We assessed the characteristics of patients in the global population (N = 377) with HBV-(107) and non-HBV-(270)related HCC.We found that 85.05% of patients with HBV-related HCC were diagnosed in Asia, which was significantly higher compared with other areas (P < 0.001). Patients with HBV-related HCC had a higher incidence(82.24%vs.61.85%)( P < 0.001) in male and younger ages(median,maximum and minimum of age were 53,83,23 vs. 64,90,16)(P < 0.01) than non-HBV-related.In addition, the pathological grade of HBV-related HCC was grade 3-4 in common, and have a poor of overall survival (OS) and disease-free survival(DFS) than non-HBV-related (P < 0.001)(Fig.1, Table 1).
Mutational profile of HCC patients
Of total 377 HCC patients, 41198 single nucleotide variants（SNV）mutations of 13,668 genes were detected, most of mutations were less than 5,and a total of 440 mutations were more than 10. The most common mutation types of gene were Missense(31925,77%) and Frameshift mutations(5269,13%), the rest of which were Stop_gained(1851,4%),Splice_Site(1709,4%),Indel(444,1%) and CN_amp(290,1%) respectively.The detection rates of mutations more than 10% inHCC patients were TP53, TTN, CTNNB1, MUC16, ALB, MT-NDS,APOB and RYR2(Table 2,Fig.2).
Comparison of OncoPrint of HBV- and non-HBV-related HCC patients
The results of OncoPrint of HCC show that the mutation detection rate of TTN(19%vs.30%),SPTA1(2%vs.10%) and USH2A(2%vs9%) in HBV-related HCC were significantly lower than in non-HBV-related(Fig 3(A)).In addition, AXIN1, MAST4, CDKN2A, KRT10, CACNA2D1 and COL4A5 were significantly higher tested in patients with HBV-related HCC(P < 0.01). TTN, BAP1, CSMD1, SPTA1, USH2A, DNAH17 and MYO18B were significantly higher tested in patients with non-HBV-related HCC(P < 0.01)(Fig.3(A,B,C)).
Mutational signatures of HBV- and non-HBV-related HCC patients
We analyzed mutational gene signatures detected in HBV and non-HBV-related HCC in MusiCa(http://bioinfo.ciberehd.org:3838/MuSiCa/).The results show that a total of 8545 mutation genes were tested in HBV-related HCC,and 27105 mutation genes were tested in non-HBV-related HCC(Fig.4(A)). Novel mutational genes compared with enrolled in COSMIC database,which were detected in non-HBV-related HCC were significantly more than HBV-related(4.16%vs.3.67%,P=0.036)(Fig.4(B),Table 3).In addition,in HBV-related HCC patients, the mutations of C>T and T>A were more enriched in C*G. In contrast, the mutations of T>C were more enriched in C*C and G*C in non-HBV-related HCC(Fig.4(C)).Mutational signature 26,6 and 16 were detected in HBV-related HCC, while were not detected in non-HBV-related.Mutational signature 17,20 and 12 in non-HBV-related HCC were significantly higher than HBV-related(Fig.4(D)).
Tumor mutation burden (TMB) and effects on OS of mutation genes between HBV- and non-HBV-related HCC patients.
TMB of non-HBV-related HCC was significantly higher than HBV-related (P<0.01).
TMB of RYR2,MUC16,TTN and TP53 mutiaions was significantly higher than wild type (WT) in HCC patients(P<0.001)(Fig.5).Mutations of TTN, MUC16, RYR2, DNAH7 and ARID2 had significant effects on OS in HBV-related but were not associated with prognosis of non-HBV-related HCC.In contrast, mutations of TP53, APOB, ARID1A, LRP1B, SYNE2, CUBN and NBEA had significant effects on OS in non-HBV-related, but were not associated with prognosis of patients with HBV-related HCC(Fig.6,Fig.7).