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Pharmacogenomics

Genetics and nonmelanoma skin cancer in kidney transplant recipients

Kidney transplant recipients (KTRs) have a 65- to 250-fold greater risk than the general population of developing nonmelanoma skin cancer. Immunosuppressive drugs combined with traditional risk factors such as UV radiation exposure are the main modifiable risk factors for skin cancer development in transplant recipients. Genetic variation affecting immunosuppressive drug pharmacokinetics and pharmacodynamics has been associated with other transplant complications and may contribute to differences in skin cancer rates between KTRs. Genetic polymorphisms in genes encoding the prednisolone receptor, GST enzyme, MC1R, MTHFR enzyme and COX-2 enzyme have been shown to increase the risk of nonmelanoma skin cancer in KTRs. Genetic association studies may improve our understanding of how genetic variation affects skin cancer risk and potentially guide immunosuppressive treatment and skin cancer screening in at risk individuals. Keywords:  genetics • immunosuppression • nonmelanoma skin cancer • pharmacogenetics • renal transplant • skin cancer

Renal transplantation provides the optimal long-term benefit for appropriately selected patients requiring renal replacement therapy [1] ; leading to improved survival, quality of life and lower treatment costs [2] . Modern day immunosuppression has reduced rates of allograft rejection and improved allograft survival. However, duration of immunosuppression is associated with increased long-term medication related complications [3] . Skin cancers are a serious complication that frequently affects solid organ transplant recipients. Nonmelanoma skin cancer (NMSC), including basal cell carcinomas (BCC) and squamous cell carcinomas (SCC), are the most common types of skin cancer affecting kidney transplant recipients (KTRs) and worldwide occur at 65- to 250times the frequency of the general population [4,5] . NMSC development in KTRs increases with time since transplantation and occurs with a cumulative incidence of 61 and 82% in patients immunosuppressed for >20 years in England and Australia, respectively [4,6] .

 10.2217/PGS.14.156 © 2015 Future Medicine Ltd

Skin cancer is also an important cause of mortality in KTRs and the Australia and New Zealand Dialysis and Transplantation Registry reports NMSC as the most common cause of cancer related deaths for KTRs between the years 2005 and 2009 [7] . Risk factors for skin cancer in KTRs include Caucasian ethnicity, fair skin, cumulative UV radiation (UVR), increasing age, male gender, previous NMSC and genetic predisposition [8] . Post-transplant immunosuppressive drug treatment is an additional risk factor for NMSC however the precise relationship between NMSC and immunosuppression remains poorly defined. KTRs are prescribed a combination of immunosuppressive drugs to prevent immune mediated rejection of the transplanted kidney. Immuno­ suppressive drugs used in organ transplantation are proposed to contribute to NMSC via a number of mechanisms that include direct carcinogenic effects [9] and reduced immune surveillance [10] . Variation in NMSC risk between patients is likely

Pharmacogenomics (2015) 16(2), 161–172

Michael T Burke*,1, Nicole Isbel1, Katherine A Barraclough2, Ji-Won Jung3, James W Wells3 & Christine E Staatz4 Department of Nephrology, University of Queensland at the Princess Alexandra Hospital, Brisbane, Australia 2 Department of Nephrology, Royal Melbourne Hospital, Melbourne, Australia 3 The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia 4 School of Pharmacy, University of Queensland, Brisbane, Australia *Author for correspondence: Tel.: +61 7 3176 7488 Fax: +61 7 3176 5480 [email protected] health.qld.gov.au 1

