TP53 Single Nucleotide Polymorphisms Research Articles

Association of TP53 Single Nucleotide Polymorphisms with Prostate Cancer in a Racially Diverse Cohort of Men.

Growing evidence indicates the involvement of a genetic component in prostate cancer (CaP) susceptibility and clinical severity. Studies have reported the role of germline mutations and single nucleotide polymorphisms (SNPs) of TP53 as possible risk factors for cancer development. In this single institutional retrospective study, we identified common SNPs in the TP53 gene in AA and CA men and performed association analyses for functional TP53 SNPs with the clinico-pathological features of CaP. The SNP genotyping analysis of the final cohort of 308 men (212 AA; 95 CA) identified 74 SNPs in the TP53 region, with a minor allele frequency (MAF) of at least 1%. Two SNPs were non-synonymous in the exonic region of TP53: rs1800371 (Pro47Ser) and rs1042522 (Arg72Pro). The Pro47Ser variant had an MAF of 0.01 in AA but was not detected in CA. Arg72Pro was the most common SNP, with an MAF of 0.50 (0.41 in AA; 0.68 in CA). Arg72Pro was associated with a shorter time to biochemical recurrence (BCR) (p = 0.046; HR = 1.52). The study demonstrated ancestral differences in the allele frequencies of the TP53 Arg72Pro and Pro47Ser SNPs, providing a valuable framework for evaluating CaP disparities among AA and CA men.

Relationship Between Genetic Polymorphisms in Cell Cycle Regulatory Gene TP53 and Polycystic Ovarian Syndrome: A Case-Control Study and In Silico Analyses.

Polycystic ovarian syndrome (PCOS) is a complex endocrine and metabolic condition with several potential causes. Insulin resistance is a hallmark of PCOS that often coexists with hirsutism, hyperandrogenism, being overweight, and hormonal imbalances. The functioning of multiple replication and transcription factors is regulated by tumor suppressor genes (TSGs), which play a crucial role in maintaining genomic integrity and controlling the cell cycle of granulosa cells. In the present study, we examined how three single nucleotide polymorphisms (SNPs) in TP53, a cell cycle regulatory gene, affect the risk of developing PCOS in asample of an Iranian population. Genomic DNA was extracted from 200 PCOS patients and 200 healthy women to analyze TP53 rs17880604, rs1625895, and rs1042522 SNPs using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Our findings revealed that the majority of PCOS cases were overweight [25 < body mass index (BMI) < 30]. A positive association was observed between the TP53 rs1042522 SNP and the risk of PCOS under codominant heterozygous and overdominant genetic patterns (odds ratio > 1). Meanwhile, a negative association was observed between TP53 SNPs (rs1625895, rs17880604) and susceptibility to PCOS under codominant heterozygous and dominant models of inheritance (odds ratio < 1). Moreover, different genotype and haplotype combinations of rs17880604/rs1625895/rs1042522 conferred a decreased risk ofPCOS in our population. We found no statistical difference in the frequency of TP53 genotypes between PCOS cases and/or controls in terms of BMI, waist circumference, prolactinlevel, and markers of lipid and carbohydrate profile (P > 0.05). Molecular dynamic prediction showed that the missense substitution in the 17p13.1 position (rs1042522) could change the properties and secondary structure of the p53 protein. As inherited risk factors, TP53 variations may play a pivotalrole in the pathogenesis ofPCOS among Iranian women. Replicated population-based studies on other ethnicities are required to findthegenetic contributionof variants of TP53, or SNPs located in otherTSGs, to the etiology of this endocrine disease.

TP53 common variants and interaction with PPP1R13L and CD3EAP SNPs and lung cancer risk and smoking behavior in a Chinese population

