Abstract
BACKGROUND & AIMS: Patients with alpha-1 antitrypsin deficiency (AATD) have a 20- to 50-fold higher risk of developing primary liver cancer (PLC), such as hepatocellular carcinoma (HCC), in both cirrhotic and noncirrhotic livers, highlighting AATD as a potential oncogenic factor. In this exploratory study, we aimed to describe the frequency and characteristics of AATD alleles in patients with HCC arising in noncirrhotic livers. METHODS: The two most common pathogenic AATD variants, the Z (SERPINA1 p.Glu366Lys) and S (SERPINA1 p.Glu264Val) alleles, were identified using a multiplex digital polymerase chain reaction (PCR) system in a French cohort of 91 patients who developed HCC in a noncirrhotic liver and without major liver risk factors, including alcohol consumption, viral hepatitis, or metabolic-associated steatohepatitis. RESULTS: We found that 22.83% (21/91) of patients with HCC carried at least one S or Z allele of SERPINA1, a prevalence that was higher than in the general French population (16.9%) and in the UK population with PLC (12%). The distribution of genotypes was heterozygous for the M and S alleles (18/21), heterozygous for the M and Z alleles (2/21), and homozygous for the S allele (1/21). Interestingly, AAT globules were observed in nontumoral liver tissue in 7 cases (37%), including individuals heterozygous for the M and S alleles and the individual homozygous for the S allele. CONCLUSION: Our study provides descriptive data on the presence of S and Z variants of SERPINA1 in patients with HCC arising in noncirrhotic livers, highlighting their potential relevance for further investigation. CLINICAL TRIAL NUMBER: NCT07145385.