Background: ?1-Antitrypsin deficiency is characterized by elevated elastase activity and excessive elastin degradation, which may impact cancer development and progression.

Aim: We tested the hypothesis that individuals with ?1-antitrypsin deficiency have increased susceptibility to cancer in the Danish population.

Methods: In a Nationwide nested study, we identified 2,702 individuals with ?1-antitrypsin deficiency and 26,750 control subjects without ?1-antitrypsin deficiency matched on birthday, sex, and municipality. We recorded admissions due to cancer as outcomes during a median follow-up of 62 years.

Results: Individuals with ?1-antitrypsin deficiency versus control subjects had increased risks of skin cancer (HR: 2.18, CI: 1.81-2.63), liver cancer (HR: 3.91, CI: 2.23-6.85), leukaemia (HR: 1.76, CI: 1.12-2.79), and cancer overall (HR: 1.25, CI: 1.13-1.38). When the analysis of skin cancer was stratified by skin disease or COPD, the risks for skin cancer were elevated in those with these diseases as opposed to those without (Ps for interaction: ?0.003). When the analysis of skin cancer was stratified by liver cirrhosis or ischemic heart disease similar results to those presented were seen (Ps for interaction: ?0.76). When the analysis of skin cancer was stratified by skin cancer type, individuals with ?1-antitrypsin deficiency had adjusted hazard ratios of 2.71 (CI: 2.21-3.32) for non-melanoma skin cancer and 0.93 (CI: 0.59-1.46) for melanoma, respectively.

Conclusion: Individuals with ?1-antitrypsin deficiency have increased risks of non-melanoma skin cancer, liver cancer, and leukaemia in the Danish population.