BackgroundTP53 encodes a tumor suppressor protein containing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. The effect of TP53 inactivation is well-known, and genetically determined smaller variations in TP53 activity are related to cancer. Lung cancer causes the highest rates of morbidity and mortality in the world. Epidemiology studies have assessed the association of TP53 single nucleotide polymorphisms with lung cancer. MethodsWe systematically examined the association of five htSNPs (haplotype-tagging single nucleotide polymorphism) (rs12951053, rs1042522, rs8079544, rs12602273 and rs8064946) across the entire TP53 locus and interaction between genes TP53 and PPP1R13L and CD3EAP and smoking-duration related to lung cancer risk in this Chinese study including 544 cases and 550 controls. ResultsNo significant associations were observed in analysis of alleles and genotypes with co-dominant, dominant, recessive, and log-additive models after adjustment for smoking status. Haplotype analysis showed that haplotype9 (rs12951053A-rs1042522C-rs8079544C-rs12602273G-rs8064946C) [OR (95% CI) = 0.13 (0.03–0.59), p = 0.0079] was associated with decreased risk of lung cancer after adjusted for smoking-duration. The analysis of smoking-duration within TP53 haplotypes showed that there were more carriers of haplotype1 (AGCCG), 2 (CCCGC) and 4 (CCCCG) in smoking-subgroup of >20 (years) (all p < 0.05). MDR testing analysis identified two significant models (both p < 0.0010) of gene-gene-environment interaction in relation to lung cancer risk in whole study group. ConclusionThe present results provide novel evidence that the haplotype of TP53 htSNPs and interaction between genetic variation in TP53 and CD3EAP and smoking-duration may associate with lung cancer risk, and provide additional evidence of association between TP53 htSNP haplotypes and long-term smoking-related behavior.

Interaction between common variants of MDM2 and PPP1R13L and CD3EAP and TP53 SNPs in relation to lung cancer risk among Chinese.

BackgroundLung cancer is a complex disease that diagnosed the most common cancer and led cause of cancer death. MDM2 (MDM2 proto-oncogene) encodes a nuclear-localized E3 ubiquitin ligase. The encoded protein can promote tumor formation by targeting tumor suppressor proteins, such as TP53, for proteasomal degradation. Epidemiology studies have investigated the association of MDM2 single nucleotide polymorphisms (SNP) and interaction between genetic and environmental factors with lung cancer.MethodsThis Chinese case-control study comprised 627 cases and 633 controls explored the role of MDM2 five htSNPs (rs1690924, rs1846402, rs2291857, rs3730581 and rs3730635, haplotype-tagging SNP) tagging 95% of the common haplotypes across the gene and the interactions of MDM2, PPP1R13L, CD3EAP and TP53 in the same pathological pathway on lung cancer risk, together with smoking-duration.ResultsNone of the htSNPs in MDM2 were associated with lung cancer risk in co-dominant, dominant, recessive, and log-additive models (adjusted for smoking-duration). Haplotype analysis showed that global haplotype association was statistically significant (P=0.0036, adjusted for smoking-duration) and haplotype5 (rs1690924A-rs1846402G-rs2291857C-rs3730581G-rs3730635A) was associated with reduced risk of lung cancer [OR (95%) =0.52 (0.33–0.82), P=0.0053, adjusted for smoking-duration]. MDR interaction analysis showed that two the best significant models and strong synergy between MDM2 and TP53.ConclusionsMDM2 five-htSNPs haplotype exhibited association with lung cancer susceptibility, interaction of MDM2 and TP53 htSNPs and smoking-duration contributed to lung cancer risk and strong synergy between MDM2 and TP53 htSNPs influenced lung cancer predisposition. Our results suggest that MDM2, TP53 and smoking-duration interact in relation to lung carcinogenesis.

TP53 genetic polymorphisms and susceptibility to cervical cancer in Bangladeshi women: a case-control study.

Pharmacogenetic study of TP53 gene polymorphisms has not been conducted extensively in cervical cancer. The aim of this study was to assesses the TP53 codon 72 and codon 47 polymorphisms and their relation to cervical cancer risk in Bangladeshi women. 134 cervical cancer patients and 102 age matched healthy controls were included from two institutions in Bangladesh. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used for genotyping two TP53 single nucleotide polymorphisms (codon 72 and codon 47) in patients and controls. The results indicate that the TP53 Arg/Pro heterozygosity (adjusted OR 2.32, 95% CI 1.28-4.34, p = 0.01), Pro/Pro mutant homozygosity (adjusted OR 4.15, 95% CI 1.75-9.86, p = 0.001), along with the combined genotype (Arg/Pro + Pro/Pro) (adjusted OR 2.83, 95% CI 1.61-4.97, p < 0.001) significantly increases the risk of cervical cancer. Moreover, the cervical cancer patients with a first-degree relative cancer patient possesses 4.45 folds more risk (p = 0.019) of carrying a proline allele in codon 72 of the TP53 gene compared to those patients who do not have any first-degree relative with cancer. Finally, polymorphism in the codon 47 of the TP53 gene did not significantly increase the risk of cervical cancer in Bangladeshi women. To conclude, this is the first study to identify that polymorphism in the TP53 codon 72 significantly increases the risk of cervical cancer in a female population in Bangladesh.

