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

C. A. Harwood, N. R. Attard, P. O'Donovan, P. Chambers, C. M. Perrett, C. M. Proby, J. M. McGregor, P. Karran

    Research output: Contribution to journalArticle

    37 Citations (Scopus)

    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 T (G) under bar TC 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.

    Original languageEnglish
    Pages (from-to)1276-1284
    Number of pages9
    JournalBritish Journal of Cancer
    Volume99
    Issue number8
    DOIs
    Publication statusPublished - 2008

    Keywords

    • azathioprine
    • basal cell carcinoma
    • PTCH gene
    • immunosuppression
    • organ transplant recipients
    • SKIN-CANCER
    • HUMAN HOMOLOG
    • SONIC HEDGEHOG
    • NEVUS SYNDROME
    • P53 MUTATIONS
    • PATCHED PTCH
    • RISK-FACTORS
    • UVA LIGHT
    • IN-VIVO
    • GENE

    Cite this

    Harwood, C. A., Attard, N. R., O'Donovan, P., Chambers, P., Perrett, C. M., Proby, C. M., ... Karran, P. (2008). PTCH mutations in basal cell carcinomas from azathioprine-treated organ transplant recipients. British Journal of Cancer, 99(8), 1276-1284. https://doi.org/10.1038/sj.bjc.6604665
    Harwood, C. A. ; Attard, N. R. ; O'Donovan, P. ; Chambers, P. ; Perrett, C. M. ; Proby, C. M. ; McGregor, J. M. ; Karran, P. / PTCH mutations in basal cell carcinomas from azathioprine-treated organ transplant recipients. In: British Journal of Cancer. 2008 ; Vol. 99, No. 8. pp. 1276-1284.
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    title = "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 T (G) under bar TC 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.",
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    author = "Harwood, {C. A.} and Attard, {N. R.} and P. O'Donovan and P. Chambers and Perrett, {C. M.} and Proby, {C. M.} and McGregor, {J. M.} and P. Karran",
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    Harwood, CA, Attard, NR, O'Donovan, P, Chambers, P, Perrett, CM, Proby, CM, McGregor, JM & Karran, P 2008, 'PTCH mutations in basal cell carcinomas from azathioprine-treated organ transplant recipients', British Journal of Cancer, vol. 99, no. 8, pp. 1276-1284. https://doi.org/10.1038/sj.bjc.6604665

    PTCH mutations in basal cell carcinomas from azathioprine-treated organ transplant recipients. / Harwood, C. A.; Attard, N. R.; O'Donovan, P. ; Chambers, P.; Perrett, C. M.; Proby, C. M.; McGregor, J. M.; Karran, P.

    In: British Journal of Cancer, Vol. 99, No. 8, 2008, p. 1276-1284.

    Research output: Contribution to journalArticle

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    T1 - PTCH mutations in basal cell carcinomas from azathioprine-treated organ transplant recipients

    AU - Harwood, C. A.

    AU - Attard, N. R.

    AU - O'Donovan, P.

    AU - Chambers, P.

    AU - Perrett, C. M.

    AU - Proby, C. M.

    AU - McGregor, J. M.

    AU - Karran, P.

    PY - 2008

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    N2 - 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 T (G) under bar TC 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.

    AB - 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 T (G) under bar TC 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.

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    KW - basal cell carcinoma

    KW - PTCH gene

    KW - immunosuppression

    KW - organ transplant recipients

    KW - SKIN-CANCER

    KW - HUMAN HOMOLOG

    KW - SONIC HEDGEHOG

    KW - NEVUS SYNDROME

    KW - P53 MUTATIONS

    KW - PATCHED PTCH

    KW - RISK-FACTORS

    KW - UVA LIGHT

    KW - IN-VIVO

    KW - GENE

    U2 - 10.1038/sj.bjc.6604665

    DO - 10.1038/sj.bjc.6604665

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