Linking widely used drug azathioprine to skin cancers

A drug used to treat inflammatory bowel disease, arthritis and vasculitis as well as to prevent organ rejection in transplant patients has been identified as an important contributor to skin cancer development.

The research, published in 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.

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.

The senior author said, "We recommend all physicians give appropriate advice on UVA avoidance including year-round sun protection for their patients on azathioprine," and said they were not necessarily advocating withdrawal of azathioprine.

"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," the senior author said.

"It is important that sun protection, skin surveillance and early diagnosis/lesion removal are part of the routine management of patients on azathioprine."

cSCC is a common skin cancer with more than 40,000 new cases diagnosed annually in the UK, with significant health economic implications.

Importantly, this new study also reveals the molecular landscape of cSCC and highlights potential targets that may be developed for future therapeutic approaches to manage cSCC.

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.

Authors combined whole-exome analyses from 40 primary cSCC tumours, comprising 20 well-differentiated and 20 moderately/poorly differentiated tumors, with accompanying clinical data from a longitudinal study of immunosuppressed and immunocompetent patients and integrate this analysis with independent gene expression studies. They identified commonly mutated genes, copy number changes and altered pathways and processes. Comparisons with tumor differentiation status suggested events which may drive disease progression.

Mutational signature analysis reveals the presence of a novel signature (signature 32), whose incidence correlates with chronic exposure to the immunosuppressive drug azathioprine. Characterization of a panel of 15 cSCC tumor derived cell lines reveals that they accurately reflect the mutational signatures and genomic alterations of primary tumors and provide a valuable resource for the validation of tumor drivers and therapeutic targets.

Another author said, "Although patient numbers were small and these findings should be verified in a larger independent cohort, this molecular study provides a strong case for an association between this novel mutational signature and long-term azathioprine use."

https://www.dundee.ac.uk/news/2018/study-links-widely-used-drug-azathioprine-to-skin-cancers.php