The tumor suppressor P53 and its negative regulator mouse double minute 2 (MDM2) play crucial roles in carcinogenesis. Previous case-control studies also revealed that P53 72Arg>Pro and MDM2 309T>G polymorphisms contribute to the risk of common cancers. However, the relationship between these two functional polymorphisms and adult acute lymphoblastic leukemia (ALL) susceptibility has not been explored. In this study, we performed a case-control study to explore the association between MDM2 and P53 gene polymorphisms and ALL risk in a Chinese population. We found an increased adult ALL risk associated with the MDM2 GG (odds ratio [OR]=2.79, 95% confidence interval [95% CI]=1.67-4.68) and TG (OR=1.49, 95% CI=0.95-2.53) genotypes. An increased risk associated with the P53 Pro/Pro genotype (OR=2.22, 95% CI=1.30-3.79) compared with the Arg/Arg genotype was also observed. Furthermore, the gene-gene interaction of MDM2 and P53 polymorphisms increased the adult ALL risk in a super-multiplicative manner (OR for the presence of both MDM2 GG and P53 Pro/Pro genotypes=8.05, 95% CI=2.53-25.58). These findings suggest that polymorphisms of MDM2 and P53 genes may be genetic modifiers for developing adult ALL.

Genomic and immunologic surveillance mechanisms are crucial in protection from cancer. The tumor suppressor protein p53, encoded by TP53, is a major regulator of genome surveillance. Among the natural sequence variants of TP53, rs1042522 (R72P) modifies the risk for solid tumors. To investigate its relevance in childhood acute lymphoblastic leukemia (ALL) susceptibility, we genotyped 114 cases and 414 newborn controls from Wales (UK) for polymorphisms in TP53 (R72P), its negative regulator MDM2 (single-nucleotide polymorphism SNP309, rs2279744), and selected HLA complex genes whose products interact with TP53. TP53 R72P showed a risk association with gene dosage effect (P=0.002) resulting in a strong association of homozygous genotype (OR=2.9, 95% CI=1.5-5.6) and no sex effect. SNP309 did not show any association with primary susceptibility to childhood ALL, even after stratification by sex. However, females with SNP309 minor allele had earlier onset of childhood ALL (median age at diagnosis was 36 months in females, but 60 months in males; P=0.002). The HLA complex genes did not show any statistically significant interaction with R72P. We have therefore identified TP53 R72P as a possible risk modifier for childhood ALL and the association of MDM2 with age at onset with sex effect suggests prenatal hormonal programming of childhood ALL susceptibility.

The close functional relationship between p53 and the breast cancer susceptibility genes BRCA1 and BRCA2 has promoted the investigation of various polymorphisms in the p53 gene as possible risk modifiers in BRCA1/2 mutation carriers. Specifically, two polymorphisms in p53, c.97-147ins16bp and p.Arg72Pro have been analysed as putative breast cancer susceptibility variants, and it has been recently reported that a p53 haplotype combining the absence of the 16-bp insertion and the presence of proline at codon 72 (No Ins-72Pro) was associated with an earlier age at the onset of the first primary tumour in BRCA2 mutation carriers in the Spanish population. In this study, we have evaluated this association in a series of 2932 BRCA1/2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2.

p53-binding protein 1 (P53BP1), a central transducer of DNA-damage signals to p53, is required for both intra-S-phase and G2-M checkpoints, suggesting that these two proteins may work together in the p53-mediated transcriptional activation and DNA damage-repair signaling pathways. Because the p53-binding region of 53BP1 maps to the C-terminal BRCT domains, which are homologous to those found in the breast cancer protein BRCA1, we hypothesized that genetic variation in P53BP1 and p53 may contribute to breast cancer predisposition. To test this hypothesis, we simultaneously genotyped single nucleotide polymorphisms of T-885G, Glu353Asp, and Gln1136Lys in P53BP1 and Arg72Pro in p53 in a case-control study of 404 breast cancer cases and 472 cancer-free controls. We found that the P53BP1 variant genotypes (alleles) of T-885G and Gln1136Lys were associated with a significantly increased risk of breast cancer among p53 Pro/Pro carriers (OR=2.36, 95% CI 1.16-4.83 for -885TG/GG; OR=2.24, 95% CI 1.15-4.37 for 1136Gln/Lys+Lys/Lys and OR=2.82, 95% CI 1.15-6.94 for >4 variant alleles of these 3 loci). In addition, the variant genotypes of above 3 loci of P53BP1 were significantly associated with elevated risk of progesterone receptor (PR) negative breast cancer, and the T-885G and Gln1136Lys with estrogen receptor (ER) negative breast cancer. Furthermore, we found a significant gene-gene interaction between P53BP1 Gln1136Lys and p53 Arg72Pro variants in relation to breast cancer, and the OR of interaction for the presence of both P53BP1 1136Gln/Lys+Lys/Lys and p53 72Arg/Pro+Pro/Pro genotypes was 1.93 (95% CI 1.06-3.52) (P=0.031 for interaction). These findings indicate that the SNPs in P53BP1 and p53 jointly contribute to breast cancer risk, particularly ER (-) or PR (-) breast cancer, and the p53 Arg72Pro polymorphism may serve as a risk modifier. Further functional studies are needed to confirm our findings.

