title: Novel point mutations and mutational complexes in the enhancer II, core promoter and precore regions of hepatitis B virus genotype D1 associated with hepatocellular carcinoma in Saudi Arabia.
abstract: In this study, a cohort of 182 patients [55 hepatocellular carcinoma (HCC) and 127 non-HCC] infected with hepatitis B virus (HBV) in Saudi Arabia was investigated to study the relationship between sequence variation in the enhancer II (EnhII), basal core promoter (BCP) and precore regions of HBV genotype D (HBV/D) and the risk of HCC. HBV genotypes were determined by sequencing analysis and/or enzyme-linked immunosorbent assay. Variations in the EnhII, BCP and precore regions were compared between 107 non-HCC and 45 HCC patients infected with HBV/D, followed by age-matched analysis of 40 cases versus equal number of controls. Age and male gender were significantly associated with HCC (p = 0.0001 and p = 0.03, respectively). Serological markers such as aspartate aminotransferase, albumin and anti-HBe were significantly associated with HCC (p = 0.0001 for all), whereas HBeAg positivity was associated with non-HCC (p = 0.0001). The most prevalent HBV genotype was HBV/D (94%), followed by HBV/E (4%), HBV/A (1.6%) and HBV/C (0.5%). For HBV/D1, genomic mutations associated with HCC were T1673/G1679, G1727, C1741, C1761, A1757/T1764/G1766, T1773, T1773/G1775 and C1909. Age- and gender-adjusted stepwise logistic regression analysis indicated that mutations G1727 [odds ratio (OR) = 18.3; 95% confidence interval (CI) = 2.8-118.4; p = 0.002], A1757/T1764/G1766 (OR = 4.7; 95% CI = 1.3-17.2; p = 0.01) and T1773 (OR = 14.06; 95% CI = 2.3-84.8; p = 0.004) are independent predictors of HCC development. These results implicate novel individual and combination patterns of mutations in the X/precore region of HBV/D1 as predictors of HCC. Risk stratification based on these mutation complexes would be useful in determining high-risk patients and improving diagnostic and treatment strategies for HBV/D1.
authors.affiliation: King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; Department of Virology and Liver Unit, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Anis
authors.initials: A
authors.lastname: Khan
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Al Balwi
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Ali
authors.initials: A
authors.lastname: Hajeer
authors.forename: Faisal M
authors.initials: FM
authors.lastname: Sanai
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Al Abdulkarim
authors.forename: Latifah
authors.initials: L
authors.lastname: Al Ayyar
authors.forename: Motasim
authors.initials: M
authors.lastname: Badri
authors.forename: Dib
authors.initials: D
authors.lastname: Saudi
authors.forename: Waleed
authors.initials: W
authors.lastname: Tamimi
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizokami
authors.forename: Bandar
authors.initials: B
authors.lastname: Al Knawy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000821:virology*; D002648:Child; D004742:Enhancer Elements, Genetic; D005260:Female; D005838:Genotype; D006515:Hepatitis B virus / Q000145:classification / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology / Q000821:virology*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D012529:Saudi Arabia
keywords: X-gene; genotype D; hepatitis B virus; hepatocellular carcinoma; mutational complexes; point mutations; sequence analysis