Genetic polymorphisms as non-modifiable susceptibility factors to laryngeal cancer.

Laryngeal squamous cell carcinoma (LSCC) is a highly disabling disease to the patient, affecting speech, swallowing and respiratory skills. Smoking and alcohol abuse are principal risk factors linked to this disease. Genetic factors can be involved in carcinogenesis by controlling the cell cycle, cell survival, angiogenesis, and invasiveness. Single nucleotide polymorphisms (SNPs) involving specific genes could modulate the risk of LSCC related to known carcinogens by modifying cellular responses, but not all genetic associations are known.In a case–control study, we assess the associations between cyclooxygenase-2 (COX2), epidermal growth factor (EGF), EGF receptor (EGFR), and tumor suppressor P53 SNPs on the risk of LSCC development in the Chilean population. A total of 85 LSCC patients and 95 healthy volunteers were recruited. SNPs genotype were analyzed from genomic DNA by Polymerase Chain Reaction (PCR)-Restriction Fragment Length Polymorphism (RFLP) and associations were estimated by odds ratios (ORs) using unconditional logistic regressions.A significant association between COX2 and TP53 SNP and LSCC risk was found, with an OR = 3.27 for COX2 c.-1329A>G (rs689466) SNP, and an OR = 1.94 for TP53 c.215C>G, Pro72Arg (rs1042522) SNP. These findings suggest that COX2 c.-1329A>G and TP53 c.215C>G (Pro72Arg) SNPs may be risk factors for LSCC.Through this research, we identify two low penetrance genetic variants that may be evaluated as novel biomarkers for this disease, in South American Mestizo populations.

Common genetic variants in the TP53 pathway and their impact on cancer.

The TP53 gene is well known to be the most frequently mutated gene in human cancer. In addition to mutations, there are > 20 different coding region single-nucleotide polymorphisms (SNPs) in the TP53 gene, as well as SNPs in MDM2, the negative regulator of p53. Several of these SNPs are known to alter p53 pathway function. This makes p53 rather unique among cancer-critical genes, e.g. the coding regions of other cancer-critical genes like Ha-Ras, RB, and PI3KCA do not have non-synonymous coding region SNPs that alter their function in cancer. The next frontier in p53 biology will consist of probing which of these coding region SNPs are moderately or strongly pathogenic and whether they influence cancer risk and the efficacy of cancer therapy. The challenge after that will consist of determining whether we can tailor chemotherapy to correct the defects for each of these variants. Here we review the SNPs in TP53 and MDM2 that show the most significant impact on cancer and other diseases. We also propose avenues for how this information can be used to better inform personalized medicine approaches to cancer and other diseases.

Genetic variants in the liver kinase B1-AMP-activated protein kinase pathway genes and pancreatic cancer risk.

The liver kinase B1-AMP-activated protein kinase (LKB1-AMPK) pathway has been identified as a new target for cancer therapy, because it controls the glucose and lipid metabolism in response to alterations in nutrients and intracellular energy levels. In the present study, we aimed to identify genetic variants of the LKB1-AMPK pathway genes and their associations with pancreatic cancer (PanC) risk using 15 418 participants of European ancestry from two previously published PanC genome-wide association studies. We found that six novel tagging single-nucleotide polymorphisms (SNPs) (i.e, MAP2 rs35075084 T > deletion, PRKAG2 rs2727572 C > T and rs34852782 A > deletion, TP53 rs9895829 A > G, and RPTOR rs62068300 G > A and rs3751936 G > C) were significantly associated with an increased PanC risk. The multivariate logistic regression model incorporating the number of unfavorable genotypes (NUGs) with adjustment for age and sex showed that carriers with five to six NUGs had an increased PanC risk (odds ratio = 1.24, 95% confidence interval = 1.16-1.32 and P < 0.0001), compared to those with zero to four NUGs. Subsequent expression quantitative trait loci (eQTL) analysis further revealed that these SNPs were associated with significantly altered mRNA expression levels either in 373 normal lymphoblastoid cell lines (TP53 SNP rs9895829, P < 0.05) or in whole blood cells of 369 normal donors from the genotype-tissue expression project (GTEx) database [RPTOR SNP rs60268947 and rs28434589, both in high linkage disequilibrium (r2 > 0.9) withRPTOR rs62068300, P < 0.001]. Collectively, our findings suggest that these novel SNPs in the LKB1-AMPK pathway genes may modify susceptibility to PanC, possibly by influencing gene expression.

