Meta-analysis of Association Studies of CYP1A1 Genetic Polymorphisms with Digestive Tract Cancers Susceptibility in Chinese

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Meta-analysis of CYP1A1 Polymorphisms with Digestive Tract Cancers Susceptibility in Chinese

Asian Pac J Cancer Prev, 15 (11), 4689-4695

Introduction

In recent years, the incidence of digestive tract cancers throughout the world, has shown a marked increase and become a worldwide health burden, especially in developing countries like China. Nevertheless, the incidence has gradually decreased in many western countries. The survival rate of digestive tract cancers in China is far behind europe and the united states. Digestive tract cancers is a heterogeneous, multifactorial disease while its initiation or development can be attributed to the cumulative effect of genetic predispositions, environment

1Department of Gastroenterology, The First People’s Hospital of Chongqing New North Zone, ²Department of Gastroenterology, 8QLYHUVLW\RI7KH)LUVW$IÀOLDWHG+RVSLWDORI&KRQJTLQJ0HGLFDO&KRQJTLQJ&KLQD )RUFRUUHVSRQGHQFHjiangz1753@163.com

Abstract

Background: A great number of studies have shown that cytochrome P450 1A1 (CYP1A1) genetic polymorphisms, CYP1A1 Msp I and CYP1A1 Ile/Val, might be risk factors for digestive tract cancers, including esophageal cancer (EC), gastric cancer (GC), hepatic carcinoma (HC), as well as colorectal cancer (CC), but the results are controversial. In this study, a meta-analysis of this literature aimed to clarify associations of CYP1A1 genetic polymorphisms with digestive tract cancers susceptibility in Chinese populations. Materials and Methods:

Eligible case-control studies published until December 2013 were retrieved by systematic literature searches from PubMed, Embase, CBM, CNKI and other Chinese databases by two investigators independently. The associated literature was acquired through deliberate search and selection based on established inclusion criteria. Fixed- effects or random-effects models were used to estimate odds ratios (ORs and 95%CIs). The meta-analysis was FRQGXFWHGXVLQJ5HYLHZ0DQDJHUDQG6WDWDVRIWZDUHVZLWKVWDELOLW\HYDOXDWHGE\ERWKVWUDWLÀHGDQG

VHQVLWLYLW\DQDO\VHV0RUHRYHUVHQVLWLYLW\DQDO\VLVDQGSXEOLFDWLRQELDVGLDJQRVWLFVFRQÀUPHGWKHUHOLDELOLW\DQG

stability. Results: Eighteen case-control studies with 1, 747 cases and 2, 923 controls were selected for CYP1A1 MspI polymorphisms, and twenty case-control studies with 3, 790 cases and 4, 907 controls for the CYP1A1 Ile/

Val polymorphisms. Correlation associations between CYP1A1 Ile/Val polymorphisms and digestive tract cancers susceptibility were observed in four genetic models in the meta-analysis (GG vs AA:OR= 2.03, 95%CI =1.52- 2.72; AG vs AA: OR=1.26, 95%CI =1.07-1.48; [ GG+AG vs AA] :OR =1.42, 95%CI=1.20-1.68, [GG vs AA+AG ]:OR=1.80, 95%CI =1.40-2.31). There was no association between CYP1A1 Msp I polymorphisms and digestive WUDFWFDQFHUVULVN6XEJURXSDQDO\VLVIRUWXPRUW\SHVKRZHGDVLJQLÀFDQWDVVRFLDWLRQRICYP1A1 Ile/Val genetic polymorphisms with EC in China. However, available data collected by the study failed to reveal remarkable associations of GC or HC with CYP1A1 Ile/Val genetic polymorphisms and EC, GC or CC with CYP1A1 MspI genetic polymorphisms. Conclusions: Our results indicated that CYP1A1 Ile/Val genetic polymorphisms, but not CYP1A1 Msp I polymorphisms, are associated with an increased digestive tract cancers risk in Chinese populations. Additional well-designed studies, with larger sample size, focusing on different ethnicities and FDQFHUW\SHVDUHQRZZDUUDQWHGWRYDOLGDWHWKLVÀQGLQJ

Keywords: CYP1A1 - genetic - polymorphisms - digestive tract cancers - meta-analysis

RESEARCH ARTICLE

Meta-analysis of Association Studies of CYP1A1 Genetic Polymorphisms with Digestive Tract Cancers Susceptibility in Chinese

