six genes confer a high risk for hereditary breast cancer : brca1 , brca2 , tp53 , pten , cdh1 , and stk11 . germline mutations in brca1 , brca2 , and p53 are the most common known causes of hereditary breast cancer . brca1 and brca2 are involved in dna damage repair and recombination , cell cycle checkpoint control , apoptosis , and transcriptional regulation . p53 is a tumor suppressor that plays a pivotal role in the cellular response to dna damage by inducing pathways involved in apoptosis , cell cycle arrest , and dna repair . mutations and genetic polymorphisms can alter p53 function and activity , thereby impairing the cellular response to dna damage . previous studies of the relationship between brca status and p53 status have reported inconsistent results . several investigations have demonstrated that p53 over - expression is more common in breast tumors associated with brca1 mutation than with brca2 mutation or non - carriers [ 69 ] . others have identified p53 over - expression in tumors with brca2 mutation in comparison with non - carriers . conversely , several reports have found no association between p53 over - expression and brca status . greater insights into the specific dna repair mechanism in brca mutations and p53 status in breast cancer create more opportunities for effective treatment of patients . we sought to clarify the relationship between brca mutation status and p53 expression status by performing a meta - analysis . the pubmed , embase , and cochrane library databases were searched for suitable studies published before june 2015 . publications with the following search terms in the title , abstract , or key words were included : tp53 , p53 , p53 expression , brca , brca1 , brca1 mutation , brca2 , brca2 mutation , and breast cancer . when multiple studies were identified , we evaluated their potential eligibility for inclusion by scanning abstracts and full texts . the inclusion criteria were : 1 ) original investigation with evaluation of p53 status in 3 groups ( brca1mut , brca2mut , and non - carriers ) ; 2 ) included sufficient data to determine odds ratio ( or ) and 95% confidence interval ( ci ) ; 3 ) published as an original article in english ; 4 ) breast cancer patients including both hereditary and sporadic ; and 5 ) being a high - quality case - control study ( newcastle - ottawa scale ( nos ) 7 points . the exclusion criteria were : 1 ) data obtained from animal models ; 2 ) brca1mut and brca2mut not examined individually ; 3 ) review article or letter ; 4 ) lacking essential data ( e.g. , number of p53-positive and -negative individuals in each group not separately indicated ) ; and 5 ) use of duplicate data . for each of the eligible manuscripts , 2 investigators ( pl and xt ) independently extracted the following data : first author name ; year of publication ; country ; numbers of brca1mut patients with p53(+ ) , brca1mut patients with p53( ) , brca2mut patients with p53(+ ) , brca2mut patients with p53( ) , non - carrier patients with p53(+ ) , and non - carrier patients with p53( ) ; method of brca testing ; and method of p53 testing . we evaluated the association between p53 status and brca status using or and 95% ci . the  and i test methods were used to evaluate data heterogeneity in the studies . the fixed - effects model was used when i < 50% and p>0.05 for  ; otherwise , the random - effects model was used . the pubmed , embase , and cochrane library databases were searched for suitable studies published before june 2015 . publications with the following search terms in the title , abstract , or key words were included : tp53 , p53 , p53 expression , brca , brca1 , brca1 mutation , brca2 , brca2 mutation , and breast cancer . when multiple studies were identified , we evaluated their potential eligibility for inclusion by scanning abstracts and full texts . the inclusion criteria were : 1 ) original investigation with evaluation of p53 status in 3 groups ( brca1mut , brca2mut , and non - carriers ) ; 2 ) included sufficient data to determine odds ratio ( or ) and 95% confidence interval ( ci ) ; 3 ) published as an original article in english ; 4 ) breast cancer patients including both hereditary and sporadic ; and 5 ) being a high - quality case - control study ( newcastle - ottawa scale ( nos ) 7 points . the exclusion criteria were : 1 ) data obtained from animal models ; 2 ) brca1mut and brca2mut not examined individually ; 3 ) review article or letter ; 4 ) lacking essential data ( e.g. , number of p53-positive and -negative individuals in each group not separately indicated ) ; and 5 ) use of duplicate data . for each of the eligible manuscripts , 2 investigators ( pl and xt ) independently extracted the following data : first author name ; year of publication ; country ; numbers of brca1mut patients with p53(+ ) , brca1mut patients with p53( ) , brca2mut patients with p53(+ ) , brca2mut patients with p53( ) , non - carrier patients with p53(+ ) , and non - carrier patients with p53( ) ; method of brca testing ; and method of p53 testing . we evaluated the association between p53 status and brca status using or and 95% ci . the  and i test methods were used to evaluate data heterogeneity in the studies . the fixed - effects model was used when i < 50% and p>0.05 for  ; otherwise , the random - effects model was used . a total of 718 articles were identified by initial database searches . after excluding duplicates , laboratory studies , reviews , and other irrelevant studies , 58 reports remained . we then excluded 11 studies that provided only brca1mut and p53 data , 6 studies that provided only brca2mut and p53 data , 11 studies that contained insufficient data , 9 