TP53 rs1042522 and rs8064946 variants in myocardial infarction.

This studyinvestigated the hypothesis that the single nucleotide polymorphisms (SNPs) of TP53 gene are related to a risk of myocardial infarction. The coding SNP at codon 72 (rs1042522) and non-coding rs8064946 SNP were genotyped by polymerase chain reaction with sequence specific primers in 205 Czech patients with myocardial infarction and 148 Czech control subjects. The distribution of both SNPs was in agreement with the Hardy-Weinberg equilibrium and was similar to other European populations. Our power analysis showed 96 % of probability to detect an odd ratio equal to 2. Neither rs1042522 nor rs8064946 were associated with the risk of myocardial infarction. The haplotypes combined of rs1042522 and rs8064946 were not associated with myocardial infarction in the present study. The TP53 SNPs are not strongly associated with genetic predisposition to myocardial infarction (Tab. 3, Fig. 3, Ref. 23).

Blood-tissue analysis of TP53 polymorphisms and survival of patients with glioma.

The role of single nucleotide polymorphisms (SNPs) in TP53 in the pathogenesis of glioma is still debated. The aim of our study was to investigate the role of several TP53 SNPs in the risk of glioma and their possible role as prognostic biomarkers of overall and progression-free survival. We examined 12 SNPs in TP53 from peripheral blood and neoplastic tissue of patients with a diagnosis of glioma who underwent surgery from 2012 to 2015. Direct genomic sequencing of TP53 was performed to detect the presence of polymorphisms. We compared data with a matched cancer-free control group and the NCBI SNPs database. Overall and progression-free survival were analyzed in patients with glioblastoma subjected to gross total resection and concomitant radio-chemotherapy. No association was observed with glioma susceptibility and overall survival. Two new SNPs were detected: c.97-46 G>A (intron 3) and c.783-31 A>G (intron 7). The number of SNPs observed was higher (21.4%) in blood than in tumoral samples. We observed a significant reduction in progression-free survival in patients with at least one exonic SNP. We can hypothesize an involvement of TP53 SNPs in response mechanisms to adjuvant treatment that may affect progression-free survival. Moreover, our blood-tissue combined study revealed a significant difference in SNPs between blood and tumoral samples, probably due to glioma heterogeneity and genomic instability.

THE DISTRIBUTION OF TP53 GENE POLYMORPHISMS IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS, SUFFERERS OF CHORNOBYL NUCLEAR POWER PLANT ACCIDENT

The TP53 exonic and intronic SNPs were analyzed in 236 CLL patients by polymerase chain reaction and direct sequencing. The main group included 106 IR exposed CLL patients and thecontrol group was composed of 130 IR non-exposed CLL patients. Nineteen TP53 SNPs were found in the observed CLL cohort. No significant differences were found between the main and the control groups, but increased frequencies of T/T rs12947788 + G/G rs12951053 homozygotes and rs146340390 C/T variants were found among IR-exposed CLL patients compared with healthy Europeans (data from the 1000 Genomes Project). Rare nucleotide substitution rs146340390 (c.665C>T) was found only in the main group. These features were primarily typical for the most affected group of IR-exposed patients, namely, cleanup workers engaged in emergency works in the 2nd quarter of 1986. These preliminary findings don't contradict the assumption on possible influence of IR on CLL development via the p53-dependent pathway. This article is a part of a Special Issue entitled "The Chornobyl Nuclear Accident: Thirty Years After".