Chang Liu

¹

, Zheng Jiang

²

*, Qian-xi Deng

²

, Ya-nan Zhao

²

factors, and their complex interplay. Moreover, possible risk factors for digestive tract cancers include cigarette smoking, alcohol consumption, food, low intake of vegetables, salty food, pickled vegetables, nutrient GHÀFLHQF\FKURQLFPXFRVDOLUULWDWLRQDQGDIDPLO\KLVWRU\

of cancer. According to International Agency for Research on Cancer, China will enter a period of high incidence of cancers in the next period of time. As the current growth rate, new cancer cases of chinese populatioon will be PRUHWKDQÀYHPLOOLRQVDQQXDOGHDWKVE\PLOOLRQVLQ

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cause of cancer-related deaths in the world with a rising incidence. A growing body of epidemiological evidence has evident regional characteristics. The morbidity and mortality rates of EC in China are the highest in the world, and over 50% of patients have locally advanced RU PHWDVWDWLF GLVHDVH DW SUHVHQWDWLRQ -XQ HW DO

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fourth most common cancer and the second leading cause RIFDQFHUGHDWKLQWKHZRUOG*RQ]DOH]HWDO,Q

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Cytochrome P450 superfamily is the important phase , PHWDEROL]LQJ HQ]\PH CYP1A subfamily includes CYP1A1 which is widely distributed in the lung, kidney, gastrointestinal tract, skin, larynx, placenta, lymphocyte, and brain tissues outside the liver. It is mainly involved in the metabolism of polycyclic aromatic hydrocarbons.

Polycyclic aromatic hydrocarbon activation, as a carcinogen, is closely related with the occurrence and GHYHORSPHQWRIWXPRU&UHZHHWDOCYP1Al is DQLVR]\PHRIF\WRFKURPH3ORFDWHGRQFKURPRVRPH

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studied in relation to cancer risk: 0VS, and ,OH9DO polymorphism. The former occurs in the CYP1A1 gene

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W\SH&&W\SH:HFDQFOHDU0VS, polymorphic types by UHVWULFWLRQHQ]\PH0VS,. The ,OH9DO polymorphism is also known as the exon7 polymorphism. The amino acids of CYP1A1 exon 7 A*UHSODFHPHQWDUHHTXLYDOHQWWRFRGRQ

462 of ,,H into 9DO isoleucine valine. The polymorphism of ,OH9DO KDV WKUHH JHQRW\SHV PXWDWLRQ KRPR]\JRXV

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In the context of the world, extensive case control studies had been conducted to investigate the potential role of the CYP1A1 polymorphisms about digestive tract cancers in China. However, the research results were unclear, which could be due to the differences in the small VDPSOHVL]HLQVXIÀFLHQWVWDWLVWLFVHIIHFWVRIHQYLURQPHQWDO

and genetic interactions power. Meta-analysis might increase statistical power to address this problem. In this paper, the meta-analysis study was performed to explore the relationship between 0VS, and ,OH9DO genetic polymorphisms in the CYP1A1 gene and digestive tract cancers in Chinese populations.

Materials and Methods

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written in Chinese and English languages. Published literatures from PubMed, Embase, CBM, Chinese 1DWLRQDO .QRZOHGJH ,QIUDVWUXFWXUH &1., :DQIDQJ

Data and other Chinese databases were retrieved by

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keywords and their combinations: CYP1A1, esophageal cancer, gastric cancer, colorectal cancer, liver cancer and hepatic carcinoma, gene polymorphism and China or Chinese. Meanwhile, reference lists of the relevant articles were also collected.

The inclusion and exclusion criteria of this meta- DQDO\VLVZHUH$QHHGIRUWKHH[SHULPHQWDOGHVLJQDQG

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histological diagnosis of digestive tract cancers. The study cases were accorded with the diagnostic standard JXLGH,QFRQWUROFDVHQRQJDVWURLQWHVWLQDOV\PSWRPV

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there were the total number and genotype distribution and IUHTXHQF\ZLWKWKH+DUG\:HLQEHUJEDODQFHp<0.05 that GLGQRWFRQIRUPWRWKH+DUG\:HLQEHUJEDODQFH

Data extraction

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group.The following information was collected from each WKHHOLJLEOHUHSRUWVWKHÀUVWQDPHRIWKHDXWKRUSXEOLVKHG

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resolved by discussion among all the authors.

