DNA adducts, detected by 32P postlabelling, in human cholangiocarcinoma.
BACKGROUND
Reported mortality from intrahepatic cholangiocarcinoma (CCa) has risen steeply in the UK and other industrialised countries over the past 30 years, the cause of which has not been explained. DNA adduct formation is promutagenic and demonstrates exposure to a DNA damaging agent. It is a key step in chemically induced carcinogenesis. We hypothesise that the increase in CCa mortality is caused by a rise in a genotoxic environmental agent(s), causing cholangiocyte DNA damage.


OBJECTIVE
To investigate and compare tumour and tumour adjacent CCa tissue, and non-cancer control bile duct tissue, for DNA adducts as a biomarker of genotoxin exposure.


METHODS
DNA from 32 intrahepatic CCa patients (and in 28 cases DNA from adjacent non-tumour tissue) and from biliary ducts of seven non-cancer patients were investigated for the presence of DNA adducts using the nuclease P1 method of (32)P postlabelling. DNA adduct levels (number of adducts/10(8) nucleotides) were quantified.


RESULTS
There was no significant difference in relative adduct labellings (RALs) between tumour adjacent DNA (median 8.6, range 1.2-51.6) and CCa DNA (7.2, 1.8-48.4). However, RALs were significantly higher in DNA from cancer patients (tumour adjacent and CCa DNA) compared with non-cancer patient DNA (2.9, 0.6-11.5; p=0.032, two tailed Mann-Whitney U test). Different adduct patterns were also seen in CCa compared with non-cancer patients.


CONCLUSIONS
Quantitative and qualitative differences in adducts between cancer and non-cancer patients support the hypothesis that genotoxins may play a role in the development of intrahepatic CCa.
Khan
S A
SA
The Liver Centre, Division of Medicine A, Faculty of Medicine, Imperial College London, St Mary's Hospital Campus, South Wharf St, London W2 1PG, UK. shahid.khan@ic.ac.uk
Carmichael
P L
PL
Taylor-Robinson
S D
SD
Habib
N
N
Thomas
H C
HC
D000328:Adult; D000368:Aged; D001650:Bile Duct Neoplasms / Q000235:genetics*; D001653:Bile Ducts, Intrahepatic; D018281:Cholangiocarcinoma / Q000235:genetics*; D018736:DNA Adducts; D004249:DNA Damage; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010761:Phosphorus Radioisotopes
D018736:DNA Adducts; D010761:Phosphorus Radioisotopes