such as AR, ERa and ERb) that determine metabolicprofiles and signaling, respectively, in both normal and diseasedhuman prostate is crucially important to associate sex hormone-related pathways and PC risk.

EMERGING DATA ON THE ROLE OF MICRORNA AND THEIRVARIANTS IN PC RISK: THEIR POTENTIAL ROLE AS NOVEL PCBIOMARKERSMicroRNAs (miRNAs) are small noncoding RNAs that take part inpost-transcriptional regulation either by arresting the translationor by cleavage (degradation) of mRNA targets. MiRNA regulation isperformed by pairing the miRNA to sites in the messenger RNA ofprotein coding genes. miRNAs have been thought to be involvedin many biologic processes (i.e. cell proliferation, death anddifferentiation) and are believed to regulate the expression ofapproximately one-third of all human genes. Mature miRNAs bindto their target mRNAs by complete or incomplete complementa-tion of their 50-end nucleotides 1–8 (seed sequences) with abinding site in the 30- or 50-untranslated regions of targettranscripts or in the coding sequences. This process results indirect cleavage of the targeted mRNAs or inhibition of translation.Currently, nearly 1700 human miRNAs have been identified.63–65

In recent years, miRNAs have emerged as possible diagnosticand prognostic biomarkers that may stratify prostate tumors basedon specific genetic profiles and thereby improve aspects of patientmanagement, such as staging and treatment.63–65 Although manycancer drugs poorly distinguish between cancer and normal cells,development of more precise and specific ways to recognize tumorcells would be of vital importance. The use of such genetic markerscan create a unique new niche for the development of molecularlybased drugs that can move PC research closer to personalizedmedicine and complement the current standard of care.63–65 Onthe other hand, it has already been shown that miRNAs areaberrantly expressed in PC. In androgen-dependent and -independent PC cell lines, a differential expression of miR-148ahas been found. MiR-125b expression has been reported to beincreased in benign prostate lines compared with PC lines, andandrogen receptor-positive cell lines expressed more miR-125bthan androgen receptor-negative cell lines.63–65 Furthermore,recent data have also evidenced a relatively small number ofmiRNAs involved in regulating inflammation in normal andpathologic aging. They are represented by miR-155, miR-21 andmiR-146a, which are able to target particularly the TLR/NF-kBpathway, and named inflamma-miRs. In physiologic conditions,transcription of miR-155, miR-21 and miR-146a is at baselinelevels.66,67 In contrast, the activation of proinflammatory TLRsignaling immediately determines a strong induction of theirexpression through an NF-kB-dependent mechanism.66,67 Theseobservations lead to the hypothesis that tissue and circulatinginflamma-miRs may contribute to regulating the activation of theinflammatory network and the consequent release of the so-calledsenescence-associated secretory phenotype (represented by amyriad of factors, i.e. proinflammatory mediators).17,66,67 Inaddition, they could be used to verify the damage induced byactivation of the inflammatory response.17,66,67 Inflamma-miRs havebeen implicated in the regulation of the immune and inflammatoryresponse, and their abnormal expression may contribute to thelow-level chronic inflammation17,66,67 that has been documentedboth in normal aging and in the major age-related diseases such asPC. In particular, circulating inflamma-miRs could have diagnostic/prognostic relevance in human diseases, such as PC, which share acommon inflammatory background.66,67

Furthermore, recent evidence suggests that their activity andthe expression of the miRNA targets are modulated by geneticvariants in their sequence. Accordingly, two recent studies haveunderlined the association of SNPs, located at miRNA-binding sites(miRNA-binding SNPs) and likely able to affect the expression ofthe miRNA targets, with PC risk.68,69 In particular, George et al.,68

by genotyping a North Indian population constituted by 159 PCpatients and 230 matched controls for hsa-mir196a2 (rs11614913),hsa-mir146a (rs2910164) and hsa-mir499 (rs3746444) SNPs,observed that patients with a heterozygous genotype in hsa-mir196a2 and hsa-mir499 showed significant risk for developingPC (P¼ 0.01, OR¼ 1.70 and Pp0.001, OR¼ 2.27, respectively).Similarly, the variant allele carrier was also associated with PC(P¼ 0.01, OR¼ 1.66 and Pp0.001, OR¼ 1.97, respectively),whereas hsa-mir146a revealed no association with PC. None ofthe miRNA polymorphisms were associated with Gleason gradeand bone metastasis. Thus, combined genotypes of miRNA-relatedvariants may be used to predict the PC risk and may be useful foridentifying patients at high risk.68 Another group of researchersanalyzed the association between the G4C polymorphism(rs2910164) of miR-146a (located in the sequence of miR-146aprecursor, and resulting in a change from a G:U pair to a C:Umismatch in its stem region) and PC risk and the expression ofmiR-146a with different genotypes in PC tissues in the southernChinese Han population.69 A total of 251 PC and 280 controlsubjects were included in this study, and 15 PC tissue sampleswere used to test the expression of the miRNA precursors by real-time quantitative reverse transcription–polymerase chain reaction.