As a heterogeneous kind of malignances, Non-Hodgkin lymphoma (NHL) is the most common hematologic cancer worldwide with the significantly increased morbidity in China. Accumulated evidences demonstrated that oncoprotein MDM4 plays a crucial role in the TP53 tumor suppressor signaling pathway. An rs4245739 A>C polymorphism locating in the MDM4 3'-untranslated region creates a miR-191 target site and results in allele-specific MDM4 expression. In this study, we examined the association between this polymorphism as well as the TP53 Arg72Pro (rs1042522 G>C) genetic variant and Non-Hodgkin Lymphoma (NHL) risk in a Chinese Han population. Genotypes were determined in 200 NHL cases and 400 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. We found significantly increased NHL risk among carriers of the TP53 72Pro allele compared with those with the 72Arg allele (P=0.002 for the Pro/Pro genotype). We also observed a significantly decreased NHL risks among carriers of the MDM4 rs4245739 C allele compared with those with the A allele in Chinese (P=0.014 for the AC genotype). Stratified analyses revealed the associations between these SNPs and NHL risk are especially noteworthy in young or male individuals. Additionally, the associations are much pronounced in NHL patients with B-cell lymphomas or grade 3 or 4 disease. Our results indicate that the TP53 Arg72Pro and the MDM4 rs4245739 polymorphisms contribute to NHL susceptibility and support the hypothesis that genetic variants in the TP53 pathway genes can act as important modifiers of NHL risk.

In India, Epithelial ovarian cancer has emerged as one of the most common malignancies affecting women. Tumor protein 53 (TP53) induces expression of the B cell lymphoma 2-associated X protein (BAX) gene by directly binding to the TP53-binding element in the BAX promoter. Therefore, we hypothesized that single-nucleotide polymorphism of BAX promoter -248G>A and TP53 72Arg>Pro gene may jointly contribute to ovarian cancer risk.

Papillary thyroid carcinoma (PTC) etiologically occurs as a radiation-induced or sporadic malignancy. Genetic factors contributing to the susceptibility to either form remain unknown. In this retrospective case-control study, we evaluated possible associations between single-nucleotide polymorphisms (SNPs) in the candidate DNA damage response genes (ATM, XRCC1, TP53, XRCC3, MTF1) and risk of radiation-induced and sporadic PTC. A total of 255 PTC cases (123 Chernobyl radiation-induced and 132 sporadic, all in Caucasians) and 596 healthy controls (198 residents of Chernobyl areas and 398 subjects without history of radiation exposure, all Caucasians) were genotyped. The risk of PTC and SNPs interactions with radiation exposure were assessed by logistic regressions. The ATM G5557A and XRCC1 Arg399Gln polymorphisms, regardless of radiation exposure, associated with a decreased risk of PTC according to the multiplicative and dominant models of inheritance (odds ratio (OR) = 0.69, 95% confidence interval (CI) 0.45-0.86 and OR = 0.70, 95% CI 0.59-0.93 respectively). The ATM IVS22-77 T > C and TP53 Arg72Pro SNPs interacted with radiation (P = 0.04 and P = 0.01 respectively). ATM IVS22-77 associated with the increased risk of sporadic PTC (OR = 1.84, 95% CI 1.10-3.24) whereas TP53 Arg72Pro correlated with the higher risk of radiogenic PTC (OR = 1.80, 95% CI 1.06-2.36). In the analyses of ATM/TP53 (rs1801516/rs664677/rs609429/rs1042522) combinations, the GG/TC/CG/GC genotype strongly associated with radiation-induced PTC (OR = 2.10, 95% CI 1.17-3.78). The GG/CC/GG/GG genotype displayed a significantly increased risk for sporadic PTC (OR = 3.32, 95% CI 1.57-6.99). The results indicate that polymorphisms of DNA damage response genes may be potential risk modifiers of ionizing radiation-induced or sporadic PTCs.