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Analyze_Association_of_BRCA2_Arg372His.2

Analyze Association of BRCA2Arg372His Polymorphism

With Ovarian Cancer Risk

Cunfang Wang,PhD*and Cunzhong Yuan,MD,PhD T

Objective:Studies investigating the association between BRCA2Arg372His polymor-phism and ovarian cancer risks have yielded conflicting results.

Methods:We carried out a meta-analysis of 8488ovarian cancer cases and 14,510controls from 7case-control studies in 5articles published.The association between BRCA2Arg372His polymorphism and ovarian cancer susceptibility was calculated using pooled odds ratios (ORs)appropriately derived from fixed effects models.

Results:There were no significant associations between BRCA2Arg372His polymorphisms and ovarian cancer risk in overall comparisons in all genetic models (HH vs NN:OR,1.06;95%confidence interval [95%CI],0.96Y 1.18;P =0.25;NH vs NN:OR,1.02;95%CI,0.96Y 1.07;P =0.6;NH +HH vs NN:OR,1.01;95%CI,0.98Y 1.04;P =0.42;HH vs NN +NH:OR,1.06;95%CI,0.95Y 1.17;P =0.29).

Conclusions:This meta-analysis indicates that the BRCA2Arg372His polymorphism is not associated with ovarian cancer risk for https://www.wendangku.net/doc/ee2034593.html,n and African populations should be further studied.

Key Words:Ovarian cancer,BRCA2,ARG372HIS,Gene polymorphism,Meta-analysis Received November 6,2014,and in revised form December 18,2014.Accepted for publication May 14,2015.(Int J Gynecol Cancer 2015;25:1338Y 1344)

varian cancer is the deadliest cancer of the female re-productive system,with over 21,980new cases and over 14,270deaths in the United States in 2014.1In most of the carcinomas,ovarian cancer is a multifactorial disease,and hormonal factors,environment and genetic factors all play significant roles in its development.2Y 4The genetic basis of ovarian cancers has been investigated in many studies.BRCA1,BRCA2,SMAD6,RAD51C ,RAD51D ,LIN28B ,CASP8,MLH1,MSH2,RB1,and MTDH have all been

implicated.5Y 13Recently,3genomewide association studies found several common susceptibility alleles in 4loci to be strongly associated with ovarian cancer risk.3,14Y 16Examina-tion of genetic polymorphisms may explain individual differ-ences in cancer risk.17

Mutations in several DNA repair genes contribute to the origin of many cancer types.BRCA1and BRCA2are cru-cial proteins involved in homologous recombination,which is the most accurate method of double-stranded DNA break

R EVIEW A RTICLE

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&Volume 25,Number 8,October 2015

*Shandong Provincial Key Laboratory of Microbiological Engineering,Qilu University of Technology;and ?Department of Obstetrics and Gynecology,Qilu Hospital of Shandong University,Ji’nan,Shandong,P .R.China.

Address correspondence and reprint requests to Cunzhong Yuan,MD,PhD,Department of Obstetrics and Gynecology,Qilu Hospital,Shandong University,Jinan,Shandong,250012,China.Fax:82-531-82169268.E-mail:yuancunzhong@https://www.wendangku.net/doc/ee2034593.html,.Cunfang Wang,PhD,Shandong Provincial Key Laboratory of Microbiological Engineering,Qilu University of Technology,Jinan,Shandong,250353,China.Fax:82-531-82379872.E-mail:cunfangwang@https://www.wendangku.net/doc/ee2034593.html,.

This work was supported by the Natural Science Foundation of Shandong Province (ZR2014JL019),National High Technology Research and Development Program

(‘‘863’’Program)of China (2014AA020605),China Postdoctoral Science Foundation (2014M551918),Science and Technology Development Project of Shandong Province (2014GSF118071,2013GNC11306,2013GSF12202),the National Natural Science Foundation of China (81272857),Independent

Innovation Foundation of Shandong University (2012TS142).The authors declare no conflicts of interest.

DOI:10.1097/IGC.0000000000000499

repair.18Y20Germline mutations in BRCA1/2are highly pene-trant ovarian cancer,conferring lifetime risks of up to40% (BRCA1)and20%(BRCA2)for ovarian cancer.20In the BRCA2gene,ARG372HIS is the only amino acid changing polymorphism with a rare allele frequency of greater than6% and was named as rs144848.BRCA2ARG372HIS increased the risk of breast cancer and has been reported in HH homo-zygotes in a large case control study.21,22

The association between BRCA2ARG372HIS and ovarian cancer has been extensively studied.However,pre-vious experimental results remain conflict.21,23Y26Although almost studies demonstrated no significant in the genotype frequencies of BRCA2ARG372HIS between ovarian cancer cases and controls,21,23Y26other studies showed statistical difference association.24These inconclusive and conflicting results may be partially owing to small samples and various populations.Meta-analysis is useful in assessing all the evi-dence from such studies.Therefore,we performed the meta-analysis to give a more precise evaluation of the association between BRCA2ARG372HIS polymorphism and ovarian cancer susceptibility.

