Common alpha-1 antitrypsin deficiency genotypes: lung cancer risk and tumour molecular profile
TL;DR
Carriage of common AAT-deficient alleles was inversely associated with LC after adjustment for major confounding factors, and the association with higher PD-L1 expression suggests that these common AAT-deficient genotypes may be associated with differences in tumour phenotype rather than acting as a direct aetiological factor.
Abstract
Alpha-1 antitrypsin deficiency (AATD) has been linked to chronic inflammation and protease–antiprotease imbalance involved in lung carcinogenesis. Evidence regarding the relationship between the most common AAT-deficient genotypes and lung cancer (LC) is inconsistent. We aimed to evaluate the association between the most common AAT-deficient genotypes carrying S or Z alleles and LC, considering clinical, environmental and molecular factors. A hospital-based case-control study was conducted including 407 patients with a recent diagnosis of LC and 1201 controls. AAT genotypes were determined and clinical and environmental data were collected, including residential radon measurements. Multivariable logistic regression models adjusted for age, sex, smoking status and radon exposure were used. Analyses were further stratified by histological type, age at diagnosis and tumour molecular alterations. Most participants carrying deficient SERPINA1 genotypes had common mild deficiency variants (predominantly Pi*MS), and no individuals with the Pi*ZZ genotype were identified. The prevalence of AAT-deficient alleles was 24.4% in cases and 32.4% in controls. Carriage of AAT-deficient alleles was inversely associated with LC compared with individuals with the Pi*MM genotype (adjusted OR = 0.71; 95% CI: 0.53–0.97). Active smoking, older age and radon > 300 Bq/m³ were significantly associated with LC. No associations were observed between AAT genotype and histological type, age at diagnosis or EGFR mutations. High PD-L1 expression (≥ 50%) was more frequent in tumours from carriers of AAT-deficient alleles (adjusted OR = 1.82; 95% CI: 1.00–3.33). In this study, carriage of common AAT-deficient alleles was inversely associated with LC after adjustment for major confounding factors. The association with higher PD-L1 expression suggests that these common AAT-deficient genotypes may be associated with differences in tumour phenotype rather than acting as a direct aetiological factor.