PTCH mutations in basal cell carcinomas from azathioprine-treated organ transplant recipients.
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.
Centre for Cutaneous Research, Institute of Cell and Molecular Science, Bart's and The London, Queen Mary School of Medicine and Dentistry, 4 Newark Street, London, UK. caharwood@doctors.org.uk
C A
CA
Harwood
N R
NR
Attard
P
P
O'Donovan
P
P
Chambers
C M
CM
Perrett
C M
CM
Proby
J M
JM
McGregor
P
P
Karran
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001379:Azathioprine / Q000009:adverse effects*; D002280:Basal Cell Carcinoma / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D016867:Immunocompromised Host / Q000235:genetics*; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016377:Organ Transplantation / Q000009:adverse effects; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D016133:Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000235:genetics*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D013472:Sunlight / Q000009:adverse effects
D007166:Immunosuppressive Agents; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D001379:Azathioprine