METHODS

Identification of Eligible Studies

We carried out the meta-analysis following the criteria of Preferred Reporting Items for Systematic Reviews and Meta-Analyses(checklist S1).We accomplished a search of the PubMed and Embase database,by the following keywords and subject terms:‘‘BRCA2’’,‘‘ARG372HIS,’’‘‘A372H,’’‘‘N372H,’’‘‘H372N,’’‘‘rs144848,’’‘‘polymorphism,’’‘‘ovarian cancer,’’and their combination.In this meta-analysis,2authors (Yuan and Wang)independently examined all the studies re-trieved to evaluate their appropriateness for the inclusion.In addition,we examined all the references cited in the articles and relevant reviews.If an article reported the results,including those from different studies,each study was treated as a separate comparison in our meta-analysis.3

Studies were required3criteria:

(a)Evaluated BRCA2ARG372HIS polymorphisms and

ovarian cancer risk,

(b)With sufficient published data to enable estimation of

an odds ratio(OR)with its95%confidence interval (95%CI),and

(c)Have respective or prospective cohort case Y control studies. Data Extraction

Two authors(Wang and Yuan)independently extrac-ted data from selected literature according to the inclusion criteria.The following information was acquired from each study if available:the first author’s name,year of publication, countries of origin,ethnicity of the population,the numbers of cases and controls,and genotype distributions of BRCA2 ARG372HIS in both cases and controls.We resolved dis-agreements by joint review and consensus.

Quality Score Assessment

The quality of the7studies from5articles were as-sessed according to the predefined scale for quality assessment by two authors independently(Table1)which has been de-scribed previously.4,27,28We assessed quality score according to ‘‘source of cases,’’‘‘source of controls,’’‘‘specimens of cases for determining genotypes,’’‘‘Hardy-Weinberg equilibrium in controls,’’‘‘total sample size.’’Any differences were resolved by discussion between the2authors.Total scores ranged from 0(worst)to15(best).Studies scoring less than10were defined as‘‘low quality’’and those with10or higher as‘‘high quality.’’Statistical Analysis

We calculated pooled ORs with95%CIs to access the strength of association between BRCA2ARG372HIS and ovarian cancer susceptibility,according to the genotype frequencies of ARG372HIS in cases and controls.29P value less than0.05was considered statistically significant;all tests and CIs were2-sided.The pooled ORs were initially calculated by a fixed-effects model.30

The BRCA2ARG372HIS polymorphism and ovarian cancer risk were estimated for the homozygotes(HH vs NN),the heterozygotes(NH vs NN),the dominant genetic model(NH+ HH vs NN),and the recessive genetic model(HH vs NN+NH). In addition,we carried out sensitivity analysis by omitting each study to find potential outliers,and we performed the publication bias by a funnel plot.The degree of asymmetry was calculated using Egger test(P G0.05was considered a significant pub-lication bias).31The analysis was accomplished by Review

TABLE1.Scale for quality assessment

Criteria Score

Source of cases

Population or cancer registry3

Mixed(hospital and cancer registry)2

Hospital1

Other0

Source of controls

Population-based3

V olunteers or Blood bank2

Hospital-based(cancer-free patients)1

Not described0

Specimens of cases for determining genotypes

Blood or normal tissues3

Mixed(blood and archival paraffin blocks)1

Tumor tissues or exfoliated cells of tissue0

Hardy-Weinberg equilibrium in controls

Hardy-Weinberg equilibrium3

Hardy-Weinberg disequilibrium0

Total sample size

Q10003

Q500and G10002

Q200and G5001

G2000

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Manager statistical software (RevMan version 5.0.17.0;The Nordic Cochrane Center,Rigshospitalet,Copenhagen,Denmark)and STA TA software (version 11.2;Stata Corporation,College Station,TX).Control population Hardy-Weinberg equilibrium was tested by a public web-based statistical tool (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl);the threshold for dis-equilibrium was P less than 0.05.