studies that evaluated brca1 and 2 together , and 5 studies that used animal models . the 16 remaining eligible articles [ 12,1529 ] were subsequently included in the meta - analysis ( figure 1 ) . the 16 eligible studies were published between 1999 and 2015 and all were case - control studies . a total of 4288 patients were included in this meta - analysis , with 681 brca1mut carriers , 366 brca2mut carriers , and 3241 non - carriers . all patients came from 1 of 10 countries ( japan , china , finland , spain , the netherlands , italy , france , australia , usa , and the uk ) . methods used to assess brca mutation were fluorescence in situ hybridization ( fish ) , denaturing high - performance liquid chromatography ( dhlpc ) , single - strand conformation polymorphism ( sscp ) , protein truncation test ( ptt ) , horseradish peroxidase ( hrp ) , and high - resolution melting ( hrm ) . immunohistochemistry ( ihc ) , sscp , and fish were the methods used for p53 detection . we found that brca1 was significantly associated with p53 overexpression compared with brca2 ( or=1.929 ; 95% ci=1.4572.554 ; p<0.001 using the random - effects model ; figure 2 ) compared with the non - carrier group , p53 overexpression was more common in brca1 carriers ( or=1.509 ; 95% ci=1.2211.864 ; p<0.001 using the random - effects model ; figure 3 ) we found no difference in p53 protein expression between brca2 carriers and non - carriers ( or=0.842 ; 95% ci=0.6421.13 ; p=0.211 using the fixed - effects model ; figure 4 ) , with no obvious evidence of heterogeneity . sensitivity analyses was used to verify the influence of each single study on the overall results in each comparison . , had the most significant impact on the total effect ( figure 5 ) and it had the most cases of all included studies . however , when the study was removed , the ors were not substantially changed . the or was 1.882 ( 95% ci=1.4862.427 ) for excluding the study , and the previous or was 1.929 ( 95% ci=1.4572.554 ) a total of 718 articles were identified by initial database searches . after excluding duplicates , laboratory studies , reviews , and other irrelevant studies , 58 reports remained . we then excluded 11 studies that provided only brca1mut and p53 data , 6 studies that provided only brca2mut and p53 data , 11 studies that contained insufficient data , 9 studies that evaluated brca1 and 2 together , and 5 studies that used animal models . the 16 remaining eligible articles [ 12,1529 ] were subsequently included in the meta - analysis ( figure 1 ) . the 16 eligible studies were published between 1999 and 2015 and all were case - control studies . a total of 4288 patients were included in this meta - analysis , with 681 brca1mut carriers , 366 brca2mut carriers , and 3241 non - carriers . all patients came from 1 of 10 countries ( japan , china , finland , spain , the netherlands , italy , france , australia , usa , and the uk ) . methods used to assess brca mutation were fluorescence in situ hybridization ( fish ) , denaturing high - performance liquid chromatography ( dhlpc ) , single - strand conformation polymorphism ( sscp ) , protein truncation test ( ptt ) , horseradish peroxidase ( hrp ) , and high - resolution melting ( hrm ) . immunohistochemistry ( ihc ) , sscp , and fish were the methods used for p53 detection . we found that brca1 was significantly associated with p53 overexpression compared with brca2 ( or=1.929 ; 95% ci=1.4572.554 ; p<0.001 using the random - effects model ; figure 2 ) . there was no obvious evidence of heterogeneity ( i=46.8% , p=0.024 ) . compared with the non - carrier group , p53 overexpression was more common in brca1 carriers ( or=1.509 ; 95% ci=1.2211.864 ; p<0.001 using the random - effects model ; figure 3 ) we found no difference in p53 protein expression between brca2 carriers and non - carriers ( or=0.842 ; 95% ci=0.6421.13 ; p=0.211 using the fixed - effects model ; figure 4 ) , with no obvious evidence of heterogeneity . sensitivity analyses was used to verify the influence of each single study on the overall results in each comparison . , had the most significant impact on the total effect ( figure 5 ) and it had the most cases of all included studies . however , when the study was removed , the ors were not substantially changed . the or was 1.882 ( 95% ci=1.4862.427 ) for excluding the study , and the previous or was 1.929 ( 95% ci=1.4572.554 ) . moreover , the heterogeneity was not significantly changed . brca1 was significantly associated with p53 overexpression compared with brca2 and non - carrier genotypes . p53 mutation is frequently identified in high - grade estrogen receptor - negative , progesterone receptor - negative , basal - like breast cancer with increased genomic instability and poor prognosis . additionally , brca1 breast cancer typically behaves in a manner similar to that described above . first , both p53 and brca1 are tumor suppressors involved in many cellular processes ranging from dna double - strand repair to cell - cycle arrest , cells apoptosis , and transcriptional control . second , both p53 and brca1 are located on chromosome 17 , and simultaneous loss of heterozygosity ( loh ) at p53 and brca1 may occur via misregulation of chromosome 17 . this could result in protein - truncating p53 mutations occurring in cis with the brca1 germline mutation . finally , loh at the p53 locus might occur more efficiently in brca1-deficient cells because brca1 is also involved in the g2-m and spindle assembly checkpoints . cells possess numerous dna repair pathways in which several proteins interact with each other in response to damage detection . . this may be because of reduced efficiency of dna repair activity in brca1 cells . dong et al .   