Prognostic value of ERCC1, ERCC2, XRCC1, and TP53 single nucleotide polymorphisms in patients with early-stage non-small cell lung cancer.

Identification of biomarkers used for the prognostic evaluation of non-small cell lung cancer (NSCLC) patients is important. The aim of this study was to evaluate the potential prognostic value of XRCC1, ERCC1, ERCC2, and TP53 single nucleotide polymorphisms (SNPs) in completely resected NSCLC patients. In total, 130 patients, surgically treated for NSCLC between 2000 and 2012, were included. An analysis of SNPs from peripheral blood cells was performed by polymerase chain reaction. XRCC1 Arg399Gln, ERCC1 Asn118Asn, ERCC2 Lys751Gln, and TP53 Arg72Pro polymorphisms were evaluated in conjunction with clinical and pathological parameters and survival. Kaplan-Meier method and Cox regression analysis were used. Median age rate was 59.3, ranging between 36 and 78 years. Median relapse-free survival duration (RFS) was found as 46.2 months. In those with ERCC2 CC allele, median RFS was detected as 28.3 months (95 % confidence interval (CI), 20.8-35.8), 46.9 months in those with CT heterozygous (95 % CI, 18.6-75.2), and 80.1 months for those with TT mutant allel (95 % CI, 33.0-127.2). Median RFS was seen to be longer in mutant group and also statistically significant (P = 0.018). Additionally, upon evaluating CC normal group with CT + TT alleles including mutant alleles, median RFS was found as 56.5 months (95 % CI, 24.6-88.4) in CT + TT group, and this was statistically significant (P = 0.005) Also, median RFS was 15.1 months in those including ERCC2 CC allele and 56.5 months in CT + TT allele in the group with no adjuvant treatment (P = 0.001). In conclusion, our study showed that ERCC2/XPD polymorphism is an independent prognostic factor in operated NSCLC patients, and these findings should be supported with prospective studies.

Abstract 4714: The association of glioma germline risk SNPs with mutation-based molecular subgroups

Abstract Background: Specific germline alterations within the TERT, EGFR, CCDC26, CDKN2A/B, PHLDB1, TP53 and RTEL1 regions are associated with development of glioma. While some of these germline variants are associated with all gliomas (e.g. rs2736100 in TERT), others are associated with a specific morphologic and/or molecular subtype. For example, the RTEL1 region variants are associated with primary glioblastoma and rs55705857 in CCDC26 is associated with 1p/19q co-deleted oligodendrogliomas and with IDH mutant astrocytic gliomas. We hypothesized that germline variants in these regions will be associated with other molecular subtypes. The Cancer Genome Atlas (TCGA) and other groups have described molecular subtypes of glioma based on acquired somatic mutation patterns. Herein, we grouped glioma patients into mutation-based molecular subgroups based on three molecular alterations and determined if germline polymorphisms are associated with these mutation-based molecular subtypes. Methods: Five molecular subtypes were defined based on combinations of the following molecular alterations: TERT promoter mutation (TERTmut vs. TERTwt), IDH1/2 mutation (IDH mut vs. IDH wt) and 1p/19q co-deletion (1p19qcodel vs. 1p19q noncodel). Germline single nucleotide polymorphisms (SNPs) were evaluated by custom Illumina array analysis of blood-derived DNA and 1K genome imputation. Results: One hundred ninety-nine gliomas (24 oligodendrogliomas, 59 mixed oligoastrocytomas, 41 grade 2-3 astrocytomas and 75 glioblastomas) had both SNP data and mutation data available in order to assign them into the five molecular subgroups. The prevalence of each of the molecular subtypes was as follows: TERTmut/IDHmut/1p19qcodel (20%), TERTmut/IDHmut/1p19qnoncodel (5%), TERTmut/IDHwt/1p19qnoncodel (32%), TERTwt/IDHmut/1p19qnondel (35%) and TERTwt/IDHwt/1p19qnoncodel (8%). The TERT SNP (rs2736100) was protective for TERTmut/IDHmut/1p19qnoncodel and TERTwt/IDHmut/1p19qnoncodel gliomas. The CCDC26 SNP (rs55705857) was strongly associated with the risk of developing TERTmut/IDHmut/1p19qcodel and TERTwt/IDHmut/1p19qnoncodel gliomas. The TP53 SNP (rs7837822) was strongly associated with risk of developing TERTmut/IDHmut/1p19qnoncodel and TERTwt/IDHmut/1p19qnoncodel gliomas. Interestingly, while one RTEL1 region SNP (rs6062297) was strongly associated with glioma risk, RTEL1 SNPs rs6010620 and rs2297440 were protective for the development of TERTmut/IDHwt/1p19qnoncodel gliomas. We are currently in the process of validating these results using the TCGA glioblastoma and low grade glioma data. Conclusions: Glioma patients can be meaningfully classified according to their acquired mutation subtype. Importantly, our results suggest that there are significant associations between germline polymorphisms and mutation-based glioma molecular subtypes. Citation Format: Jeanette E. Eckel-Passow, Thomas M. Kollmeyer, Gobinda Sarkar, Anisha Chada, Paul A. Decker, Matthew L. Kosel, Alissa A. Caron, Hugues Sicotte, Kannabiran Nandakumar, Naresh Prodduturi, Brian P. O'Neill, Daniel H. Lachance, Robert B. Jenkins. The association of glioma germline risk SNPs with mutation-based molecular subgroups. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4714. doi:10.1158/1538-7445.AM2014-4714

