Five P53 SNPs Involved in Low Rectal Cancer Risk and Prognosis in a Chinese Population.

Although the impact and potential mechanisms of p53 polymorphisms on human malignancies have been intensively studied, analyses for association between p53 polymorphisms and colorectal cancer (CRC) risk were still limited to some common variants. Moreover, the majority of previous studies did not classify the specimens of CRC based on tumor location. This case-control study aimed to evaluate the association of five p53 polymorphisms (rs1042522, rs12947788, rs1625895, rs2909430 and rs12951053) with the risk of low rectal cancer (LRC) and investigate the prognostic significance. A total of 347 cases and 353 controls from a Chinese population were recruited and genotyped using KASP assay. Individuals carrying the variant rs12947788 A allele were observed to associate with an increased risk of LRC. After stratification for clinicopathological parameters, rs12947788 was significantly co-related with the histological type of LRC under a dominant model. Although none of the selected p53 polymorphisms was significantly associated with patient prognosis in total population, significant associations with the overall survival were revealed in the heterozygosis carriers vs. wild type carriers model through subgroup analyses based on clinical characteristics. Moreover, haplotype analyses showed that C-A-G-A-A haplotype was associated with a significantly higher LRC risk as compared to the other haplotypes. In low rectal cancer, P53 protein expression was obviously higher in p53 rs1042522 mutant carriers than in other genotypes. Our study further proves the involvement of p53 polymorphisms in pathogenesis of LRC and may provide potential therapeutic implications.

Expression of DDB2 Protein in the Initiation, Progression, and Prognosis of Colorectal Cancer.

BACKGROUND: Damage-specific DNA binding protein 2 (DDB2) is implicated in the recognition of DNA damage and the initiation of nucleotide excision repair process. The aim of this study was to explore the role of DDB2 in the initiation, progression, and prognosis of colorectal cancer (CRC). METHODS: Totally tissues of 300 CRC and 300 adjacent, 267 colorectal adenoma (CRA) and 214 normal (NOR) were collected. The expression of DDB2 protein was detected by immunohistochemical staining. RESULTS: DDB2 protein was highly expressed in CRC and CRA compared with NOR (P < 0.001, respectively) in the dynamic sequence of NOR → CRA → CRC; CRC tissue demonstrated increased DDB2 expression compared with non-tumor adjacent tissues (P < 0.001). DDB2 expression was higher in T1-T2 than that in T3-T4 in CRC (P = 0.023); cloddy/nested CRC demonstrated increased DDB2 expression than infiltrative CRC (P = 0.007). Survival analysis showed that high DDB2 expression was associated with favorable survival in colon cancer (adjusted HR 0.20, 95% CI 0.06-0.72, P = 0.014) and female CRC patients (adjusted HR 0.27, 95% CI 0.08-0.92, P = 0.036). CONCLUSION: DDB2 protein expression was associated with the initiation, progression, and prognosis of CRC, and might function as a tumor biomarker for the diagnosis and prognosis of CRC.

DNA repair protein XPA is differentially expressed in colorectal cancer and predicts better prognosis.

As an indispensable factor in DNA damage recognition step of nucleotide excision repair, XPA interacts with a series of proteins to initiate repair process. The expression characteristics of XPA in colorectal cancer (CRC) and its influence on CRC prognosis remain elusive. Tissue specimens of CRC and nontumor adjacent tissues from 283 patients were collected. XPA protein expressions were detected by immunohistochemistry staining. Nonparametric test was used to investigate the difference of XPA expression between CRC and nontumor adjacent tissues, as well as the correlation between XPA expression and clinicopathological parameters of CRC. Univariate and multivariate Cox proportional hazards models were applied to estimate the relationship between XPA expression and CRC prognosis. Meanwhile, we analyzed TCGA data to investigate the relation between XPA mRNA expression and survival of CRC. XPA protein expression was significantly decreased in CRC tissues compared with nontumor adjacent tissues (P = 0.001). Subgroup analysis indicated consistently significant down-regulation of XPA in CRC tissues in age > 60 (P = 0.026), age ≤ 60 (P = 0.008), colon cancer (P = 0.009), and rectal cancer (P = 0.015) patients and males (P = 0.004). For clinicopathological parameters, CRC patients with drinking habits revealed XPA overexpression than nondrinkers (P = 0.032). For prognosis, CRC patients with high XPA protein expression had longer overall survival (OS) (HR = 0.62, 95%CI: 0.39-0.97, P = 0.037). Stratified analysis suggested a better prognosis in relation to high XPA protein expression in patients over 60 years (adjusted HR = 0.48, P = 0.021), with rectal cancer (HR = 0.56, P = 0.037), without distant metastasis (HR = 0.58, P = 0.033), without tumor deposits (HR = 0.40, P = 0.006; adjusted HR = 0.44, P = 0.028), and with tumor diameter over 4 cm (HR = 0.49, P = 0.023). DNA repair protein XPA is significantly decreased in colorectal cancer tissues than in adjacent nontumor tissues. High expression of XPA protein showed significant relationship with better survival of CRC, especially rectal cancer. XPA might be a novel biomarker but might not be an independent factor to predict prognosis of CRC patients.

The association of six polymorphisms of five genes involved in three steps of nucleotide excision repair pathways with hepatocellular cancer risk.

BACKGROUND: Hundreds of single nucleotide polymorphisms (SNPs) of the genes encoding nucleotide excision repair (NER) proteins are involved in every step of the DNA recognition-unwinding-incision process, which may affect cancer risk. However, only a limited number of studies have examined the association of NER SNPs with hepatocellular cancer (HCC) risk. RESULTS: In screening stage, single-locus analysis showed that six SNPs in five genes were associated with HCC risk, including three risk SNPs (XPA rs10817938, XPC rs1870134 and ERCC2 rs238417) and three protective SNPs (ERCC1 rs2298881 and rs3212961, and ERCC5 rs873601). In verification stage, only XPC rs1870134 was verified to be associated with HCC risk (P = 4.7 × 10-4). Furthermore, multivariate logistic regression and MDR analysis consistently revealed a gene-gene interaction among ERCC1 rs2298881 and XPC rs1870134 SNPs associated with HCC risk (Pinteraction = 0.023). When analyzing the effect of the positive SNP on the mRNA expression, we found XPC rs1870134 GG genotype which was associated with an increased HCC risk showed lower XPC mRNA expression. METHODS: This study designed as "screening-verification" experiments and included a total of 1472 participants (570 HCC patients vs. 902 controls). We explored 39 SNPs in eight genes involved in NER Pathways, including XPA, XPC, DDB2, ERCC3, ERCC2, ERCC1, ERCC4 and ERCC5, using Sequenom MassARRAY and KASPar platform. Eighty-six cases of HCC and the neighboring noncancerous tissues were subjected to the measurement of mRNA expression level of the promising gene. CONCLUSIONS: XPC promoter rs1870134 SNP and SNP-SNP interaction were associated with HCC risk.