Sequence variations of precore/core and precore promoter regions of hepatitis B virus in patients with or without viral reactivation during cytotoxic chemotherapy.
Reactivation of the hepatitis B virus (HBV) is a well-described complication among cancer patients undergoing cytotoxic chemotherapy. Mutations in the preC/C and the preC promoter regions of HBV have been reported in some patients who developed this condition. A G-to-A mutation at nt 1896 in the preC/C region (HBeAg negative/ anti-HBe positive) has been associated with more severe liver disease than that caused by wild type virus. In addition, it has been suggested that patients with these mutations may be more likely to reactivate than those with the wild type virus. Whether or not such mutations were present before the commencement of or developed during the course of cytotoxic chemotherapy is not known. In this study, 28 cancer patients (consisting of 14 consecutive patients who developed HBV reactivation and another 14 who had no reactivation during cytotoxic chemotherapy) are reported. The objectives were firstly, to determine the prechemotherapy HBeAg status and nucleotide sequences of the preC/C and preC promoter regions of HBV in order to determine if these parameters affected the rate of reactivation, and secondly, for those who developed reactivation, to determine whether the mutations were present before chemotherapy or developed during, possibly as a result of, cytotoxic chemotherapy. HBV DNA was amplified by PCR and nucleotide sequencing performed on samples taken prior to chemotherapy and at the time of reactivation. Results revealed that 16 of the 28 patients were HBeAg negative/anti-HBe positive. Of these 16, four (57%) of the seven patients who had nt 1896 mutation, but only one (17%) of the six who had the wild type HBV genome, developed reactivation. Three had no detectable HBV DNA. In the majority of cases, the type of virus, i.e. wild/mutant at preC/C, that was detected during the reactivation was identical to that detected in the pretreatment samples. With respect to the preC promoter region, the two commonest mutations detected were at nt 1762 (A to T) and nt 1764 (G to A). When this region was translated into amino acid sequences, stop codons leading to truncated X protein at carboxyl terminus were found in four patients, three of whom developed HBV reactivation. We conclude that chronic HBV carriers who are HBeAg negative/anti-HBe positive with nt 1896 mutation (G to A) may be more likely to develop HBV reactivation during cytotoxic chemotherapy than those with the wild type virus. Cytotoxic chemotherapy does not appear to select out mutant HBV, or to be consistently mutagenic in patients who develop HBV reactivation. The occurrence of stop codons in the amino acid sequences of the X protein in three patients who developed HBV reactivation, including one who was detected only at the time of reactivation, is of particular interest, as such mutant viruses remain replication competent.
Yeo
W
W
Department of Clinical Oncology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin.
Zhong
S
S
Chan
P K
PK
Ho
W M
WM
Wong
H T
HT
Chan
A S
AS
Johnson
P J
PJ
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001483:Base Sequence; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006509:Hepatitis B / Q000150:complications / Q000821:virology*; D006515:Hepatitis B virus / Q000235:genetics* / Q000254:growth & development; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D017422:Sequence Analysis, DNA; D015534:Trans-Activators / Q000235:genetics; D014758:Viral Core Proteins / Q000235:genetics*; D054334:Viral Regulatory and Accessory Proteins; D014775:Virus Activation
D000970:Antineoplastic Agents; D015534:Trans-Activators; D014758:Viral Core Proteins; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein