Published online Mar 22, 2023. doi: 10.4291/wjgp.v14.i2.21
Peer-review started: December 11, 2022
First decision: February 8, 2023
Revised: February 19, 2023
Accepted: March 15, 2023
Article in press: March 15, 2023
Published online: March 22, 2023
Processing time: 99 Days and 14 Hours
Cholangiocarcinoma (CCA) is a cancer of the hepatobiliary tract, and its incidence is extremely high in northeastern Thailand. This is related to the lifestyle of the inhabitants of this area consuming often raw fish, which carries the risk of ingesting fish-borne parasites, Opisthorchis viverrini (OV), a known CCA risk factor. While infection with OV has been listed as a carcinogen to humans by The International Agency for Research on Cancer, the parasitic infection alone is not sufficient to develop CCA; in fact, co-administration of a chemical carcinogen such as N-nitrosodimethylamine is necessary to induce CCA in animal model. In addition, genetic background related to the activation or detoxification of chemical carcinogens is reported to be involved in CCA risk. Also, elevated plasma IL-6 was associated with increased risk of CCA in patients infected with OV.
We already reported that infection with OV and genetic polymorphism of a drug-metabolizing enzyme gene, namely GSTM1, is related to CCA risk and that the combined effect of polymorphisms of the genes 8-oxoguanine glycosylase 1 and GSTM1 is also relevant CCA risk in northeastern Thailand. In the present study, we further investigated possible associations of maintenance of chronic infection, exposure to a chemical carcinogen(s) and genetic background with CCA risk in northeastern Thailand.
To examine relations between risk for CCA and genetic polymorphisms in carcinogen-metabolizing (CYP2E1, GSTT1 and GSTM1) and inflammation-related genes (IL-6, IL-10 and NF-kB), and potential interactions among genetic polymorphisms of these genes on the CCA risk.
All cases with CCA were identified between 1999 and 2005 upon a visit to the Ubon Ratchathani Cancer Centre in the northeastern province of Thailand. This hospital-based case-control study enrolled 95 case-control pairs matched by age (± 5 years) and sex. We examined relations between risk for CCA and genetic polymorphisms in carcinogen-metabolizing and inflammation-related genes, serum anti-OV, alcohol consumption, and smoking. Smoking and alcohol consumption status were ascertained using a structured questionnaire used in previous studies. Conditional logistic regression was employed to estimate CCA risk as OR due to each of genetic polymorphisms and possible interactions of those polymorphisms.
Although any single polymorphism was not significantly associated with CCA risk, persons with the GSTT1 wild-type and CYP2E1 c1/c2 + c2/c2 genotype had a 3-fold increased risk as compared with persons having the GSTT1 wild-type and CYP2E1 c1/c1 wild genotype. The presence of anti-OV in serum was associated with a 7- to 11-fold increased risk for CCA independently of the genetic polymorphisms of carcinogen-metabolizing and inflammation-related genes.
An inflammatory condition produced by infection with OV indicated as raised anti-OV in serum has been associated with CCA risk. Our study added the finding that persons with the GSTT1 wild-type and CYP2E1 c1/c2 + c2/c2 genotype had a 3-fold increased risk for developing CCA. Therefore, both gene-gene interactions and OV infection should be considered as risk factors for cholangiocarcinogenesis in northeastern Thailand.
CCA is still an intractable cancer. While our study revealed the interaction of polymorphisms of GSTT1 and CYP2E1 possibly contributes to development of CCA, the numbers of cases and controls were not large. The conclusions from this work should be confirmed in a future study with more cases and controls. In addition, genes encoding other drug-metabolizing enzymes should also be tested with respect to gene-gene interactions.