revealed that p53 mediates homologous recombination during dna repair by inhibiting excessive brca1 function via a mechanism of transcriptional regulation . consistent with this , we found that brca1mut was significantly associated with p53 overexpression compared with brca2 or non - carriers . however , the relationship between p53 expression and brca2 is less clear than that for brca1 . identified p53 overexpression in approximately 50% of brca2 , whereas others reported that less than 20% of such tumors had elevated p53 . our meta - analysis found no difference in p53 protein expression in brca2 carriers and non - carriers . at present , the methods for detection of site - directed mutation of p53 gene include direct method , indirect method , and biosense technique . the premise of direct method is that the normal sequence and structure of the detected genes have been elucidated . direct sequencing ( ds ) , pcr restriction fragment length polymorphism analysis ( pcr - rflp ) , single - strand conformation polymorphism analysis ( sscp ) , and high - resolution melting ( hrm ) are used in the direct method . although these methods are used in clinical practice , it is common to have some problems : it is complicated and time - consuming , generates false - positive results , and requires expensive equipment . the indirect method is based on the expression of p53 protein and determines whether there is a point mutation of p53 gene . the indirect method includes immunohistochemistry ( ihc ) , tissue microarray , flow cytometry , and enzyme - linked immunosorbent assay . ihc is widely used in clinical applications , but there are false - positive and false - negative results . biosense technology has the advantages of good selectivity , high sensitivity , high speed , low cost , high automation , miniaturization , and integration . gene mutations were detected in tissues of partial protein - negative expression , while the expression of protein - positive tissue showed no gene changes . the following types of mutations are predicted to escape detection : mutations in noncoding regions , which are estimated to account for a minimum of 10% of pathogenetic brca1 and brca2 mutations ; large deletions undetectable by pcr - based assays ; and mutations within the first and last 180 nucleotides of the amplicons analyzed by ptt . moderate heterogeneity was found in this study , which is reasonable considering the various races , ages , and different detection methods . asymmetrical funnel plots  indicated publication bias , perhaps due to diverse reasons ( e.g. , studies with favorable results are more likely to be published , poor methodological quality of small studies , inclusion of numerous studies without registration , true heterogeneity , artifactual results , and other causes ) . first , the eligible studies examined were conducted in different populations and were case - control studies ; therefore , recall bias and selection bias were inevitable . second , as only english articles were selected , language bias may be a factor . third , positive results are more likely to be published than negative findings , and this may also be a source of bias . fourth , various methods for assessing brca1 and brca2 were used in different eligible studies , and different standards were used to define positivity . fourth , while detection of p53 was predominately via ihc , the antibody source , dilution rate , and cut - off value varied in different studies . finally , in view of the relationship between protein expression and gene mutation , the present results should be regarded as an approximation . brca1 and p53 are associated with poor prognosis in breast cancer , and p53 loss rescues the proliferative deficiency of brca1 cells . assessing the presence of both mutations could serve as a potential auxiliary biomarker for breast cancer prognosis . our findings suggest that the homologous recombination - deficient - targeting therapeutics used in treating p53-deficient tumors might be most effective in those tumors also carrying brca1 mutations . our meta - analysis suggests that brca1mut breast cancer patients were more likely to have p53 overexpression compared with brca2mut and non - carriers . this information may provide valuable guidance for clinicians performing related studies in the future .
backgroundresearch on brca mutation has meaningful clinical implications , such as identifying risk of second primary cancers and risk of hereditary cancers . 
 this study seeks to summarize available data to investigate the association between brca status and p53 status by meta-analysis.material/methodswe searched pubmed , embase , and cochrane library databases for relevant studies . 
 meta - analysis was conducted using stata software . 
 we summarized odds ratios by fixed - effects or random - effects models.resultsthis study included a total of 4288 cases from 16 articles , which including 681 brca1 mutation carriers ( brca1mut ) , 366 carriers of brca2 mutation ( brca2mut ) , and 3241 carriers of normal versions of these genes . 
 brca1mut was significantly associated with p53 over - expression compared with brca2mut ( or 1.851 , 95% ci=1.3932.458 ) or non - carriers ( or=2.503 , 95% ci=1.4934.198 ) . 
 no difference was found between p53 protein expression in brca2 mut carriers and non - carriers ( or=0.881 , 95% ci=0.6701.158).conclusionsour meta - analysis suggests that brca1mut breast cancer patients are more likely to have p53 overexpression compared with brca2mut and non - carriers . 
 this information provides valuable information for clinicians who perform related studies in the future .