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It is unclear whether recent safety concerns (ie, elevated rates of lung cancer and lymphoma) related to similar medications (ie, other JAK inhibitors) are shared with this novel TYK2 inhibitor. We used a partial loss\u2010of\u2010function 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\u2010Hodgkin lymphoma. Summary genetic association data on lung cancer risk were obtained from a GWAS meta\u2010analysis of 29\u2009266 cases and 56\u2009450 controls in the Integrative Analysis of Lung Cancer Risk and Aetiology (INTEGRAL) consortium. Summary genetic association data on non\u2010Hodgkin lymphoma risk were obtained from a GWAS meta\u2010analysis of 8489 cases and 374\u2009506 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 1.09\u20101.23, <jats:italic>P<\/jats:italic>\u00a0=\u00a02.29 \u00d7\u200910<jats:sup>\u22126<\/jats:sup>) and non\u2010Hodgkin lymphoma (OR 1.18, 95% CI 1.05\u20101.33, <jats:italic>P<\/jats:italic>\u00a0=\u00a05.25 \u00d7\u200910<jats:sup>\u22123<\/jats:sup>). Our analyses using an established partial loss\u2010of\u2010function mutation to mimic TYK2 inhibition provide genetic evidence that therapeutic TYK2 inhibition may increase risk of lung cancer and non\u2010Hodgkin lymphoma. These findings, consistent with recent reports from postmarketing trials of similar JAK inhibitors, could have important implications for future safety assessment of deucravacitinib and other TYK2 inhibitors in development.<\/jats:p>","DOI":"10.1002\/ijc.34180","type":"journal-article","created":{"date-parts":[[2022,6,24]],"date-time":"2022-06-24T06:36:02Z","timestamp":1656052562000},"page":"2155-2160","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Association of germline <scp>TYK2<\/scp> variation with lung cancer and <scp>non\u2010Hodgkin<\/scp> lymphoma risk"],"prefix":"10.1002","volume":"151","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4371-0873","authenticated-orcid":false,"given":"James","family":"Yarmolinsky","sequence":"first","affiliation":[{"name":"Medical Research Council Integrative Epidemiology Unit University of Bristol  Bristol UK"},{"name":"Population Health Sciences Bristol Medical School, University of Bristol  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher I.","family":"Amos","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4486-7496","authenticated-orcid":false,"given":"Rayjean J.","family":"Hung","sequence":"additional","affiliation":[{"name":"Lunenfeld\u2010Tanenbaum Research Institute Sinai Health  Toronto Ontario Canada"},{"name":"University of Toronto  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2818-5487","authenticated-orcid":false,"given":"Victor","family":"Moreno","sequence":"additional","affiliation":[{"name":"Biomarkers and Susceptibility Unit, Oncology Data Analytics Program Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat  Barcelona Spain"},{"name":"Colorectal Cancer Group, ONCOBELL Program Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat  Barcelona Spain"},{"name":"Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP)  Madrid Spain"},{"name":"Department of Clinical Sciences, Faculty of Medicine University of Barcelona  Barcelona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberley","family":"Burrows","sequence":"additional","affiliation":[{"name":"Medical Research Council Integrative Epidemiology Unit University of Bristol  Bristol UK"},{"name":"Population Health Sciences Bristol Medical School, University of Bristol  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karl","family":"Smith\u2010Byrne","sequence":"additional","affiliation":[{"name":"Cancer Epidemiology Unit, Oxford Population Health University of Oxford  Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua R.","family":"Atkins","sequence":"additional","affiliation":[{"name":"Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC\/WHO)  Lyon France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0518-8714","authenticated-orcid":false,"given":"Paul","family":"Brennan","sequence":"additional","affiliation":[{"name":"Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC\/WHO)  Lyon France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Colon Cancer Family Registry (CCFR), Colorectal Cancer Transdisciplinary Study (CORECT), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) Consortium","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James D.","family":"McKay","sequence":"additional","affiliation":[{"name":"Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC\/WHO)  Lyon France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard M.","family":"Martin","sequence":"additional","affiliation":[{"name":"Medical Research Council Integrative Epidemiology Unit University of Bristol  Bristol UK"},{"name":"Population Health Sciences Bristol Medical School, University of Bristol  Bristol UK"},{"name":"University Hospitals Bristol, NHS Foundation Trust, National Institute for Health Research Bristol Biomedical Research Centre, University of Bristol  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Davey Smith","sequence":"additional","affiliation":[{"name":"Medical Research Council Integrative Epidemiology Unit University of Bristol  Bristol UK"},{"name":"Population Health Sciences Bristol Medical School, University of Bristol  Bristol 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