Statistical analysis

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was used for the meta-analysis. The associations were estimated by calculating pooled OR with &,. There were four kinds of different models calculated for each JHQRW\SH KRPR]\JRXV DQG ZLOGW\SH KHWHUR]\JRXV

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evaluated by the Q-statistic and ,²-statistic. The test level ZDVIRUDOSKD ,IWKHUHVHDUFKUHVXOWVZHUHp!

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to the type of tumor. Sensitivity analysis was also tested by removing one study at a time to calculate the overall KRPRJHQHLW\DQGHIIHFWVL]H3XEOLFDWLRQELDVZDVDVVHVVHG

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Results

Literature search

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Twenty Chinese articles and ten English articles were LQFOXGHGLQWKHÀQDODQDO\VLV<XHWDO=KDQJHW

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case-control studies of &<3$0VS,SRO\PRUSKLVPV

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of CYP1A1 ,OH9DOSRO\PRUSKLVPVFDVHVDQG

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in English of both &<3$ 0VS, and CYP1A1 ,OH9DO polymorphisms, then another one article in the ,OH9DO JHQHDERXWWZRFDVHVZHUHVKRZQLQ7DEOHVDQG

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The relationship between CYP1A1 gene 0VS, polymorphism and digestive tract cancers: meta-analysis in Chinese populations.

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find significant association between &<3$ 0VS,

polymorphism and digestive tract cancers susceptibility LQ WKH RYHUDOO DQDO\VLV XQGHU DOO JHQHWLF PRGHOV :H

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The relationship between CYP1A1 ,OH9DO substitution JHQHSRO\PRUSKLVPVDQGGLJHVWLYHWUDFWFDQFHUVPHWD

analysis in Chinese populations:

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Z p_z )RU ** vs AA+AG: there was VWDWLVWLFDO KHWHURJHQHLW\ LQ VWXGLHV p ,²

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association .

In the further subgroup analyses based on tumor type,

Table 1. Case-control Studies about CYP1A1 MspI Polymorphisms and Digestive Tract Cancers

First Publication Area Genotype Distribution Tumor

author year Case Control type

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Table 2. Case-control Studies about CYP1A1 IleVal Substitution Polymorphisms and Digestive Tract Cancers

First Publication Area Genotype Distribution Tumor

author year Case Control type

$$$*** $$$***

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there was little association between CYP1A1 gene 0VS, polymorphism and digestive tract cancers risk including EC, GC, CC, and HC. However, there was association between CYP1A1 ,OH9DO substitution gene polymorphisms DQG GLJHVWLYH WUDFW FDQFHUV ULVN LQ (& JURXS > ** vs

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effect:Z p_z $* vs $$OR&,:

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for overall effect: Z p_z ** vs $$$* :OR &, WHVW IRU RYHUDOO HIIHFW

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or HC in CYP1A1 ,OH9DO polymorphisms and EC, GC and CC in CYP1A1 0VS, polymorphisms.The Partial forest SORWVZHUHVKRZQLQ)LJXUHV

Sensitivity analyses

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ORs. The corresponding pooled ORs were not markedly altered under all models in both the overall analyses and the subgroup analyses, with more than two studies. It indicated that our results were statistically robust. Looking for heterogeneity: all studies were eliminated one by one in the genetic model, these analyses, however, the results did not altered substantially under any genetic models.

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detected for studies published on 0VS, polymorphism 7&&& vs TT, P_E && vs TC+TT, P_E

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dominant model detected for studies published on 0VS, SRO\PRUSKLVP7&&& vs TT, p_E && vs TC+TT, p_E && vs TT, p_E 7& vs TT, p_E and ,OH9DO SRO\PRUSKLVP $*** vs AA, p_E

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vs AA, p_E P_EE<0.05 suggested the presence of SXEOLFDWLRQELDVWKHSXEOLFDWLRQELDVHVZHUHQRWHYLGHQW

because the funnel plots appeared to be approximately V\PPHWULFDO0RUHRYHU(JJHU·VWHVWDQG%HJJ·VWHVWZDV

Table 3. Summary of Pooled ORs and 95%CI for CYP1A1 0VS, Genetic Polymorphism

&&vs77 &7vs77 &&&7vs77 &&vs77&7 OR&, p,² OR&, p,² OR&, p,² OR&, p,² 7RWDOp ,²  p ,²  p ,²  p ,²=29%