part of

ISSN 1462-2416

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Review  Burke, Isbel, Barraclough, Jung, Wells & Staatz partly explained by genetic influences affecting the disposition and action of immunosuppressive drugs. Pharmacogenetics aims to individualize pharmacological treatment by improving drug efficacy and reducing toxicity. It most commonly involves candidate gene studies and the identification of single genetic variants linked to specific pharmacological phenotypes [11] . It is estimated that genetics accounts for 20–95% of variability in drug disposition and effects [12] . SNPs can influence the gene expression of proteins involved in the metabolism, distribution and action of drugs and so contribute to individual variation in drug effect [13] . SNPs have been identified in genes responsible for variation in exposure to, and actions of, commonly used immunosuppressive medications [14–17] . Pharmaco­genetics has proven to be important in predicting a range of transplantation associated adverse events including delayed graft function (DGF), cytomegalo­ virus (CMV) viremia, post-transplantation diabetes mellitus [18] and BK viremia [19] . A SNP is often associated with multiple drug complications suggesting that increased drug exposure or action can be the beginning of a common pathway for immuno­ suppressive drug complications. Therefore, it is likely that genetic factors influencing the pharmacokinetics and pharmacodynamics of immunosuppressants will affect the risk of NMSC. Genetic variation not involving pharmaco­genetics has also been examined in KTRs and found to be important in influencing skin cancer risk. MC1R and GST polymorphisms are proposed to influence the risk of NMSC through effects on epidermal melanin production and the repair of UV induced oxidative damage, respectively. Differences in COX-2 polymorphisms and HLA isotype also increase the risk of NMSC, although the mechanism of action is not well understood. MTHFR polymorphisms affect the methylation of skin cancers and the epidermis in KTRs and are associated with NMSC risk. This review aims to provide an overview of the association between genetics and skin cancer in kidney transplant recipients. Polymorphisms influencing the pharmacokinetics and/or pharmacodynamics of immunosuppressant drugs will be considered, as will polymorphisms that affect skin cancer risk via nonpharmacogenetic pathways. This will provide the clinician and scientist with an up to date assessment of the topic as well as identifying promising areas for future research. Immunosuppressants & pharmacogenetics Glucocorticoids (prednisolone and prednisone), calcineurin inhibitors (cyclosporine and tacrolimus) and antiproliferative agents (azathioprine and myco­

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phenolic acid) are commonly used in modern immuno­ suppressive regimens for the prevention of allograft rejection. Patients usually receive triple therapy with one member from each of these drug classes. In this section, we review how genetics affects NMSC risk depending on immunosuppressive drug treatment. Studies reporting an association between immunosuppressant pharmacokinetics or pharmacodynamics and other transplant related complications will also be assessed due to their potential impact on NMSC development. Glucocorticoids (prednisolone & prednisone) Glucocorticoids inhibit allograft rejection by causing a rapid decline in circulating T lymphocytes through a combination of redistribution [20] , inhibition of proinflammatory cytokines [21] and induction of apoptosis [22,23] . B cells are affected to a lesser extent and antibody production is largely preserved [24] . In 2012, 67.6% of kidney transplant recipients reported to the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients (OPTN) were prescribed corticosteroids at the time of transplantation [25] . In nontransplant recipients, one prospective observational study of 1051 participants reported no association between oral glucocorticoids and risk of NMSC [26] . However, a registry study of 59,043 people reported a standardized incidence ratio for cutaneous SCC of 1.32 (95% CI: 1.09–1.59) in those prescribed glucocorticoids [27] . This is further strengthened by a population-based case control study conducted in the US, in which 873 nontransplant patients with a previous history of BCC or SCC were matched for age and gender with a group of 532 controls [28] . A current or past history of oral glucocorticoid use was associated with an increased risk of SCC (adjusted odds ratio 2.31, 95% CI: 1.27–4.18). Risk of BCC was not significantly increased (adjusted odds ratio = 1.49; 95% CI: 0.90–2.47). These studies had short follow-up periods and low cumulative gluco­corticoid dosages and so conclusions should be applied with caution to transplant patients who often receive life-long treatment with glucocorticoids. In light of this and the complex mechanism of action of gluco­corticoids, further studies are required to establish if these drugs contribute to skin cancer development in KTRs. One candidate gene based study reported an association between a prednisolone receptor gene poly­ morphism and NMSC in nontransplant patients. Prednisolone and prednisone are metabolized by CYP3A isoenzymes (encoded by CYP3A gene) and are substrates of the cellular efflux transporter P-gp (encoded by the ABCB1 gene) [29] . The pregnane X receptor (encoded by the NR1I2 gene) regulates expression of

