Arg72Pro TP53 polymorphism and cancer susceptibility: A comprehensive meta‐analysis of 302 case‐control studies

Abstract

Arg72Pro is a common polymorphism in TP53, showing differences in its biological functions. Case-control studies have been performed to elucidate the role of Arg72Pro in cancer, although the results are conflicting and heterogeneous. Here, we analyzed pooled data from case-control studies to determine the role of Arg72Pro in different cancer sites. We performed a systematic review and meta-analysis of 302 case-control studies that analyzed Arg72Pro in cancer susceptibility. Odds ratios were estimated for different tumor sites using distinct genetic models, and the heterogeneity between studies was explored using I 2 values and meta-regression. We adopted quality criteria to classify the studies. Subgroup analyses were done for tumor sites according to ethnicity, histological, and anatomical sites. Results indicated that Arg72Pro is associated with higher susceptibility to cancer in some tumor sites, mainly hepatocarcinoma. For some tumor sites, quality of studies was associated with the size of genetic association, mainly in cervical, head and neck, gastric, and lung cancer. However, study quality did not explain the observed heterogeneity substantially. Meta-regression showed that ethnicity, allelic frequency and genotyping method were responsible for a substantial part of the heterogeneity observed. Our results suggest ethnicity and histological and anatomical sites may modulate the penetrance of Arg72Pro in cancer susceptibility. This meta-analysis denotes the importance for more studies with good quality and that the covariates responsible for heterogeneity should be controlled to obtain a more conclusive response about the function of Arg72Pro in cancer.The tumor TP53 suppressor gene plays a pivotal role in protecting cells against genotoxic insults of endogenous or environmental agents, which orchestrate a diversity of pathways from transcriptional responses to apoptosis. 1,2 Although TP53 mutations are thought to be associated with carcinogenesis, 3,4 polymorphisms in TP53 seem to have a modest effect on cell phenotype, leading to different patterns of cancer susceptibility. 5 Among known TP53 polymorphisms, 6 Arg72Pro is the most studied, and in vitro assays have demonstrated a differential ability to trigger apoptosis 7 and susceptibility for degradation by the E6 protein of the HPV-16 virus. 8 However, in the epidemiologic field, even with a considerable number of reports analyzing the p53 Arg72Pro polymorphism and risk of cancer in case-control studies, results remain conflicting rather than conclusive. For breast cancer, for example, results vary from protective 9-12 to no association [13][14][15] or increase in risk. [16][17][18] Similar conflicting results are also observed for esophageal, 19-22 lung, 23-25 and colorectal cancer [26][27][28] and other cancer types. To better understand the role of Arg72-Pro, recent meta-analysis studies have been performed for different cancer types, such as lung, 29 gastric, 30 and cervical cancer. 31 However, each of these meta-analyses is restricted to a specif...

p53 Arg72Pro and MDM2 309 SNPs in hereditary retinoblastoma

“…9 Several studies have highlighted the risk-modifying effect of these polymorphisms in common cancers and the rare Li-Fraumeni syndrome caused by germinal TP53 mutations. [10][11][12] The possible role of the MDM2 309SNP in RB has only recently been addressed through a family-based approach. 13 For the first time we here investigated both SNPs.…”

The p53 codon 72 polymorphism is associated with risk and early onset of breast cancer among Saudi women

“…Similarly, the most recent meta-analysis indicated that the codon 72 polymorphism may not be associated with breast cancer risk in a Caucasian population. However, previous meta-analyses concerning the p53 codon 72 polymorphism also revealed conflicting results (23)(24)(25)(26). The precise reasons for this discrepancy remained to be elucidated (8,11).…”

“…One possibility is that the effect of this polymorphism varies according to the genetic background of the studied population. Francisco et al suggested that ethnicity and histological and anatomical sites modulate the penetrance of R72P in cancer susceptibility (26). The other possibility includes the size of the studied population and stringent levels of statistical significance (7).…”

TP53 Gene Polymorphisms in Cancer Risk: The Modulating Effect of Ageing, Ethnicity and TP53 Somatic Abnormalities

“…A high heterogeneity of results was observed in breast Hu et al, 2010b;Lu et al, 2011b;Ma et al, 2011;Peng et al, 2011;Sergentanis and Economopoulos, 2010b;The Breast Cancer Association Consortium, 2006;Zhang et al, 2010b;Zhuo et al, 2009a), colon and rectum (Dahabreh et al, 2010;Liu et al, 2011;Tang et al, 2010;Wang et al, 2010b) cancers. Though still not quite clear, cancer of the ovary (Schildkraut et al, 2009;Zhang et al, 2008), endometrium (Francisco et al, 2010;Jiang et al, 2010b), stomach (Francisco et al, 2010;Gao et al, 2009;Liu et al, 2011), bladder (Jiang et al, 2010a;Li et al, 2010), prostate Zhang et al, 2011b;Zhu et al, 2011), and skin (Francisco et al, 2010;Jiang et al, 2011) appear to be affected. As for the rs17878362 polymorphism, a clear association of the A2 allele with a high risk of breast cancer Hu et al, 2010a;Hu et al, 2010b;Zhang et al, 2011a) and a lack of involvement in lung (Hu et al, 2010a), ovary (Schildkraut et al, 2009), colon and rectum (Hu et al, 2010a) cancer susceptibility has been demonstrated.…”

“…However, in spite of the present disagreements and methodological flaws, association tendencies for some cancer localizations are clear (Table 2). Simply stated, the rs1042522 C allele is associated with increased susceptibility to cancers, including of the lung (Dai et al, 2009;Francisco et al, 2010;Li et al, 2009;Yan et al, 2009), head and neck (Francisco et al, 2010), thyroid (Francisco et al, 2010), esophagus Zhao et al, 2010), pancreas , liver Francisco et al, 2010), gallbladder , nasopharynx (Zhuo et al, 2009b), and cervix (Francisco et al, 2010;Klug et al, 2009). No significant contribution of TP53 rs1042522 polymorphism to oral cancer has been reported (Zhuo et al, 2009c).…”