(& p ,²  p ,²  p ,²  p ,²=28%

*& p ,²  p ,²  p ,²  p ,²=29%

&& p ,²  p ,²  p ,²  p ,²

Table 4. Summary of Pooled ORs and 95%CI for CYP1A1 Ile/Val Genetic Polymorphism

**vs$$ $*vs$$ **$*vs$$ **vs$$$*

OR&, p,² OR&, p,² OR&, p,² OR&, p,²

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Figure 2. Codominant Model Genetic Model between CC vs TT and CYP1A1 MspI Genentic Polymorphism

Figure 3. Codominant Model Genetic Model between (AG vs AA) and CYP1A1 Ile/Val Genentic Polymorphism

Figure 1. Literature Search Flow Diagram

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IRU WKH TXDQWLWDWLYH HYDOXDWLRQ RI WKH V\PPHWU\ RI WKH

meta-analysis funnel plot and its results were listed in Figure 4.

Discussion

CYP1A1 is an important aspect that plays an essential role in the metabolic activation of major classes of procarcinogens, thus affecting the metabolism of the environmental carcinogens and altering susceptibility WR GLJHVWLYH WUDFW FDQFHUV(Q]\PH JHQH LQ WKH SKDVH RI

metabolism is more than 95% CYP and these variant HQ]\PHV FRXOG HQKDQFH WR[LFLW\ RI WKH H[WUDQHRXV

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word, the CYP1A1 gene is considered to be an vital indicator of carcinogens. At present, a series of studies about humans not animals or cellulars have indicated that CYP1A1 polymorphisms may contribute to the risk RIGLJHVWLYHWUDFWFDQFHUVWKHQWKHUDWHYDULHVVLJQLÀFDQWO\

among different races and ethnicities.

,QWKHSDVW\HDUVWKHUHKDGEHHQDORWRIVWXGLHV

on the CYP1A1 polymorphism and EC, GC, CC, HC susceptibility in China and abroad, but these claims were inconsistent as the current research results. The reason might be that there was an obvious contrast between east and west and this difference in populations implied WKDWPXWDWLRQVLQJHQRW\SHIUHTXHQFLHVUHVXOWLQYDULRXV

degrees of cancers susceptibility. Some researches had contributed enormously to the understanding of digestive WUDFW FDQFHUV 2QH PHWDDQDO\VHV SXEOLVKHG LQ

with the association between CYP1A1 0VS,,OH9DO

polymorphisms and cancers risk among asians failed to cover all conclusive articles published in Chinese databases, and was short of match properly for the Chinese population, not for digestive tract cancers with XQFOHDUFDVHDQGFRQWUROQXPEHUV:XHWDO7R

RXUNQRZOHGJHRXUVWXG\ZDVWKHÀUVWLQYHVWLJDWLRQRI

the worldwide evidence about the Chinese population on the association of CYP1A1 genetic polymorphisms ZLWK GLJHVWLYH WUDFW FDQFHUV 2WKHU VWXGLHV )XMXQ +DQ

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association of two cytochrome CYP1A1 polymorphisms with gastric cancer risk that also failed to show that the &<3$ 0VS, genetic polymorphism conferred no VLJQLÀFDQWULVNIRU*&+RZHYHUVWXGLHVZHUHQHFHVVDU\

WR SURYLGH PRUH RQ WKH QXPEHU IRU WKH HYDOXDWLRQ2QH

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there was no association between endometrial cancer risk and the CYP1A1 ,OH9DO polymorphism.But their studies had only seven researches, merely for CYP1A1 ,OH9DO DQG(&$UHFHQWO\SXEOLVKHGDUWLFOH<XQHWDOZDV

included in our meta-analysis. At the moment, for the most part, these studies aimed at the all races rather than individual race. Further, we devoted to the individual race, it could get less heterogeneities and more reliable results.

About races, location and environment, the morbidity of a vast country of digestive tract cancers like China could be higher, accompany with different countries.

Therefore, our leverage lied in the parallel comparison of the accuracy in Chinese people instead of the world.

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and ethnic influence, thus increase the reliability of the results. So further epidemiological and molecular biological studies were necessary to clarify the role of CYP1A1 genetic polymorphisms in digestive tract cancers and other countries.Genetic polymorphism referd to one or more allelic mutation genetic variation and the occurrence of multi-peak curve discontinuities in the crowd.For the moment, CYP1A1 genetic polymorphism was one of the most common kinds, which we had discussed in the study group. To evaluate the association of CYP1A1 genetic polymorphism and susceptibility to digestive tract cancers in the Chinese population, we performed an updated systematic meta-analysis. In CYP1A1 genetic 0VS, polymorphism group, thirteen of eighteen studies showed no correlation between CYP1A1 0VS,genetic polymorphism and digestive tract cancers.