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 Genetics & nonmelanoma skin cancer in kidney transplant recipients 

the CYP3A and ABCB1 genes. Many of the biological effects of the glucocorticoids are regulated by the glucocorticoid receptor (encoded by the h-GR/NR3C1 gene), which is located on chromosome five and has nine exons. However the mechanisms underlying the enhancement of glucocorticoid sensitivity by the BclI polymorphism of the glucocorticoid receptor gene are yet to be determined [30] . Polymorphisms in the CYP3A, ABCB1, NR1I2 and h-GR/NR3C1 genes may play a role in inter-individual variation in response to glucocorticoids. One pharmacogenetic study from the US examining 1050 Caucasians reported a relationship between the BclI polymorphism (rs41423247) in the glucocorticoid receptor gene NR3C1 and skin cancer (Table 1) [31] . An increased risk of SCC was associated with BclI GC (OR for SCC 2.5, 95%, CI: 1.1–5.3) and BclI GG (OR for SCC 5.6, 95% CI: 1.1–29) in patients with a history of oral glucocorticoid usage. No statistically significant increased risk of BCC was found. This study suggests the risk of SCC may be increased by the presence of BclI polymorphisms in the glucocorticoid receptor gene in patients with a history of prednisolone use. Studies are required to examine

Review

the association between NR3C1, P-gp, CYP3A and NR1I2 polymorphisms and risk of NMSC in KTRs treated with glucocorticoids. Calcineurin inhibitors (cyclosporine & tacrolimus) Calcineurin inhibitors (CNI) inhibit allograft rejection by blocking calcineurin phosphatase and inhibiting T-cell activation [43] . According to OPTN data, in 2012, 91.1 and 3.2% of KTRs in the USA were prescribed tacrolimus and cyclosporine, respectively [25] . The effective and safe use of cyclosporine and tacrolimus requires therapeutic drug monitoring due to large interindividual variation in exposure and the narrow therapeutic window of these drugs. Calcineurin inhibitors contribute to skin cancer through the inhibition of DNA repair [9] , suppression of p53-dependent cell senescence [44] and modification of immune function [45] . A randomized controlled trial by Dantal et al. showed a reduction in skin cancers in KTR treated with a reduced dose of cyclosporine compared with normal dose cyclosporine, and helped identify the importance of immunosuppressive drug exposure in

Table 1. Genetic association studies assessing risk of nonmelanoma skin cancer in immunosuppressed patients. Gene

Variant

Genotype prevalence†

Population

Major findings

Ref.

h-GR/NR3C1

BclI GG rs41423247 [32]

0.47 [33]

Prednisolone treated (not KTR)

↑SCC OR: 5.6 (CI: 1.1–29) if history of GC use

[31]

h-GR/NR3C1

BclI GC rs41423247 [32]

0.47 [33]

Prednisolone treated (not KTR)

↑ SCC OR: 2.5 (CI: 1.1–5.3) if history of GC use

[31]

TPMT

Wild-type versus TPMT*3A; *3B; *3C (variant alleles)

0.10 (variant alleles)

KTR

No difference in NMSC risk with variant allele

[34]

GST

GSTM1 (null)

0.46

KTR

↑ risk of SCC with variant allele, OR 3.1 (CI: 1.04–9.44)

[35]

GST

GSTM3 AA

0.71

KTR

↓ SCC numbers with variant allele, RR: 0.50 (CI: 0.28–0.87)

[36]

GST

GSTM3 AB

0.27

KTR

↑ SCC numbers with >7 mg pred, RR: 2.29 (p = 0.042)

[36]

GST

GSTT1 null

0.80

KTR

↓ SCC numbers with C rs20417 [41]

0.3

KTR

Protective for BCC if A, 3435C>T, 2677G>T/A reduced the activity of P-gp and increased peripheral blood mononuclear cell tacrolimus concentrations without an effect on tacrolimus blood concentrations [51] . Whether ABCB1 polymorphisms encoding reduced PGP expression are associated with NMSC in KTRs has not been previously investigated but is a promising area for future research. Pharmacokinetic variability in tacrolimus-treated patients is best attributed to a SNP in CYP3A5 6986A>G (rs776746) and patients with this homozygous polymorphism are nonexpressers who have a reduced dose requirement compared with expressers [58] (Table 2) . A study by Glowacki et al. involving 209 French KTRs with a mean follow-up of 21.8 months reported recipient CYP3A5 6986A>G polymorphisms affected inter-