7


They observed that subjects carrying CC homozygotes had a 0.65-fold reduced risk (95% CI¼ 0.43–0.99) compared with thosecarrying GG/GC genotypes (P¼ 0.03), and the C allele displayed alower prevalence of PC compared with the G allele (OR¼ 0.73,95% CI¼ 0.57–0.94, P¼ 0.01). Moreover, hsa-miR-146a quantifica-tion showed that homozygous carriers of the C variant hadsignificantly decreased miRNA levels compared with carriers of theGG/GC genotype. Thus, the natural genetic variation in pre-miR-146a affects the amount of mature miR-146a and contributes tothe genetic PC predisposition.69

These data suggest miRNA and their SNPs as novel PC riskbiomarkers, although further studies are certainly indispensable.

OUR HYPOTHESIS: INTERPLAY BETWEEN SEX STEROID ANDIMMUNE INFLAMMATORY NETWORK AND DETECTION OF AGENETIC RISK PC PROFILE BY USING AN ALTERNATIVEAPPROACHConsidering our expertise in age-related inflammatory diseases,we hypothesize that a complex endocrine–inflammatory immuneinteraction is primarily implicated in human PC pathophysiology.In this framework, the major goal of our recent studies7,41,59–61

was to analyze the role of modifier SNPs in genes, codifyingmolecules involved in inflammatory and sex steroid pathways (seeTables 1 and 2), as described above, in PC risk. In addition, it alsosought to identify a genetic risk profile. The detection of a riskprofile potentially allows both the early identification of indivi-duals at risk for disease and the possible discovery of potentialtargets for medication. On the other hand, the major interest ofcurrent research is to improve early detection of age-relateddiseases, cancer included, by developing tools to move diagnosisbackward in disease temporal course—that is, before the clinicalmanifestation of the malady. Indeed, in this preclinical phase thetreatment might have a decisive role in preventing or significantlyretarding the disease manifestation. The better understanding ofthe function and regulation of the inflammatory/sex steroidpathways in PC may help identify the mechanisms of its onset andprogression, as well as detect new targets for the refinement ofnew treatment such as the pharmacogenomics approach.

In achieving this purpose, we used in our association geneticstudies a particular approach, characterized by analyzing anadditional control group represented by centenarians (as men-tioned above), ‘exceptional individuals’ able to avoid majorcommon age-related diseases, including cancer.41,59–61 This kindof approach has been named ‘positive biology’, as it seeks tounderstand the causes of positive phenotypes, trying to explainthe biologic mechanisms of health and well-being.70

As described in the study by Balistreri et al.,41 we identified arisk profile in PC patients when compared with centenarians. Inparticular, we detected an overexpression of a proinflammatorygenetic risk profile in PC patients with respect to centenariansrepresented by ‘þ 896Aþ TLR4/þ 2408Gþ TLR2/þ 2029CþTLR2/� 765Gþ PTGS2/� 1708Aþ 5-Lo’ high proinflammatorygenotype (36% versus 11%, P¼ 0.002; OR¼ 4.59, CI: 1.6–12.8,P¼ 0.004). In addition, analyzing the association between PC riskand nine functional SNPs of the AR, SRD5A2, CYP19, ERS1 and ERS2genes involved in sex hormone pathways, we observed that sevenout of nine SNPs were associated with PC risk. Most of the selectedalleles were also under-represented in centenarians.59

All together, these data lead one to hypothesize that thegenetic background promoting proinflammatory responses mayhave opposite roles in PC and longevity. On the other hand, wehave previously demonstrated that alleles associated with age-related diseases are not included in the genetic profile favoringlongevity.61,71,72 Accordingly, the SNPs selected in our PC studiesseem to function in an antagonistically pleiotropic manner. Theyexert a beneficial role in younger age, maintaining the physiologicgrowth and homeostasis of the prostate gland. In contrast, in old

age they have a detrimental role, inducing aberrant cellproliferation and inflammation and being involved in thedevelopment of benign and malignant lesions.

Furthermore, our findings lead us to suggest possible ther-apeutic treatments in subjects with severe risk factors for PC. Forexample, we propose in subjects with ‘high-risk’ alleles of thePTGS2 and 5-lypoxygenase genes the possibility of developingpreventive measures using specific inhibitors of eicosanoids and/or their enzymes. In people who do not respond to (or complywith) nonsteroidal anti-inflammatory drug therapy, other moresophisticated preventive approaches have been proposed, includ-ing the use of agonists of TLR receptors in subjects who arecarriers of þ 896A/G TLR4 and þ 2408 G/A TLR2 SNPs. The aim ofsuch an approach would be to block the TLR-NF-kB signalingpathway required for induction of inflammatory responses andthe release of proinflammatory mediators. This approach mightreduce the risk of PC development.7,41,59–61 Another possibletherapeutic intervention in subjects with proinflammatory allelesof TLR4 and TLR2 genes might be antibody-mediated stimulationof TAM receptors involved in the inhibition of the inflammatoryresponse. The sequential induction of this pathway and itsintegration with upstream TLR and cytokine signaling networksmay limit the inflammatory response and maintain innate immunesystem homeostasis. A better understanding of the regulatorymechanisms of this cascade may have important implications fortherapeutic intervention in human immune disorders.41

