Germline genetic polymorphisms of CYP1A1, GSTM1 and GSTT1 genes in Indian cervical cancer: associations with tumor progression, age and human papillomavirus infection.
OBJECTIVE
Host genetic factors may play a role in human papillomavirus (HPV)-associated tumorigenesis, although the issue continues to be a focus of much debate. Biotransformation is critical in carcinogenic activity of numerous environmental carcinogens. It is therefore possible that polymorphisms of genes producing functional changes in xenobiotic metabolizing enzymes may be susceptible factors in cervical carcinogenesis. This study looked into possible relationships among these factors.


METHODS
In this case-control study, we analyzed leukocyte DNA from a total of 312 subjects for germline polymorphisms of CYP1A1 (m1 and m2), GSTM1 and GSTT1 at various stages of the cervical tumor progression spectrum, using PCR and RFLP.


RESULTS
Both m1 and m2 polymorphisms of the CYP1A1 gene were more frequent among cases (36.1% for m1 and 38.1% for m2) compared to control subjects (18.2% and 17.6% respectively). The odds ratio of a subject with homozygous CYP1A1 m1 and m2 variant being a case was highest (m1 OR = 4.77 [95% CI = 1.28-17.77]; P = 0.02 and m2 OR = 5.48 [95% CI = 1.49-20.19]; P = 0.011) respectively. The distribution of m1 and m2 CYP1A1 genotypes was also studied as a function of age and in relation to the presence of HPV 16 infection. The risk due to CYP1A1 m1 genotype, when adjusted for HPV status, showed a significantly increased risk (OR = 3.58, 95% CI = 1.88-6.81; P = 0.0001). Similar results were observed in the case of CYP1A1 m2 variant and HPV 16. There was a significant over-representation of both m1 (25.9% vs. 13.9%) and m2 (27.9% vs. 13.3%) polymorphisms in older women (46 years or more). GSTM1 and GSTT1 deletions were also prominent among cases (53.7% and 16.3% respectively) compared to controls (32.7% and 9.7% respectively). A higher proportion of both GSTT1 and GSTM1 deletions were also detected in HPV-16-positive subjects.


CONCLUSIONS
These results suggest that polymorphisms in the CYP1A1, GSTM1 and GSTT1 genes may render women more susceptible to the development of cervical cancer. The association between this susceptibility and the presence of human papillomavirus infection further emphasizes the significance of the genetic polymorphisms.
Joseph
Thomas
T
Department of Molecular Medicine, Regional Cancer Centre, Trivandrum, India.
Chacko
Priya
P
Wesley
Remani
R
Jayaprakash
P G
PG
James
Francis V
FV
Pillai
M Radhakrishna
MR
D000367:Age Factors; D016022:Case-Control Studies; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D052162:Human papillomavirus 16; D006801:Humans; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D011110:Polymorphism, Genetic; D002583:Uterine Cervical Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000821:virology*
D019363:Cytochrome P-450 CYP1A1; D005982:Glutathione Transferase; C413545:glutathione S-transferase T1