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individual variability of tacrolimus pharmaco­k inetics [53] . However, in the same study, CYP3A5 6986A>G and ABCB1 3435C>T poly­morphisms had no effect on clinical end-points including acute rejection, renal function or DGF. Infectious or malignant complications were not reported. A separate study of KTRs showed that in KTRs receiving a CYP3A5 genotypeguided dose, patients were more likely to have tacrolimus concentrations within the target range during the acute post-transplantation period however there was again no effect on clinical outcomes such as DGF, acute rejection or renal function [17] . Despite no definite evidence to show genotype based dosing improved the clinical outcomes that were assessed, NMSC risk was not studied and future research should consider examining the potential effect of CYP3A5 and ABCB1 polymorphisms on the risk of skin cancer. The POR*28 variant allele is also an essential determinant of calcineurin inhibitor pharmacokinetics. POR protein assists CYP450 enzyme activity by transporting electrons to microsomal CYP450 enzymes from nicotinamide adenine dinucleotide phosphateoxidase [59,60] . To investigate this further, a candidate SNP (POR*28) approach was used to study tacrolimus exposure and dose requirements in 298 CYP3A5 genotyped KTRs (Table 2) . The study showed that in CYP3A5 expressers, POR*28 T allele carriers had lower tacrolimus trough concentrations in the first days posttransplant, had a 25% higher tacrolimus dose requirement and reached target trough concentrations significantly later compared with POR*28 CC homozygous patients [52] . No study to date has looked at the associations between POR polymorphisms and risk of NMSC in KTRs receiving calcineurin inhibitors. Antiproliferatives (azathioprine) The antiproliferative agents, azathioprine and mycophenolic acid (MPA), inhibit allograft rejection by interfering with purine synthesis and cell proliferation. According to OPTN data, in 2012, 0.3% and 92.9% of KTRs in the US were prescribed azathioprine and MPA, respectively [25] . A population based case control study showed that patients with a high accumulated dose of azathioprine had an 8.8-fold increased risk of cutaneous SCC [61] . In contrast there is no definite evidence supporting a procancer effect with MPA. Azathioprine is a prodrug that is nonenzymatically converted to 6-mercaptopurine. 6-Mercaptopurine is metabolized by three competing pathways including TPMT, xanthine oxidase and HPRT. The primary mechanism of action of 6-mercaptopurine is the production of 6-thioguanine nucleotides, which produce cytotoxic effects through incorporation into DNA and RNA causing cell cycle arrest [62] and apoptosis [63,64] . A number of polymorphisms have

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 Genetics & nonmelanoma skin cancer in kidney transplant recipients 

Review

Table 2. Genetic associations with immunosuppressant pharmacokinetics or risk of adverse events. Gene

Variant

Genotype prevalence†

Major findings

ABCB1

2677G>T/A rs2032582 [52]

T = 0.42 A = 0.03 (variant allele frequency)

Cyc treated: ↑ DGF and CMV reactivation with T variant allele; ↑ intracellular Tac PBMC concentration with T/A variant allele

ABCB1

3435C>T; rs1045642

0.47 (variant allele frequency)

Cyc treated: ↑ DGF, CMV reactivation and NODAT; ↑ intracellular Tac PBMC concentration; Tac treated: no effect on acute rejection, renal function or delayed graft function

[52]

Ref. [18,51]

[18,51,53]

ABCB1

1199G>A; rs2229109

0.03 (variant allele frequency)

↑ intracellular Tac PBMC concentration

CYP3A5

6986A>G; rs776746

0.96 (variant allele frequency)

2.3-fold ↓ in Tac dose requirement; no association in Tac treated patients on acute rejection, renal function or delayed graft function

CYP3A4

CYP3A4*22 C>T; rs35599367

0.06 (variant allele frequency)

↓ Tac dose requirement

[55]

IMPDH1

rs2278293 rs2278294

0.43 0.41

↓ incidence of acute rejection in mycophenolic acid treated patients

[56]

UGT

UGT1A8*2

0.23

↓ diarrhea in mycophenolic acid treated patients

[57]

POR

POR*28 C>T rs1057868

0.28 (variant allele frequency)

25% ↑ tacrolimus dose requirement than POR*28 CC

[52]

[51] [17,53,54]

Confidence intervals are expressed as 95% CIs. † As reported in study unless otherwise referenced. CMV: Cytomegalovirus; Cyc: Cyclosporine; DGF: Delayed graft function; NODAT: New-onset diabetes after transplantation; PBMC: Peripheral blood mononuclear cell; PK: Pharmacokinetics; Tac: Tacrolimus.