Subgroup analysis based on ethnicity of controls and tumor type did not discover correlation between CYP1A1 0VS, polymorphisms and digestive tract cancers risk.

Particularly nine studies of EC were applied for evaluation for the &<3$ 0VS, genetic support our result while only two cases were in contrast to it. In GC groups, WKUHHVWXGLHVZLWKFDVHVOHVVWKDQPLJKWGHQRWHQR

relationship between &<3$0VS,genetic polymorphism and digestive tract cancers. Random effects model of PHWDDQDO\VLVZLWKFDVHVDQGFRQWUROVVKRZG

VLJQLÀFDQW DVVRFLDWLRQV RI SRO\PRUSKLVPV RI CYP1A1 ,OH9DO genetic in the overall analysis under all genetic models, respectively, with digestive tract cancers risk in Chinese populations. Subgroup analyses on CYP1A1 ,OH9DO substitution gene in EC group indicated that WXPRUW\SHRIFRQWUROVZHUHVLJQLÀFDQWO\DVVRFLDWHGZLWK

digestive tract cancers risk.Moreover, limited investigative numbers of the case-control followed up ethnicity studies IURP&KLQHVHUHJLRQPLJKWUHVXOWLQGLIÀFXOW\IRUJHWWLQJ

stable risk estimation. &<3$,OH9DO substitution in exon

UHVXOWVLQDWZRIROGLQFUHDVHGLQPLFURVRPDOHQ]\PH

activity and therefore the 9DO allele would be expected to increase the susceptibility to EC. However, subgroup analyses, GC group and HC group had not found any correlation between them. Two previous meta-analyses <DQJHWDO=KXRHWDOZDVFRQVLVWHQWZLWK

our results. Individuals with the ,OH9DO substitution in CYP1A1 exon 7 had increased esophageal cancer risk, with ORs&,FRPSDUHGZLWK,OH,OHRI

DQGIRU,OH9DO, 9DO9DOJHQRW\SHDQGWKHFRPELQHGJURXS1RVLJQLÀFDQW

Figure 4. Begg’s Funnel Plot of Codominant Model Genetic Model (CC vs TT) in CYP1A1 (MspI Genentic Polymorphism Group

(6)

association was found between esophageal cancer risk and &<3$0VS,genetic parameters. It was regrettable that these were not especially for the Chinese populations.

Tumor has a multi-factor, multi-step of development.

It may be involved in gene-gene and gene-environment interactions. some studies without clear explanation for the pathologic diagnostic results of some subjects and each study has its own inclusive criteria.Therefore, some selection bias might be unavoidable. Heterogeneity is an important factor to affect the results of the study.

The part of the presence of heterogeneity in all genetic models might be through sensitivity analysis and subgroup, eliminating any document for the reason of the KHWHURJHQHLW\)LQDOO\VLJQLÀFDQFHRIWKHVHUHVXOWVZDVWKH

VDPHWKDWGLGQRWYDU\ZLWKWKHDERYHVWDWHPHQW:HXVHG

WKH%HJJ·VIXQQHOSORWDQG(JJHU·VWHVWUHVSHFWLYHO\WKH

TXDOLWDWLYHDQGTXDQWLWDWLYHDVVHVVPHQWRISXEOLFDWLRQELDV

tips in this paper.Publication bias might not exist together with heterogeneity across studies, which increase the statistical power.

As was known with meta-analyses, there were several limitations to the present study. Possible sources of heterogeneity, such as the number of existing clinical trials, level, method, language and the search range limitation might be considered.Then, the consolidation results were from unadjusted estimates and therefore potential covariates. At last, despite gene-gene and gene-environment interactions could be involved in the pathogenesis of digestive tract cancers. The results of our meta-analysis should be interpreted with caution because WKHVDPSOHVL]HZDVUHODWLYHO\VPDOOIRUWKHVXEJURXSVDQG

the lack of representation of population.

In conclusion, our meta-analysis strongly suggested that a meaningful association existed between CYP1A1 ,OH

9DO polymorphisms and risk of digestive tract cancers and EC in Chinese population. Peoples with null genotypes of CYP1A1 ,OH9DO were more susceptible to developing digestive tract cancers. Further studies based on large- scale populations and gene-environment interactions are needed to determine, such as community or hospital source populations and selected population with various environmental background.

Acknowledgements

This research is not supported by the foundation

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