Author(s): Michael T Burke [*] aff1 , Nicole Isbel aff1 , Katherine A Barraclough aff2 , Ji-Won Jung aff3 , James W Wells aff3 , Christine E Staatz aff4
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 250-times 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 [greater than]20 years in England and Australia, respectively [ 4,6 ]. 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. Immunosuppressive 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 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), cytomegalovirus (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 immunosuppressive drug complications. Therefore,...