been associated with underactivity of TPMT, increasing the risk of azathioprine related myelosuppression and possibly NMSC. In the Caucasian population, homozygosity and heterozygosity for the variant allele are 0.3% and 7–11%, respectively [65] . An Irish study of 407 KTRs reported 7.9% had a single TPMT nonfunctional allele (TPMT*3A, TPMT*3B, TPMT*3C; Table 1). In the same group, 20% of KTRs with a variant allele required cessation of azathioprine due to myelosuppression, presumed secondary to increased drug exposure [34] . The remaining patients who continued on azathioprine despite the presence of a TPMT variant allele had no significant difference in skin cancer history compared with the wild-type (OR: 1.07, 95% CI: 0.51–2.26). Although in this study the variant allele TPMT*2 was inadvertently included in the wild-type population, this SNP’s prevalence is 0.5% [66] and so did not impact significantly on risk estimation. Therefore, SNPs encoding heterozygous expression of TPMT variant alleles did not increase the risk of NMSC. Furthermore, homozygous carriers of variant alleles will almost certainly develop severe myelosuppression [64] prior to developing an increased NMSC risk.

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Mycophenolic acid MPA is effective in reducing allograft rejection through the inhibition of IMPDH. Blockade of this enzyme inhibits synthesis of guanosine monophosphate nucleotides which reduces purine synthesis and proliferation of T and B cells [43] . MPA is metabolized by uridine diphosphate-glucuronosyl transferases (UGTs) to a major metabolite (7-O-MPA-glucuronide) and at least three minor metabolites. MPA and 7-O-MPA-glucuronide undergo enterohepatic recirculation through the biliary excretion transporters organic anion transporting polypeptides (OATPs) and MRP-2. Therapeutic drug monitoring is not routinely performed for MPA and so SNPs influencing its pharmacokinetics may affect long-term drug exposure and associated complications including NMSC. MPA has inhibitory actions on both the IMPDH1 and IMPDH2 isoforms of IMPDH. One study of 191 KTRs treated with MPA reported that two single nucleotide IMPDH1 polymorphisms were significantly associated with acute allograft rejection. The odds ratio was 0.34 (95% CI: 0.15–0.76; p = 0.008) for rs2278293 and 0.40 for rs2278294 (95% CI: 0.18–0.89; p = 0.02), respec-

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Review  Burke, Isbel, Barraclough, Jung, Wells & Staatz tively. The mechanism by which this polymorphism was associated with a reduction in acute rejection remains uncertain although an effect on lymphocyte proliferation was postulated [56] . Other studies of MPA treated KTRs reported increased diarrhea in non­ carriers of the UGT1A8*2 allele compared with carriers (C518G and 518GG genotypes; HR = 1.876; 95% CI: 1.109–3.175) [57] . Future studies are required to investigate the association between SNPs in IMPDH [67] , UGT [68] , OATP [69] and MRP-2 [70] with risk of NMSC in KTRs receiving MPA. Genetics & NMSC Pharmacogenetics is likely to explain an important proportion of the genetic variation in NMSC risk in KTRs. However, genetic differences not associated with immunosuppressive drugs also make a significant contribution. In this section, we focus on genetic polymorphisms not related to immunosuppressive treatment that are associated with NMSC development in KTRs. Glutathione S-transferases Glutathione S-transferases (GST) are a family of enzymes that catalyze the conjugation of glutathione to a variety of electrophilic compounds [71] . This multigenic isoenzyme family is considered essential in both detoxification of endogenous and exogenous compounds and in repairing UVR induced oxidative damage. Deletion of the GSTM1 and GSTT1 genes causes a ‘null’ genotype characterized by a deficit in enzymatic activity, while certain GSTM3 and GSTP1 alleles encode low activity enzymes [35,36] . Individuals with these polymorphisms may be at an increased risk for malignancies due to an impaired ability to detoxify carcinogens. SNPs in the GST gene family have been reported to contribute to the risk of NMSC in KTRs. A study of GST SNPs involving 183 English (Caucasian) KTRs identified a number of SNPs associated with risk of NMSC. In particular, GST M1 null was associated with an increased risk of SCC (OR: 3.1, 95% CI: 1.04–9.44) (Table 1) [35] . The same group subsequently studied 361 Australian KTRs to assess the association between risk of NMSC and GST genotype stratified by prednisolone dose (≤7 vs >7 mg/day) [36] . In this cohort, irrespective of prednisolone dose, the poly­ morphism GSTM3 AA (RR: 0.5, 95% CI: 0.28–0.87) was associated with fewer SCC. In contrast to the English cohort, the low-dose prednisolone group GSTT1 null, was associated with reduced SCC numbers (RR: 0.20, 95% CI: 0.07–0.62). The association between GSTT1 null and reduced SCC was unexpected as this polymorphism encodes for reduced GST protein expression. The authors proposed a reduction in GST

