PTCH mutations in basal cell carcinomas from azathioprine-treated organ transplant recipients

Abstract

The immunosuppressant azathioprine is used to prevent graft rejection after organ transplantation. To investigate whether azathioprine-associated mutagenesis contributes to the high incidence of skin tumours in organ transplant recipients (OTRs), we analysed PTCH gene mutations in 60 basal cell carcinomas (BCC); 39 from OTRs receiving azathioprine and 21 from individuals never exposed to azathioprine. PTCH was mutated in 55% of all tumours, independent of azathioprine treatment. In both the azathioprine and non-azathioprine groups, transitions at dipyrimidine sequences, considered to indicate mutation by ultraviolet-B radiation, occurred frequently in tumours from chronically sun-exposed skin. In BCC from non-sun-exposed skin of azathioprine-treated patients, there was an over-representation of unusual G:C to A:T transitions at non-dipyrimidine sites. These were exclusive to the azathioprine-exposed group and all in the same TGTC sequence context at different positions within PTCH. Meta-analysis of 247 BCCs from published studies indicated that these mutations are rare in sporadic BCC and had never previously been reported in this specific sequence context. This study of post-transplant BCC provides the first indication that azathioprine exposure may be associated with PTCH mutations, particularly in tumours from non-sun-exposed skin.

Basosquamous cell carcinoma in organ transplant patients: A clinicopathologic study

“…Mutations of the PTCH gene exist in the majority of BCC. 28,29 It would be interesting to investigate if PTCH mutations exist also in BSCC; this would further help elucidate the relation between BCC and BSCC.…”

Cancers Complicating Inflammatory Bowel Disease

“…The carcinogenic action of thiopurines could include an increased toxicity of ultraviolet A radiation on epithelial skin cells 71 and a direct mutagenic effect on the gene encoding PTCH. 52 In patients with inflammatory bowel disease, no excess risk of nonmelanoma skin cancer attributable to TNF-α antagonists was found in a large cohort drawn from a health plan claims database, after adjustment for thiopurine therapy. 65 Patients with inflammatory bowel disease may have a slight unexplained intrinsic higher risk of developing melanoma.…”

Skin cancer in solid organ transplant recipients: Advances in therapy and management

“…51 Recent studies looking at the carcinogenic effects of cyclosporine examined the action of cyclosporine within keratinocyte mitochondria through inhibition of mitochondrial permeability transition pore (MPTP) opening. MPTP opening is induced by oxidative stress, such as that caused by UV light, and leads to cell death.…”