RESULTS

Study Characteristics

Through a literature search,22articles were found.Of these studies,16articles were excluded because it was an irrelevant study.One article 32was excluded because they did not report the relevant genotype frequencies.We have contacted the study authors,through e-mail,for the genotype frequencies,but we did not get the genotype frequencies of rs144848from that article.This left a total of 5articles on 8488ovarian cancer cases and 14,510controls 21,23Y 26(Fig.1).The 5articles were all published in English.The main characteristics of the 7studies from 5articles are shown in Table 2.Most subjects in these studies were whites,with few Africans.The sample sizes (cases and controls)ranged from 312to 7402,and the total sample sizes ranged from 710to 11,576.The quality scores of 7studies were all classified as high quality (Q 10).

Distribution of BRCA2ARG372HIS polymorphisms genotype frequencies among ovarian cancer cases and con-trols of the 7studies is shown in Table 3.Hardy-Weinberg disequilibrium of genotype frequencies among the controls was calculated in 7studies.21,23Y 26

Meta-Analysis Results

The meta-analysis results of BRCA2ARG372HIS polymorphisms are shown in Table 3and Figure 2.Statis-tically significant differences between the case and control groups were found from 1study.24No statistically significant associations between BRCA2ARG372HIS polymorphisms and ovarian cancer risk were found in any genetic models (HH vs NN:OR,1.06;95%CI,0.96-1.18;P =0.25;NH vs NN:OR,1.02;95%CI,0.96-1.07;P =0.6;NH +HH vs NN:OR,1.01;95%CI,0.98-1.04;P =0.42;HH vs NN+NH:OR,1.06;95%CI,0.95-1.17;P =0.29),when all the 7studies were pooled in the meta-analysis.

Publication Bias and Sensitivity Analysis

The publication bias was checked by both Begg fun-nel plot and Egger test.The shape of the 4Begg funnel plots showed no significant obvious asymmetry (Fig.3).The Egger test results did not show any significant of publication bias for any of the genetic models (data not shown).

In the sensitivity analysis,single study on the pooled OR in the meta-analysis was omitted each time.The corre-sponding pooled ORs were not significant altered.

DISCUSSION

The BRCA2gene is crucial in involving homologous recombination and double-stranded DNA break repair.18Y 20It was reported that the BRCA2polymorphism related to the risk of many cancers,including breast cancer and ova-rian cancer.20The association between BRCA2

Arg372His

FIGURE 1.Study flow chart explaining the selection of the five articles included in the meta-analysis.Wang and Yuan International Journal of Gynecological Cancer

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T A B L E 2.M a i n c h a r a c t e r i s t i c s o f 7s t u d i e s i n c l u d e d i n t h e m e t a -a n a l y s i s

F i r s t A u t h o r

Y e a r C o u n t r y

A r e a o f t h e C a s e s E t h n i c i t y

C a s e s S o u r c e C o n t r o l s S o u r c e S a m p l e T y p e o f C a s e s T o t a l C a s e s /C o n t r o l s Q u a l i t y S c o r e

A u r a n e n -12003U n i t e d K i n g d o m

N o r f o l k ,E a s t A n g l i a

w h i t e A n g l o -S a x o n M i x e d (h o s p i t a l a n d c a n c e r r e g i s t r y )P o p u l a t i o n

B l o o d 680/1546

A u r a n e n -22003A u s t r a l i a

T h e E a s t e r n A u s t r a l i a n S t a t e s .

N o r t h e r n E u r o p e a n d e s c e n t M i x e d (h o s p i t a l a n d c a n c e r r e g i s t r y )P o p u l a t i o n

B l o o d

441/1097

B e e s l e y -12007

A u s t r a l i a

N e w S o u t h W a l e s ,V i c t o r i a ,a n d Q u e e n s l a n d W h i t e C a n c e r r e g i s t r y

P o p u l a t i o n

B l o o d

492/948

B e e s l e y -22007

A u s t r a l i a N e w S o u t h W a l e s a n d V i c t o r i a n C a n c e r R e g i s t r i e s W h i t e C a n c e r r e g i s t r y

P o p u l a t i o n

B l o o d

930/825

Q u a y e 2009

M i x e d (D e n m a r k ,U n i t e d K i n g d o m ,U n i t e d S t a t e s )M a l i g n a n t O v a r i a n C a n c e r s t u d y C o p e n h a g e n f r o m D e n m a r k -S E A R C H f r o m t h e U n i t e d K i n g d o m a n d G e n e t i c E p i d e m i o l o g y o f O v a r i a n C a n c e r S t u d y f r o m t h e U n i t e d S t a t e s W h i t e M i x e d (h o s p i t a l a n d c a n c e r r e g i s t r y )