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may in some cases increase reactive oxygen species triggering a greater immune response against NMSC. The associated increased SCC risk with GSTM1 null that had previously been identified in English KTRs [35] was not replicated in the group of Australian KTRs [36] . These studies suggest that GST polymorphisms influence the risk of NMSC in KTRs through either reduced oxidation; or increased inflammation and immune-mediated destruction of malignant cells. MC1R Human pigmentation is regulated by MC1R expressed in hair follicles and melanocytes of the skin. Melanocytes provide photoprotection for epidermal keratinocytes by donating melanin containing melanosomes [72] . The MC1R gene is highly polymorphic and certain polymorphisms are associated with melanoma [73] and NMSC [74] in the general population. UVR activates the receptor resulting in increased synthesis of eumelanin pigment causing darkening of the skin. Increased activation of this gene results in DNA repair, melanocyte proliferation and improved cell survival [75] . Loss of MC1R function results in synthesis of red/yellow pheomelanin pigment by melanocytes, contributing to red hair in humans [75] . A Norwegian study of 217 KTR investigated the influence of MC1R genotypes on SCC risk. The MC1R variant p.Arg151Cys, rs1805007 was identified as having a significant association with increased risk of SCC (OR: 1.99; 95% CI: 1.05–3.75) irrespective of the phenotypes considered to be protective [37] (Table 1) . This indicates the association between MC1R polymorphisms and risk of SCC in the general population also applies to KTRs. HLA system HLA genes are the most polymorphic in the human genome and encode molecules that are essential in the development of immune response, autoimmune disease and the success or failure of transplantation [76] . HLA type is considered a risk factor for the development of skin cancer in solid organ transplant patients. HLA polymorphisms may increase skin cancer risk due to donor-recipient HLA mismatches increasing the risk of allograft rejection with consequent increased immuno­suppression, or via a reduced ability to mount an immune response against oncogenic viruses or as yet undefined links to nonimmune recipient characteristics such as skin pigmentation [38] . An Australian study of 1098 KTRs transplanted between 1969 and 1994 examined the relationship between risk of NMSC and HLA type [77] . The HLA A-11 serotype was associated with an increased risk of NMSC (adjusted HR 1.7, 95% CI: 1.1–2.4; Table 1). There was no association between donor-recipient HLA

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 Genetics & nonmelanoma skin cancer in kidney transplant recipients 

