ALPHA-1 antitrypsin genotype, sex, and lung cancer: Clinical and molecular characterisation

Alpha-1 antitrypsin deficiency is associated with lung and liver disease, but its role in lung carcinogenesis remains unclear. This study aimed to compare the clinical, functional, and molecular characteristics of lung cancer according to alpha-1 antitrypsin (AAT) genotype and, additionally, to explore differences by sex and the possible influence of environmental exposures.

We conducted a cross-sectional, single-centre study including 407 patients with incident lung cancer diagnosed between 2020 and 2023. Clinical, functional, radiological, molecular, and environmental variables were collected. Comparisons were performed between carriers and non-carriers of altered AAT alleles and between women and men.

Of the 394 patients with available genotyping, 24.4% carried at least one altered allele. No significant differences were observed by genotype in smoking status, radon exposure, comorbidities, lung function, or histological subtype. Carriers showed significantly lower serum AAT levels and a higher frequency of values < 116 mg/dL (p < 0.001). PD-L1 expression ≥ 50% was more common in carriers (28.1% vs. 19.4%; p = 0.036). In the multivariable analysis, the altered AAT genotype remained independently associated with a higher probability of PD-L1 expression ≥ 50% (aOR = 2.04; 95% CI: 1.09-3.80; p = 0.026). Women had lower cumulative tobacco exposure, lower prevalence of emphysema and COPD, greater biomass exposure, higher frequency of adenocarcinoma, and more EGFR mutations (p < 0.001).

Patients carrying altered AAT alleles did not exhibit a distinctly different clinical profile, although they showed higher PD-L1 expression (≥50%). Furthermore, significant differences were observed between women and men in terms of exposure, histology and molecular alterations.