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Study links widely-used drug azathioprine to skin cancers

A drug used to treat inflammatory bowel disease and arthritis, and prevent organ rejection in transplant patients, has been identified as an important contributor to skin cancer development, in research by Queen Mary University of London, University of Dundee and the Wellcome Sanger Institute.

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The study, funded by Cancer Research UK and published in the journal Nature Communications, identified a 'strong case for an association' between the drug azathioprine and the mutational signature found in cases of cutaneous squamous cell carcinoma (cSCC) - a common form of skin cancer.

The researchers caution that their findings do not necessarily advocate the withdrawal of azathioprine, but that doctors should give patients advice on sun protection when treating potentially life-threatening diseases with azathioprine, and support early diagnosis of possible skin cancer.

There are more than 40,000 new cases of cSCC diagnosed annually in the UK, with incidence rising steadily. cSCC is particularly common in immunosuppressed individuals in whom the risk may be increased by 100-fold or more.

Important implications for patients who are on the drug

It was already known that use of azathioprine leads to increased photosensitivity to UVA light, probably contributing to development of skin cancers. This new study finds that use of azathioprine leaves a molecular fingerprint in skin cancers, further implicating it in cSCC development.

Dr Catherine Harwood from Queen Mary’s Blizard Institute said: “Our research provides compelling evidence that azathioprine is mutagenic in the skin in cooperation with ultraviolet radiation - specifically UVA - and is a significant cofactor in the development of SCC. These results have important practical implications for patients who are on the drug.

“Whilst our research is not a reason for necessarily withdrawing azathioprine, we recommend patients should be routinely advised on year-round sun protection and provided with appropriate support to ensure early diagnosis of possible skin cancer.”

Not recommending withdrawal of drug

Lead researcher Charlotte Proby from University of Dundee added: “As with all medications the risks must be balanced against the benefits, particularly with the need to treat potentially life-threatening diseases with an effective drug. It is important that sun protection, skin surveillance and early diagnosis/lesion removal are part of the routine management of patients on azathioprine.”

Importantly, the new study also reveals the molecular landscape of cSCC and highlights potential targets that may be developed for future therapies.

Different carcinogens leave a different 'mutational signature' in a cancer. By studying these signatures, researchers can start to determine what the causes of a cancer are.

Dr Jun Wang from Barts Cancer Institute at Queen Mary, who led the bioinformatics and computational investigation, said: “Previous analyses identified 30 distinct mutational signatures from more than 12,000 samples from a wide range of cancer types. In this study, we have identified a dominant mutational signature associated with azathioprine exposure from our immunosuppressed patients.

“This signature is distinct from all 30 previously known signatures. Interestingly, the majority of the driver gene mutations were caused by this drug azathioprine signature.”

More information

  • Find out more about our postgraduate programmes in Cancer and Clinical Dermatology at Queen Mary University of London.
  • Research paper: ‘The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature’ by Inman et al. Nature Communications.
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