LAUSR

Aim: A single nucleotide polymorphism (SNP) in PNPLA3 was identified as a disease susceptibility gene for fatty liver disease (FLD) and it’s associated with fibrosis progression and carcinogenesis. Additionally, mutations in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13), which encodes hepatic lipid droplet protein, have been found the involvement in various metabolic processes. Loss-of-function mutations in the human HSD17B13 gene may confer a strong protective effect on liver injury, inflammation, fibrosis, and even onset of hepatocellular carcinoma (HCC). Here, we evaluated the characteristics of Japanese patients with FLD- HCC and considered the risk factors of HCC including genetic background. Methods: We enrolled 402 patients of clinically and pathologically diagnosed with FLD (alcohol: 63, nonalcohol: 339) in our hospital from 1990-2018 (228 males, median age 54.9 [14.6-83.6] years). We analyzed the survival and new-onset HCC rates according to the etiology of FLD (alcohol and nonalcohol), hepatic fibrosis, FIB-4 index, and genetic background of PNPLA3 and HSD17B13 for consideration of the risk factors. Results: FLD-HCC was observed in 57 cases (14.2%). Comparing to the patients with HSD17B13 wild-type AA (212 cases) and mutant (A/AA or AA/AA, 190 cases), patients with wild type showed significantly increased HCC complication (wild vs. mutant; 39 [18.4%] vs. 18 [9.5%], p = 0.01) and these were tended to be high complication of hypertension (120 [56.6%] vs. 90 [47.4%], p = 0.06). In patients with mutant of HSD17B13, HCC incidence was significantly reduced in alcohol-related FLD, FIB-4 index <2.67, and PNPLA3 CC genotype, however, there was not significant difference in nonalcohol-FLD. Patients with HSD17B13 mutant showed severe steatosis (77% vs. 88.6%). Eleven cases of new HCC were developed during observation period (8.1 [0.5-25.1] years) (n = 370). Five-year incidence of HCC was 3.3% in patients with both PNPLA3 GG/GC and HSD17B13 wild type and it was significantly elevated compared to other SNP profiles (0.6%, p = 0.03). Multivariate analysis identified the risk of FLD-HCC including age, gender, and complication of hypertension. Conclusions: Genetic background of FLD may associate with onset of HCC. Inhibiting HSD17B13 activity may prevent HCC development, especially in alcohol-related FLD and patients with low risk factors. Therefore, SNPs of gene combination with other risk factors may use for screening tool for FLD-HCC. Citation Format: Tomomi Kogiso, Yuri Ogasawara, Kentaro Horiuchi, Makiko Taniai, Katsutoshi Tokushige. Characteristics of fatty liver disease-related hepatocellular carcinoma and genetic background in Japan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 760.