Alpha-1 Antitrypsin Deficiency Alleles in Non-Cirrhotic Hepatocellular Carcinoma: Insights from a Multicenter French...

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.

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.

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.

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.

NCT07145385.