CONCLUSIONS AND FUTURE PERSPECTIVES: TRANSLATION OFPATHOLOGIC IMPLICATIONS IN PERSONALIZED CANCERMEDICINEThe combination of genetic tools and clinical information withrespect to a specific cancer, such as PC, is giving new focus tomedicine by way of ‘personalized cancer medicine’.73,74 ‘Persona-lized oncology’ includes the concept that each individual solidtumor and hematologic malignancy in each person is unique incause, rate of progression and responsiveness to surgery,chemotherapy and radiation therapy’. This paradigm shiftrequires the identification of new validated biomarkers. In thenext decade, oncology will move from a reactive to a proactivediscipline—a discipline that is predictive, personalized, preventiveand participatory. In addition, tools for implementing pre-emptivemedicine based on genetic and molecular diagnostics andinterventions will emerge and these will improve prevention,early detection and access to care. Health-care oncology profes-sionals need to keep themselves informed of new tumor biomar-kers, their optimal clinical use and the management of side effects.

In the specific case of PC, this new goal might lead toreplacement of the instruments for detecting PC cancer with newand more specific biomarkers. In addition, it might also improvethe efficiency of genetic tools and new-generation sequencingtechnologies for PC prevention of individuals carrying inflamma-tory and sex steroid pathway polymorphisms and their relatives.Accordingly, these new approaches will offer the possibility ofearlier detection of the pathology and a different or specifictreatment strategy depending on an individual’s genotypes. Useof genetic biomarkers, such as polymorphisms of inflammatorygenes or genetic variants of genes codifying molecules of sexsteroid hormone pathways, may also enable one to stratifypatients on the basis of the aggressiveness of the pathology. Thisapproach might provide signatures on inflammatory and sexsteroid tissue status and help in selecting suitable patients toevaluate target modulation.

In addition, SNPs may operate in combination to create a ‘riskprofile’ and modify the effectiveness of disease therapies.Combinations of several inflammatory and sex steroid hormonepathway SNPs are found in PC patients, as mentioned above.Thus, their combinations might be used as markers in a pre- and


8


post-treatment clinical PC setting. Accordingly, their identificationmay hold promise for the realization of personalized PC medicines(Figure 2). Indeed, it might be useful to guide treatment choice inmen with newly diagnosed PC, distinguishing low-risk from high-risk disease through the identification of a risk profile. Thisapproach might provide more appropriate data on prognosticimpact than those usually obtained using histology-based Gleasonscore. However, it is still being tested and adding to studies basedon transcriptome analysis.

The combination of this information will allow medicalprofessionals to establish different medical protocols in moreaggressive PC types and offer the possibility of performingpreliminary controls in families considered at risk. Although manysignificant steps in the treatment of PC have been taken withrespect to clinical matters and genetic information, there is still along way to go.

In any case, the creation of a personalized panel of SNPbiomarkers for PC and for a specific cancer may be important forits early and accurate detection. On the other hand, PC ischaracterized by being extremely difficult to diagnose and treat,as it can take decades to progress to a clinically manifest state. Asa consequence, the necessity for a good biomarker is required todetect PC earlier and to provide tools to follow up patients duringthe early stages of the cancer.

At present, PC continues to have an unclear etiology, which is acombination of genetic and numerous environmental factors andhormonal imbalance. Furthermore, several studies have shownthat risk profiles based on known common susceptibility alleleshave limited discriminatory power for PC,75 leading someinvestigators to conclude that the clinical utility of riskprediction based on polygenic profiling is still limited. However,discrimination is not the only measure of clinical utility of a riskprediction model, and it has been suggested that polygenic riskprofiling may provide sufficient information to enable screeningfor PC cancer to be targeted to those men at highest risk;76,77

however, evidence from empirical data is needed. Nevertheless,this approach has the potential to inform public health policydecision making in the context of population screening.

CONFLICT OF INTERESTThe authors declare no conflict of interest.

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New drug targets &Possibility to apersonalized

treatment dependingon an individual’s

genotypes

Improving of efficacyof PC Prevention and

Early detection

Genetic Biomarkers:identification of a “Riskprofile” of inflammatory

and sex steroid hormonepathway SNPs

Genetic analysisand

clinicalinformations

Figure 2. Genetic analysis and clinical information permit theidentification of a ‘risk genetic profile’ represented by a combinationof inflammatory and sex steroid hormone pathway single-nucleo-tide polymorphisms (SNPs). They can represent optimal prostatecancer (PC) biomarkers, useful in improving the efficacy of PC earlydetention/prevention. At the same time, they might be used asoptimal new drug therapeutic targets. In addition, this may lead andguide, versus a preferential treatment, the personalized treatmentdepending on the individual’s genotypes.


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Prostate cancer: from the pathophysiologic implications of some genetic risk factors to translation in personalized cancer treatments