Germline TYK2 mutation and cancer risk

Deucravacitinib, a novel, selective inhibitor of TYK2 is currently under review at the FDA and EMA for treatment of moderate-to-severe plaque psoriasis. It is unclear whether recent safety concerns (i.e. elevated rates of lung cancer and lymphoma) related to similar medications (i.e. other JAK inhibitors) are shared with this novel TYK2 inhibitor. We used a partial loss-of-function variant in TYK2 (rs34536443), previously shown to protect against psoriasis and other autoimmune diseases, to evaluate the potential effect of therapeutic TYK2 inhibition on risk of lung cancer and non-Hodgkin lymphoma. Summary genetic association data on lung cancer risk were obtained from a GWAS meta-analysis of 29,266 cases and 56,450 controls in the Integrative Analysis of Lung Cancer Risk and Etiology (INTEGRAL) consortium. Summary genetic association data on non-Hodgkin lymphoma risk were obtained from a GWAS meta-analysis of 8,489 cases and 374,506 controls in the UK Biobank and InterLymph consortium. In the primary analysis, each copy of the minor allele of rs34536443, representing partial TYK2 inhibition, was associated with an increased risk of lung cancer (OR 1.15, 95% CI 1.07-1.24, P = 1.72 x 10-4) and non-Hodgkin lymphoma (OR 1.18, 95% CI 1.05-1.33, P = 5.25 x 10-3). In secondary analyses, there was weak evidence of an association of rs34536443 with advanced prostate cancer risk (OR 1.08, 95% CI 1.00-1.17, P = 0.04), but little evidence of association with three other common adult cancers examined. Our analyses using an established partial loss-of-function mutation to mimic TYK2 inhibition provide genetic evidence that therapeutic TYK2 inhibition may increase risk of lung cancer and non-Hodgkin lymphoma. These findings, consistent with recent reports from post-marketing trials of similar JAK inhibitors, could have important implications for future safety assessment of Deucravacitinib and other TYK2 inhibitors in development.