Clinical utility of complex mutations in the core promoter and proximal precore regions of the hepatitis B virus genome

Table 1 Hepatocellular carcinoma rate of specific mutation combinations and odds ratio in comparison with basal core promoter double mutation only

Specific mutation combinations	HCC1 rate	OR	95%CI	P-value
in combination with BCP2 double mutations
Wild-type	3.4% (1/29)	0.23	0.0048-2.0622	0.2391
BCP double mutations only [(A1762T + G1764A)]3	13.6% (6/44)	13
Dominant quadruple mutations
(G1613A + C1653T)	46.2% (6/13)	5.4286	5.4286-1.3530	0.0200
(C1653T + T1753V)	40.0% (2/5)	4.2222	4.2222-0.5797	0.1821
(C1653T + G1896A)	27.3% (6/20)	2.7143	2.7143-0.7495	0.1680
(T1753V + G1896A)	66.7% (14/21)	12.6667	12.6667-3.6262	0.0000
(A1846T + G1896A)	46.2% (6/13)	5.4286	5.4286-1.3530	0.0200
Dominant combinations in sextuplet mutations:
(G1613A + C1653T + A1846T + G1896A)	71.4% (5/7)	14.5142	1.8869-185.1359	0.0033
(G1613A + C1653T + A1846T + G1899A)	83.3% (5/6)	28.2555	2.5885-1517.9673	0.0012
Dominant combinations in septuplet mutations:
(G1613A + C1653T + T1753V + A1846T + G1896A)	100% (6/6)	Infinity	5.4236-infinity	0.0001
(G1613A + C1653T + A1846T + G1896A + G1899A)	85.7% (6/7)	39.3553	4.0487-2018.0433	0.0001

¹Hepatocellular carcinoma;

²Basal core promoter;

³Reference of odds ratio analyses; P-value was calculated by Fisher’s exact test for count data. BCP: Basal core promoter; HCC: Hepatocellular carcinoma.

Table 2 Comparison of hepatocellular carcinoma rate between low and high titers of hepatitis B e antigen in each mutation number group

Mutation	HBeAg-positive rate		HCC rate			HBeAg < 35 or	P-value1
number	Total	HBeAg < 35	HBeAg-positive		HBeAg-negative	HBeAg-negative rate
	% (No./total cases)	% (No./total cases)	HBeAg > 35	HBeAg < 35	% (No./total cases)	among HCCs
			% (No./total cases)	% (No./total cases)		% (No./total cases)
0	96.6% (28/29)	7.1% (2/28)	0% (0/26)	50% (1/2)	0% (0/1)	100% (1/1)	-
1	65.2% (15/23)	13.3% (2/15)	0% (0/13)	0% (0/2)	25.0% (2/8)	100% (2/2)	-
2-12	45.5% (5/11)	60.0% (3/5)	0% (0/2)	33.3% (1/3)	16.7% (1/6)	100% (2/2)	-
2-23	84.1% (37/44)	16.2% (6/37)	6.5% (2/31)	33.3% (2/ 6)	28..6% (2/7)	66.7% (4/6)	0.0530
3	71.4% (60/84)	25.0% (15/60)	10.4% (5/48)	31.3% (5/16)	31.4% (11/35)	76.2% (16/21)	0.0137
4	48.5% (47/97)	42.6% (20/47)	22.2% (6/27)	45.0% (9/20)	38.9% (21/54)	83.3% (30/36)	0.1047
5	40.0% (26/65)	46.2% (12/26)	33.3% (5/15)	41.7% (5/12)	28.2% (11/39)	76.2% (16/21)	1.0000
6	46.2% (18/39)	66.7% (12/18)	57.1% (4/7)	53.8% (7/13)	50.0% (11/22)	81.8% (18/22)	1.0000
7	47.4% (9/19)	100% (9/9)	0% (0/9)	100% (9/9)	60.0% (6/10)	100% (15/15)	-
8	12.5% (1/8)	100% (1/1)	0% (0/1)	100% (1/1)	71.4% (5/7)	100% (6/6)	-

¹Fisher’s exact test for count data was carried out to compare the significance of HBeAg status in the prediction of HCC risk between HCC patients with HBeAg > 35 and with HBeAg < 35 or -negative. Low titer HBeAg or HBeAg-negativity is significantly predominant among HCC patients;

²Only one of two mutations is A1762T or G1764A;

³Basal core promoter double mutations (A1762T/G1764A). HCC: Hepatocellular carcinoma; HBeAg: Hepatitis B e antigen.