PNPLA3 I148M polymorphism, etiology, and clinical features of hepatocellular carcinoma

Background & Aims : Recently, the Patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 C>G single nucleotide polymorphism (SNP), encoding for the I148M protein variant, has been recognized as a genetic determinant of liver fat content and to influence severity of liver damage in patients with non-alcoholic and alcoholic fatty liver disease (NAFLD and ALD) and with chronic hepatitis C (CHC). Furthermore, homozygosity for the148M allele has been associated with hepatocellular carcinoma (HCC) in CHC. Aim of the study was to evaluate the prevalence of the PNPLA3 148M variant in Italian patients with HCC and the influence on the natural history liver cancer. Patients and Methods: We studied 265 consecutive patients (M/F 203/62, age 68±9 yrs) with HCC referred to tertiary care centres in Italy with available DNA samples. HCC arose during follow up in 207 and was incidental in the remaining 58, in 5 cases HCC occurred in non-cirrhotic liver, and was diagnosed according to EASL criteria. The rs738409 genotype was determined by a Taqman assay. Results: The frequency distribution of the rs738409 SNP was 113 p.148I/I (45%), 119 p.148I/M (47%), and 33 (13%) p.148G/G (p<0.0001 vs. healthy controls). The p.148G variant was significantly more over-represented in patients with metabolic/toxic liver disease (NAFLD, ALD, iron overload, n=42) than in those with chronic viral hepatitis (HBV and HCV, n=223): 24% I/I, 57% I/M, 19% M/M vs. 46% I/I, 43% I/M, 11% M/M, respectively; p=0.02. Length of follow-up before HCC development, age at diagnosis, sex distribution, smoking history, and diabetes prevalence were not significantly different among PNPLA3 genotypes. However, the size of the larger HCC lesion tended to increase, although nonsignificantly, with the number of 148M alleles in patients presenting with multifocal disease (n=28: 2.6±1 cm I/I, 2.8±1.5 I/M, 4.2±1.8 M/M; p=0.06). At cox regression analysis, 148M PNPLA3 alleles were associated with a non significantly higher hazard ratio of death (HR 1.39, 95% c.i 0.94-2.02) independently of age, sex, etiology of liver disease, and smoking status. Conclusions: These data are consistent with previous findings indicating that the 148M PNPLA3 allele is a risk factor for HCC, in particular in the presence of steatosis related to metabolic/toxic liver diseases. A possible association of PNPLA3 genotype with biological features and prognosis of HCC should be evaluated in future larger studies