Our present meta-analysis incorporating 19 case-control studies (4479 cases and 4683 controls) examined the association between a commonly studied 16-bp duplication polymorphism within intron 3 of p53 gene and breast cancer risk. The results showed that, in overall, the vaiant Ins allele was associated with a significantly increased risk of breast cancer. Given the important role of p53 in multiple cellular functions, such as DNA repair and apoptosis, it is biologically plausible that genetic variations of p53 gene may modulate the risk of breast cancer.
It is reported that the 16-bp Ins allele was associated with lower level of p53
transcript in lymphoblastoid cell lines, suggesting that this polymorphism causes an alteration in messenger RNA (mRNA) processing 
. Moreover, the intron 3 16-bp duplication polymorphism was in strong linkage disequilibrium with the well-studied codon 72 variant and investigators have showed that a P53
haplotype (codon 72 Arg/Pro, intron 6 G>A and intron 3 duplication) is associated with reduced apoptotic and DNA repair capacity in lymphoblastoid cell lines 
. These experimental data indicate that the P53
variants may affect P53 function. Thus, it is reasonable that the 16-bp Ins allele might result in alteration of p53
gene expression and function, leading to decrease of p53 mediated apoptosis of tumor cells. In our present meta-analysis, we found that individuals with the 16-bp Ins allele were associated with higher risk of breast cancer than subjects with the Del allele, which was consistent with experimental findings.
Our results showed that the Ins allele may increase risk of breast cancer, which were consistent with a previous meta-analysis of eight studies based on breast cancer 
. In the previous meta-analysis, however, the pooled sample size was relatively small and not enough information was available for more exhaustive subgroup analysis. Thereafter, several studies with a large sample size about this polymorphism on breast cancer risk have been reported, which would greatly improve the power of the meta-analysis of this polymorphism. Subgroup analyses performed by ethnicity, subject source, and sample size were also possible now. Thus, we updated this meta-analysis to derive a more precise estimation of these associations.
In our analysis, many studies did not provide the ethnic background of their participants, which precluded more detailed analysis of this polymorphism in different ethnicities. Thus, more specific ethnical information should be provided in further studies, which should lead to better understanding of the association between the 16-bp duplication polymorphism of p53 and breast cancer risk among different ethnicities.
We found an evidence for the association between the 16-bp Ins allele and breast cancer risk among large sample studies (>500 subjects) but not among small sample studies (≤500 subjects). This is probably because studies with small sample size may have limited statistical power to detect a small effect or may have generated a fluctuated risk estimate. Thus, the use of a proper and large sample study is very crucial in reducing biases in such association studies.
In this meta-analysis, a thorough sensitivity analysis was carried out by removing each single study from pooled data and the results showed that there was no influence of the individual data on overall results. Moreover, we also calculated the overall pooled ORs on 16-bp duplication with and without the two largest studies 
, and in both instances, found that the 16-bp Ins allele was associated with the increased risk of breast cancer.
Some limitations of this meta-analysis should be acknowledged. First, in the subgroup analyses, the number of Africans and Asians was relatively small, not having enough statistical power to explore the real association. Second, misclassifications on disease status and genotypes may also influence the results, because cases in several studies were not confirmed by pathology, and the quality control of genotyping was also not well documented in several studies. In spite of these, our present meta-analysis also had some advantages. First, substantial number of cases and controls were pooled from different studies, which greatly increased statistical power of the analysis. Second, the quality of case-control studies included in this meta-analysis was satisfactory according to our selection criteria. Third, we did not detect any publication bias indicating that the whole pooled result should be unbiased.
Taken together, this meta-analysis provided evidence that the 16-bp duplication polymorphism within intron 3 of p53 gene was significantly associated with an increased risk of breast cancer. Future well-designed large studies were warranted to validate these findings in different ethnic populations.