AIM:To explore the mode of inheritance of hepatocellularcarcinoma (HCC) in a moderately high-incidence area ofEast China.METHODS:A pedigree survey was conducted in 210 families(3315 individuals) ascertained through 210 HCC probandsin Haimen,Jiangsu Province.Simple segregation analysiswas conducted using SEGRANB software.The probability ofascertainment (π),segregation ratio (p),and the proportionof sporadic cases (x) were estimated.Complex segregationanalysis was performed using the REGTL program of S.A.G.E.Models were fitted on the data of 3212 individuals thatallowed for personal HBsAg status and variable age of onsetin REGTL program.RESULTS:The estimate of segregation ratio was 0.191 bySEGRANB.The probability of ascertainment was 0.0266,andthe proportion of sporadic cases was 0.465.The results ofcomplex segregation analysis showed that Mendelianautosomal recessive inheritance of a major gene thatinfluenced the age of onset distribution of HCC,providedthe best fit to the data.In the best-fitting recessive model,the frequency of the disease allele was 0.11138.HBsAgseropositive status would significantly increase the risk ofdeveloping HCC.CONCLUSION:These results suggest that at least onemajor gene is involved in the genetic predisposition todevelop HCC at an earlier age of onset.The seropositiveHBsAg status can significantly increase the risk of developingHCC,which provides strong support for the interactionbetween genetic and environmental risk factors. AIM: To explore the mode of inheritance of hepatocellular carcinoma (HCC) in a moderately high-incidence area of ​​East China. METHODS: A pedigree survey was conducted in 210 families (3315 individuals) ascertained through 210 HCC probandsin Haimen, Jiangsu Province. Simple segregation analysis was conducted using SEGRANB software.The probability of ascertainment (π), segregation ratio (p), and the proportionof sporadic cases (x) were estimated.Complex segregationanalysis was performed using the REGTL program of SAGEModels were fitted on the data of 3212 individuals thatallowed for personal HBsAg status and variable age of onsetin REGTL program.RESULTS: The estimate of segregation ratio was 0.191 bySEGRANB.The probability of ascertainment was 0.0266, and the proportion of sporadic cases was 0.465.The results of complex segregation analysis showed that Mendelianautosomal recessive inheritance of a major gene that influenced the age of onset distribution of HCC, provided the best fit to the data best-fitting recessive model, the frequency of the disease allele was 0.11138.HBsAgseropositive status would significantly increase the risk of developing HCC.CONCLUSION: These results suggest that at least one major gene is involved in the genetic predisposition to develop HCC at an earlier age of onset. The seropositive HBsAg status can significantly increase the risk of developing HCC, which provides strong support for the interaction between genetic and environmental risk factors.