P o p u l a t i o n

B l o o d

1459/2294

R a m u s 2008N o n -H i s p a n i c w h i t e s U n i t e d S t a t e s ,E u r o p e ,a n d A u s t r a l i a N o n -H i s p a n i c w h i t e s M i x e d (h o s p i t a l a n d c a n c e r r e g i s t r y )M i x e d (p o p u l a t i o n

a n d v o l u n t e e r s )B l o o d

4174/7402

W e n h a m 2003

M i x e d (A f r i c a n A m e r i c a n a n d w h i t e ;U S )N o r t h C a r o l i n a M i x e d (A f r i c a n A m e r i c a n a n d w h i t e ;U S )

C a n c e r R e g i s t r y V o l u n t e e r s

B l o o d

312/398

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TABLE3.Distribution of BRCA2ARG372HIS genotype among ovarian cancer cases and controls included in the meta-analysis

First

Author Y ear

Genotypes

Distribution

(Case Source)

Genotypes

Distribution

(Controls Source)

P-HWE

(Controls)

HH V ersus NN

NN NH HH NN NH HH OR(95%CI)P

Auranen-1200335527253819629980.12 1.25[0.87,1.78]0.22 Auranen-2200322217643578445740.35 1.51[1.01,2.27]0.046 Beesley-1200724920340502383630.38 1.28[0.84,1.96]0.25 Beesley-2200746040169461296680.039 1.02[0.71,1.46]0.93 Quaye200977956911112009251690.61 1.01[0.78,1.31]0.93 Ramus200821961655323385929795640.74 1.01[0.87,1.17]0.93 Wenham200316912815227146250.130.81[0.41,1.58]0.53 Total44303404654764658031061 1.06[0.96,1.18]0.25

Test for heterogeneity P=0.45 NH V ersus NN NH+HH V ersus NN HH V ersus NN+NH OR(95%CI)P OR(95%CI)P OR(95%CI)P 1.00[0.83,1.21]0.98 1.02[0.92,1.12]0.74 1.25[0.88,1.77]0.21 1.03[0.82,1.30]0.81 1.05[0.94,1.18]0.4 1.49[1.01,2.21]0.046 1.07[0.85,1.34]0.57 1.05[0.94,1.17]0.4 1.24[0.82,1.88]0.3 1.36[1.11,1.66]0.0025 1.15[1.04,1.27]0.00730.89[0.63,1.26]0.52 0.95[0.83,1.09]0.440.98[0.91,1.05]0.52 1.04[0.81,1.33]0.78

0.98[0.90,1.06]0.550.99[0.95,1.03]0.62 1.02[0.88,1.17]0.82

1.18[0.86,1.61]0.3 1.07[0.90,1.26]0.450.75[0.39,1.46]0.4 1.02[0.96,1.07]0.6 1.01[0.98,1.04]0.42 1.06[0.95,1.17]0.29

Test for heterogeneity P=0.08Test for heterogeneity P=0.16Test for heterogeneity P=

0.35

FIGURE2.Forest plot of summary ORs and95%CIs for the association between BRCA2ARG372HIS polymorphisms and ovarian cancer risk in all genetic models.

Wang and Yuan International Journal of Gynecological Cancer&Volume25,Number8,October2015 1342*2015IGCS and ESGO

polymorphism and ovarian cancer risks has been exten-sively studied.However,the results have been inconsistent.We therefore performed a meta-analysis of 8488ovarian cancer cases and 14,510controls from 5articles published and 7case-control studies.

To our knowledge,this is the first meta-analysis on the association between BRCA2Arg372His polymorphisms and ovarian cancer risk.All of the literatures were high quality.Only 1sample size was less than 1000.So all studies are suitable.No significant association with ovarian cancer risk was seen in all genetic models including the 7studies.Most study subjects were white.There were few Africans and no Asian in 7studies.Ethnicity/race may be an independent factor affecting the association of the distribution of gene polymorphism and breast cancer development.33There are strong ethnic differences in lung cancer 34,renal cell cancer,35and breast cancer incidences.36The global multicenter studies can pro-vide more valuable conclusions.So further studies may be needed to explore the possible relationship between BRCA2ARG372HIS polymorphisms and ovarian cancer risk in other ethnicities and areas,non-white groups.

In conclusion,this meta-analysis shows that the BRCA2ARG372HIS were associated with ovarian cancer risk overall mainly for https://www.wendangku.net/doc/ee2034593.html,n and African populations should be further studied.

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FIGURE 3.Begg funnel plot of BRCA2ARG372HIS polymorphisms and ovarian cancer risk in all genetic models.Each hollow cycle represents a separate study for the indicated association,and its size is proportional to the sample size of each study.

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