Computational screening and molecular dynamic simulation of breast cancer associated deleterious non-synonymous single nucleotide polymorphisms in TP53 gene.

Breast cancer is one of the most common cancers among the women around the world. Several genes are known to be responsible for conferring the susceptibility to breast cancer. Among them, TP53 is one of the major genetic risk factor which is known to be mutated in many of the breast tumor types. TP53 mutations in breast cancer are known to be related to a poor prognosis and chemo resistance. This renders them as a promising molecular target for the treatment of breast cancer. In this study, we present a computational based screening and molecular dynamic simulation of breast cancer associated deleterious non-synonymous single nucleotide polymorphisms in TP53. We have predicted three deleterious coding non-synonymous single nucleotide polymorphisms rs11540654 (R110P), rs17849781 (P278A) and rs28934874 (P151T) in TP53 with a phenotype in breast tumors using computational tools SIFT, Polyphen-2 and MutDB. We have performed molecular dynamics simulations to study the structural and dynamic effects of these TP53 mutations in comparison to the wild-type protein. Results from our simulations revealed a detailed consequence of the mutations on the p53 DNA-binding core domain that may provide insight for therapeutic approaches in breast cancer.

Relation of metastatic stage at the diagnosis of non-small cell lung cancer (NSCLC) to XRCC1 and TP53 single nucleotide polymorphisms (SNPs).

e19109 Background: DNA repair pathway genes are associated with lung cancer development. The aim of this study was to evaluate the association of XRCC1, ERCC1, ERCC2 and, TP53 SNPs with the stage a...

P0146 The prognostic role of XRCC1, ERCC1, ERCC2, and TP53 single nucleotide polymorphisms in resected non-small-cell lung cancer

<h3>Background</h3> Identification of biomarkers that can be used for the prognostic evaluation of NSCLC patients is important. The aim of this study was to evaluate the potential prognostic value of <i>XRCC1</i>, <i>ERCC1</i>, <i>ERCC2</i>, and <i>TP53</i> SNPs in completely resected NSCLC patients. <h3>Methods</h3> One hundred and thirty patients, who had been surgically treated for NSCLC between 2000 and 2012, were included in this study. Analysis of SNPs from peripheral blood cells was performed by PCR. <i>XRCC1</i> Arg399Gln, <i>ERCC1</i> Asn118Asn, <i>ERCC2</i> Lys751Gln, and<i>TP53</i> Arg72Pro polymorphisms were evaluated in conjunction with clinical and pathological parameters and survival. Kaplan–Meier method and Cox regression analysis were used. <h3>Findings</h3> In the univariate analysis for disease-free survival (DFS), postoperative stage (hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.26–0.96; <i>p</i>=0.03), <i>ERCC2</i> genotype (HR 2.47, 95% CI 1.28–4.78; <i>p</i>=0.007), and PET-CT staging (HR 0.27, 95%CI 0.14–0.52; <i>p</i><0.001) were significant parameters. Adjuvant chemotherapy, age, and the other SNPs were not significant. In the multivariate analysis, post-operative stage (HR 0.40, 95% CI 0.20–0.81; <i>p</i>=0.01), <i>ERCC2</i> genotype (HR 2.66, 95% CI 1.35–5.27; <i>p</i>=0.005), PET-CT staging (HR 0.24, 95% CI 0.12–0.47; <i>p</i><0.001) retained their significance. Median DFS was 56.5months (95% CI 24.6–88.4) for the <i>ERCC2</i> mutant (TT) and heterozygote (GT) genotypes, and 28.3months (95% CI 20.8–35.8) for the <i>ERCC2</i> normal (GG) genotype (p =0.005). <h3>Interpretation</h3> In addition to stage and PET-CT staging, <i>ERCC2</i> genotype independently predicted DFS in resected NSCLC patients. Future prospective studies are needed for the further evaluation of potential prognostic SNPs in resected NSCLC.