mismatches, or the HLA-DR7 or HLA-B27 serotype and risk of NMSC. This was supported by a study of 2433 Northern Hemisphere KTRs examining the relationship between HLA-A11, HLA B27 and HLA DR7 serotype and risk of NMSC [38] in which 8.9% of the total population were HLA-A11 positive. NMSC developed in 4.3% of the total population and in 8% of the HLA-A11 patients. Therefore in KTRs, HLAA11 was again associated with an increased risk of NMSC (OR: 2.03, 95% CI: 1.11–3.53. MTHFR The MTHFR enzyme is essential in the folate production pathway. Folate is required for nucleotide synthesis, DNA replication and as a methyl donor in the process of DNA methylation [78] . Genomic instability is likely the main oncogenic consequence of hypomethylation. Low folate status has been associated with an increased risk of cancers including those affecting the lung, colon and breast [78] . The MTHFR C677 T polymorphism results in an alanine to valine substitution at codon 222 [79] and phenotypically has reduced MTHFR catalytic activity [80] . One study investigated the association between MTHFR C677 T carrier status and the risk of SCC in 367 Irish KTRs [40] . On multivariate analysis, this polymorphism was associated with an increased risk of SCC (OR: 2.54, 95% CI: 1.41–4.56). Serum folate was not associated with risk of NMSC in this cohort although the authors did concede that red cell folate may be a more accurate measure of cellular folate levels. Therefore, not only does the MTHFR C677 genotype predict an increased risk of NMSC in KTRs, it potentially identifies a subgroup of KTRs who may benefit from folic acid supplementation for the prevention of NMSC. Because abnormal DNA methylation patterns can occur in cancerous cells and are an important contributor to cancer development [78,81] , another study from the same group utilized pyrosequencing to examine the methylation profiles of SCC compared with adjacent non-neoplastic skin in those with and without the MTHFR C677T polymorphism [78] . In 40 SCC and 36 non-neoplastic skin samples from KTRs, SCC was found to be hypomethylated compared with non-neoplastic skin (p C poly­morphism exists at the COX-2 gene promoter, with the C allele causing decreased promoter activity and low prostaglandin E2 (PGE2) production [84] . A study combining KTRs from two hospitals examined whether patients with this polymorphism would exhibit less skin cancer due to the loss of PGE2-promoting activity [85] . A total of 7.7% of the 365 patients from the first hospital (mean follow-up 9.5 +/-10 years) and 6.7% of the 238 patients from the second hospital (mean follow-up 8.5 years) developed skin cancer, respectively. This study found no difference in skin cancer risk between KTRs with the CC/ CG or GG COX-2 gene promoter polymorphism at position -765. However, this study may have been inadequately powered to detect a difference due to the small number of NMSC cases. By contrast, an Italian study of 240 solid organ transplant recipients analyzed the association of three polymorphisms in the COX-2 gene and found that in a subset of patients who were transplanted before the age of 50, a -765C polymorphism was protective for the development of BCC (CC + CG vs GG, p = 0.003) [42] (Table 1) . Future trials studying the benefits of aspirin in reducing the incidence of NMSC in KTRs could consider investigating if COX-2 polymorphisms have an influence on skin cancer risk. Conclusion & future perspective NMSC is a leading cause of morbidity and mortality in KTRs. A wide variety of risk factors including reduced immune surveillance and direct oncogenic effects secondary to immunosuppressive medications contribute to NMSC in organ transplant recipients.

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Review  Burke, Isbel, Barraclough, Jung, Wells & Staatz Early candidate gene studies reported glucocorticoid receptor polymorphisms influence the risk of NMSC in KTRs. More recently genetic association studies in KTRs receiving immunosuppression have identified that NR1I2 and ABCB1 polymorphisms contribute to the development of post-transplantation complications such as BK viremia, post-transplant diabetes mellitus and delayed graft function. SNPs have been shown to associate with multiple immunosuppressive drug complications and so the risk of NMSC in KTRs with these SNPs warrants further investigation. SNPs in the GST, MC1R, MTHFR and COX-2 genes do not affect the pharmacokinetics of immunosuppressive medications but have been widely studied and found to influence the risk of NMSC in the general and transplant populations. Immunosuppressive drugs are most commonly used in combination in KTRs making it difficult to identify the risks associated with individual agents. There is a paucity of long-term randomized controlled trial data recording the development of cancer in KTRs receiving different drug regimens and drug dosages, and existing observational data are flawed by the inadequate assessment of contributory risk factors (such as sun exposure) and unequal distribution of confounders (such as era of transplant) [2] . While several studies have examined the effects of genetic polymorphisms on the pharmaco­kinetics and pharmacodynamics of immuno­ suppressants, the vast majority have not examined long-term outcomes such as development of NMSC. A number of candidate gene based studies have exhibited shortcomings including inadequate sample size, lack of replication, minimal consideration of covariates such as sun exposure and inadequate statistical adjustment for

