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.

Figure 1

PTCH mutation spectra in BCC from azathioprine- and non-azathioprine-treated patients. A similar proportion of UVB and oxidation-type mutations is present in each group. The G:C to A:T transition mutations at non-dipyrimidine sites (hatched) occured exclusively in the azathioprine-exposed group. These were all within the same TGTC sequence in different locations within PTCH.

Figure 2

Sequencing data in BCC from azathioprine-exposed individuals. (A) Mutation in PTCH exon 3 (g.75061 C>T, c.478 C>T, p. Q160X). Data from patient BCC ID 21 (top) and from a wild-type control (bottom). (B) Mutation in PTCH exon 5 (g.78881 C>T, c. 724 C>T, p. Q242X). Sequencing data are from patient BCC ID 28 (top) and from a wild-type control (bottom).