TP53 genetic polymorphisms, interactions with lifestyle factors and lung cancer risk: a case control study in a Chinese population

BackgroundA pathway-based genotyping analysis suggested rs2078486 was a novel TP53 SNP, but very few studies replicate this association. TP53 rs1042522 is the most commonly studied SNP, but very few studies examined its potential interaction with environmental factors in relation to lung cancer risk. This study aims to examine associations between two TP53 single-nucleotide polymorphisms (SNPs) (rs2078486, rs1042522), their potential interaction with environmental factors and risk of lung cancer.MethodsA case–control study was conducted in Taiyuan, China. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Multiplicative and additive interactions between TP53 SNPs and lifestyle factors were evaluated.ResultsVariant TP53 rs2078486 SNP was significantly associated with elevated lung cancer risk among smokers (OR: 1.70, 95% CI: 1.08 - 2.67) and individuals with high indoor air pollution exposure (OR: 1.51, 95% CI: 1.00-2.30). Significant or borderline significant multiplicative and additive interactions were found between TP53 rs2078486 polymorphism with smoking and indoor air pollution exposure. The variant genotype of TP53 SNP rs1042522 significantly increased lung cancer risk in the total population (OR: 1.57, 95% CI: 1.11-2.21), but there was no evidence of heterogeneity among individuals with different lifestyle factors.ConclusionsThis study confirmed that TP53 rs2078486 SNP is potentially a novel TP53 SNP that may affect lung cancer risk. Our study also suggested potential synergetic effects of TP53 rs2078486 SNP with smoking and indoor air pollution exposure on lung cancer risk.

TP53 alterations and colorectal cancer predisposition in south Indian population: A case-control study

The objective of the present study was to investigate the association between TP53 gene single nucleotide polymorphisms (SNPs) and colorectal cancer (CRC) predisposition in south Indian population and to evaluate the role of TP53 expression in the pathophysiology of CRC. A genetic association study was conducted in 103 CRC cases and 107 controls of south Indian origin. We genotyped ten selected TP53 SNPs by polymerase chain reaction-sequencing analysis. Haplotype frequencies for multiple loci and the standardized disequilibrium coefficient (D') for pairwise linkage disequilibrium (LD) were assessed by Haploview Software. In addition, to better understand the role of TP53 in the pathophysiology of CRC, the expression pattern was evaluated in analogous tumor and normal tissues from 23 CRC patients by Western blot analysis. The frequencies of Pro72Pro (P = 0.0033) genotype and Ser47/Pro72 (P = 0.00171) haplotype were significantly higher in patients as compared to controls. Strong LD was observed between codon 47 and 72 in cases (D' = 0.32) as compared to controls (D' = 0.21). The polymorphism was not observe at the remaining eight SNPs loci analyzed. Furthermore, increased TP53 expression was observed in tumor tissue than in analogous normal tissue of CRC patients. Interestingly, advanced stage tumors showed more elevated TP53 expression compared to early stage tumors. In conclusion, the TP53 Pro72Pro genotype and Ser47/Pro72 haplotype has an increased risk for CRC predisposition in south Indian population. In addition, elevated TP53 expression appears to be useful prognostic marker for CRC.