the assessment of multiple hypotheses. More studies in KTRs are required to examine the association between SNPs that affect immunosuppressive drug pharmaco­ kinetics/pharmacodynamics and risk of NMSC. Future studies examining these genetic associations would ideally be adequately statistically powered; prospective in design; adjust for covariates to minimize the risk of confounding and the introduction of bias; and account for combinations of SNPs and haplotypes. In the future, genome-wide association studies and second-generation sequencing investigating the relationship between skin cancer and immunosuppression are likely to contribute to the knowledge already gained from candidate gene research. Whole genome prediction models have already shown greater accuracy for the prediction of skin cancer in the general population compared with models including only nongenetic variants [86] . The application of comprehensive sequencing approaches can help map the known regions, refine signals and identify new signals which will increase the accuracy and reliability of genetic testing for NMSC [87,88] . The identification of SNPs capable of predicting NMSC risk would be a valuable tool in personalized and preventive medicine for KTRs. If in the future certain SNPs are identified to have a strong association for NMSC, then we would recommend that pretransplantation screening take place. A risk assessment could be designed that would be based on the presence of NMSC risk alleles, previous sun exposure, ethnicity, gender and age. Patients identified as being at an increased risk of skin cancer may then be more likely to adhere to sun avoidance strategies and cancer screening programmes. A better understanding of the relationship between pharmacogenetics and skin cancer would also assist phy-

Executive summary • Nonmelanoma skin cancer (NMSC) is a common problem affecting kidney transplant recipients and is responsible for significant morbidity and mortality. • Post-transplant immunosuppressive treatment is a major risk factor for NMSC development. The relationship between NMSC and immunosuppression remains poorly defined. • Variation in NMSC risk between patients may be partly explained by genetic influences affecting the disposition and action of immunosuppressive drugs. • Genetic polymorphisms associated with the prednisolone and melanocortin-1 receptor, glutathione S-transferase, methylenetetrahydrofolate reductase and cyclooxygenase have been associated with an increased risk of NMSC in immunosuppressed patients and HLA-A11 serotype has been associated with an increased risk of NMSC in kidney transplant recipients. • Thiopurine S-methyltransferase polymorphisms have not been associated with skin cancer risk, probably due to the development of myelosuppression resulting in either cessation or reduction in azathioprine therapy. • ABCB1 polymorphisms influence calcineurin inhibitor pharmacokinetics and increase the risk of delayed graft function, cytomegalovirus reactivation and new-onset diabetes after transplantation; however a potential effect on skin cancer risk has not been studied. CYP3A5, CYP3A4 and POR polymorphisms affect tacrolimus dose requirements but because of TDM may not have an effect on post-transplant NMSC development. Further investigation is required. • An improved understanding of the influence of pharmacogenetics on risk of skin cancer development may provide guidance for long-term immunosuppressant use in at risk individuals.

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sicians in making decisions regarding choice and intensity of immunosuppressive therapy. For example, it may identify the group of patients at greatest risk of skin cancer with CNI exposure and who would therefore most benefit from alternative treatment with mammalian target of rapamycin inhibitors. Knowledge of genetic predictors of NMSC would also contribute to a more accurate stratification of skin cancer risk and therefore facilitate rationalization of skin surveillance guidelines, ensuring a more efficient use of clinical resources.

Financial & competing interests disclosure

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12

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N Isbel has received unrestricted grants or honoraria from Novartis, Pfizer, Roche and Janssen-Ciliag. M Burke is a recipient of a Jacqout Research Entry Scholarship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Papers of special note have been highlighted as: • of interest; •• of considerable interest 1

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US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients. http://srtr.transplant.hrsa.gov/annual_reports/2012

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Provides a thorough review of mechanisms that influence glucocorticoid sensitivity including glucocorticoid receptor polymorphisms.

Halloran PF. Immunosuppressive drugs for kidney transplantation. N. Engl. J. Med. 351(26), 2715–2729 (2004).

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••

In this article the risk of malignancy is shown in a randomized controlled trial to be reduced in patients treated with low-dose cyclosporine.

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••

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 Genetics & nonmelanoma skin cancer in kidney transplant recipients 



This is the first study to show ABCB1 polymorphisms influence intracellular cyclosporine concentrations.

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Singh D, Alexander J, Owen A et al. Whole-blood cultures from renal-transplant patients stimulated ex vivo show that the effects of cyclosporine on lymphocyte proliferation are related to P-glycoprotein expression. Transplantation 77(4), 557–561 (2004).

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This study provides evidence that IMPDH1 variants are associated with acute transplant rejection in mycophenolate mofetil treated patients.

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Genetics and nonmelanoma skin cancer in kidney transplant recipients.

Kidney transplant recipients (KTRs) have a 65- to 250-fold greater risk than the general population of developing nonmelanoma skin cancer. Immunosuppr...
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