Possible Risk Reduction in Esophageal Cancer Associated with Mpo -463 a Allele

Myeloperoxidase (MPO), an enzyme found in lysosomes of phagocytes, causes hydrox radicals linked to DNA damage and activation of smoking related carcinogens. A-463 G/A polymorphism in the promoter region of the MPO gene results in reduced gene expression, which would imply lower susceptibility of esophageal cancer in mutant carriers. We conducted case-control study to test this hypothesis. Cases were 91 patients with esophageal cancer and controls were 241 non-cancer outpatients. MPO genotypes were examined by PCR-RFLP. The allele frequency for MPO-463A was found to be 8.2% for cases and 10.5% for controls. The age, sex, smoking and drinking status adjusted odds ratio for all subjects for MPO-463 GG/GA as compared to the AA was 0.61 (95% CI: 0.28-1.32). The adjusted odds ratio for the GG/GA genotype was significantly low (0.15; 0.03-0.76, P=0.022) for those aged 61 years or older who had a significantly higher odds ratio for smoking than younger subjects. No difference was observed in disease risk when prevalent and incident cases were compared. Although there are limitations for interpretation of this study because of prevalent case-control study and partial statistical significance, these results suggest that MPO-463 A allele reduce the risk of esophageal cancer.


Myeloperoxidase
(MPO), an enzyme found in lysosomes of phagocytes, causes hydrox radicals linked to DNA damage and activation of smoking related carcinogens.
A -463 G/A polymorphism in the promoter region of the MPO gene results in reduced gene expression, which would imply lower susceptibility of esophageal cancer in mutant carriers.We conducted casecontrol study to test this hypothesis.
Cases were 91 patients with esophageal cancer and controls were 241 non-cancer outpatients.MPO genotypes were examined by PCR-RFLP.The allele frequency for MPO -463A was found to be 8.2% for cases and 10.5% for controls.The age, sex, smoking and drinking status adjusted odds ratio for all subjects for MPO -463 GG/GA as compared to the AA was 0.61 (95% CI: 0.28-1.32).The adjusted odds ratio for the GG/GA genotype was significantly low (0.15; 0.03-0.76,P=0.022) for those aged 61 years or older who had a significantly higher odds ratio for smoking than younger subjects.Crude odds ratios by years from diagnosis were not different, 0.83 (0.39-1.76) for the cases whose year from diagnosis was less than three years and 0.71 (0.26-1.95) for the cases who were diagnosed three or more years before enrolment, therefore, we analyzed all cases together.Reduced odds ratios were observed for non-smokers, ex-smokers, and smokers with 50 pack-years or less, but not heavy smokers with more than 50 pack-years (see Table 3).Table 4 gives the odds ratios for life-  DISCUSSION In this study, we found the MPO -463 G/A polymorphism to be linked to esophageal cancer susceptibility, especially among the older age population more significantly affected by smoking.Compared with the GA/AA genotype, the GG genotype thus showed an approximately six times higher risk in those aged more than 60.The gender-specific effect, which was observed in a several of studies 19.25), was not observed in this study, although the number of female cases was limited.
In the present study, because of a low incidence of esophageal cancer, we analyzed all cases including prevalent cases together.To examine the difference in attribution of the polymorphism between prevalent and incident cases, we examined the odds ratios according to the years from diagnosis to enrollment (less than three years vs. three years or more), and no difference was observed between them, suggesting that the odds ratio reflected mainly the risk, not the prognosis.
MPO is an enzyme that is primarily localized in phagocytes where it generates hydroxy radicals with carcinogenic potential 20).Although the MPO GA/AA type in the present study was associated with significant reduction of risk in the older group with higher odds ratios for smoking, no statistically significant effects were evident for the younger group.Carcinogenesis is considered as accumulation of genetic events during aging, and esophageal cancer has a steep slope for age-specific increase in incidence 23).The lower risk with the GA/AA genotype observed among elderly people in the present study implies that reduced activity of MPO contributes to a decreased incidence of genetic events in the aged, while the biological findings on the onset age and esophageal carcinogenesis are very scarce.
This study used 91 cases and 241 controls.The numbers of cases were similar to previous molecular epidemiological studies for esophageal cancer, and the numbers of controls was the larger than most of previous ones 2-7).
Several case-control studies have pointed to associations between the MPO polymorphism and lung 15-18) as well as laryngeal cancers 17), chronic granulomatous disease 24) and Alzheimer disease 25).In all cases, A variant carriers had reduced disease risk.To our knowledge , ours is the first study to document an association between esophageal cancer risk and the MPO polymorphism.In summary, this study revealed that esophageal cancer risk for individuals with the MPO -463 A allele was reduced , especially in the aged, although a part of the effect might be related to the prognosis.Further studies to confirm the association in prospectively collected populations and elucidate biological relations with other metabolic pathways are now required .
pyren and aromatic amines 21).The -463 G/A polymorphism is located in the promoter region of the MPO gene, where the Alu region with a hormone-responsive element binding the transcription factor SP1, highly relevant for promoter activity, is located 18).The G variant in this polymorphism shows a remarkable 25-fold higher transcription 18).This implies much lower enzyme activity and reduced cancer risk in A variant carriers.Smoking related polymorphisms in genes encoding enzymes such as CYP1A1 or GSTM1 were previously examined with reference to esophageal cancer 3-7).Benzo(a)pyrene can be transformed to highly reactive intermediates byCYP1A1 22), but the studies failed to show any significant association between CYP1A1 and esophageal cancer among Caucasians and Japanese.GST(glutathione S-transferase), involved in detoxication, is known to have a relation to esophageal cancer 6-7).

Table 1 .
Japanese esophageal cancer patients (76 males and 15 females; median age, 61; age range, 43-76) and 241 non-cancer controls (118 males and 123 females; median age, 58; age range, 39-69) who visited Aichi Cancer Center in 1999 were recruited.Cases were firstly diagnosed as having esophageal cancers between 1984-2000.All subjects who gavewritten informed consent to participate in this study completed the self-administered questionnaire and provided blood.The questionnaire included the smoking status and alcohol consumption.Smoking status was classified into smoker, exsmoker, and never-smoker, and the level of exposure was expressed in pack-years.Alcohol consumption was classified into three categories, never or occasional drinker, 1-4 times/week drinker and more than five times/week drinker.Characteristics of cases and controls.

Table 2 .
Genotype frequencies of MPO and ORs. a

Table 3 .
Adjusted ORs and 95% CI for MPO GA/AA genotypes relative to MPO GG genotype, a) Odds ratios adjusted for age, sex, smoking status and alcohol consumption.

Table 4 .
Adjusteda) ORs and 95% CI for life-style factors with reference to the age group (60 Years <_vs >_ 61 Years).a)Adjusted for age , sex and the MPO polymorphism.stylefactors according to age group.The impact of smoking in subjects more than 61 years of age who showed reduced risk for MPO GA/GG type [adjusted odds ratio 0.15 (0.03-0.76)] was significantly high; odds ratios were 9.42 for ex-smokers, 13.8 for smokers with 50 pack-years or less, and 12.3 for smokers with more than 50 pack-years.