The prognostic role of XRCC1, ERCC1, ERCC2, and TP53 single nucleotide polymorphisms (SNPs) in resected non-small cell lung cancer (NSCLC).

e18521 Background: Identification of biomarkers that can be used for the prognostic evaluation of NSCLC patients is important. The aim of this study was to evaluate the potential prognostic value of XRCC1, ERCC1, ERCC2 and, TP53 SNPs in completely resected NSCLC patients. Methods: In total 130 patients, who had been surgically treated for NSCLC between 2000 and 2012, were included in this study. Analysis of SNPs from peripheral blood cells was performed by polymerase chain reaction. XRCC1 Arg399Gln, ERCC1 Asn118Asn, ERCC2 Lys751Gln and, TP53 Arg72Pro polymorphisms were evaluated in conjunction with clinical and pathological parameters and survival. Kaplan-Meier method and Cox regression analysis were used. Results: In the univariate analysis for disease free survival (DFS) post operative stage (HR,0.50; 95%CI, 0.26-0.96; P=0.03), ERCC2 genotype (HR, 2.47; 95%CI, 1.28-4.78; P=0.007) and PET-CT staging (HR, 0.27;95%CI, 0.14-0.52; P&lt;0.001) were significant parameters. Adjuvant chemotherapy, age and the other SNPs were not significant. In the multivariate analysis post operative stage (HR, 0.40;95%CI, 0.20-0.81; P=0.01), ERCC2 genotype (HR, 2.66;95%CI, 1.35-5.27; P=0.005), PET-CT staging (HR, 0.24;95%CI, 0.12-0.47; P&lt;0.001) retained their significance. The median DFS was 56.5 months (95%CI, 24.6-88.4 months) for the ERCC2 mutant (TT) and heterozygote (GT) genotypes, and 28.3 months (95%CI, 20.8-35.8 months) for the ERCC2 normal (GG) genotype (P=0.005). Conclusions: In addition to stage and PET-CT staging, ERCC2 genotype independently predicted DFS in resected NSCLC patients. Future prospective studies are needed for the further evaluation of potential prognostic SNPs in resected NSCLC.

HPV prevalence and genetic predisposition to cervical cancer in Saudi Arabia

BackgroundCervical cancer incidence is low in Saudi Arabian women, suggesting low prevalence to HPV infection due to environmental, cultural and genetic differences. Therefore, we investigated HPV prevalence and genotype distribution in cervical cancer as well as the association with 9 genetic single nucleotide polymorphisms (SNPs): CDKN1A (p21) C31A, TP53 C72G, ATM G1853A, HDM2 promoter T309G, HDM2 A110G, LIG4 A591G, XRCC1 G399A, XRCC3 C241T and TGFβ1 T10C, presumed to predispose to cancer.MethodsOne hundred cervical cancer patients (90 squamous cell carcinoma and 10 adenocarcinoma) and 100 age/sex-matched controls were enrolled. SNPs were genotyped by direct sequencing and HPV was detected and typed in tumors using the HPV Linear Array Test.ResultsEighty-two cases (82%) were positive for HPV sequences. Seven HPV genotypes were present as single infections (16, 18, 31, 45, 56, 59, 73) and five double infections (16/18, 16/39, 16/70, 35/52, 45/59) were detected. Most common genotypes were HPV-16 (71%), 31 (7%), and 18, 45, 73 (4% each). Only XRCC1 SNP was significantly associated with cervical cancer (P=0.02, OD=1.69; 95% CI= 1.06–2.66). However, nested analysis revealed a preponderance of HPV-positivity in patients harboring the presumed risk allele TP53 G (P=0.06). Both XRCC1 and TP53 SNPs tended to deviate from Hardy-Weinberg equilibrium (HWE; P=0.03-0.07).ConclusionsHPV prevalence (82%) in cervical cancer is at the lower range of the worldwide estimation (85 - 99%). While XRCC1 G399A was significantly associated with cervical cancer, TP53 G72C showed borderline association only in HPV-positive patients. Deviation from HWE in HPV-positive patients indicates co-selection, hence implicating the combination of HPV and SNPs in cancer predisposition. Thus, SNPs could be more relevant biomarkers of susceptibility to cervical cancer when associated with HPV infection.