The p73 G4C14‐to‐A4T14 polymorphism is associated with risk of lung cancer in the Han nationality of North China

p73, a structural and functional homolog of p53, plays an important role in tumor carcinogenesis. Previous studies have suggested that the association between the p73 G4C14‐to‐A4T14 polymorphism and the risk of lung cancer, but the results have not been entirely consistent. We examined whether the p73 G4C14‐to‐A4T14 polymorphism was related to the risk of developing lung cancer in a Chinese population. The p73 G4C14‐to‐A4T14 polymorphism was genotyped in 293 lung cancer patients and 380 cancer‐free controls of Han nationality in North China using PCR‐RFLP. Multivariate logistic regression analysis was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). We observed that compared with the GC/GC genotype, the genotypes containing AT allele (GC/AT + AT/AT genotypes) were associated with significantly increased susceptibility to lung cancer (OR, 1.48; 95% CI, 1.08–2.02; P = 0.014). In addition, compared with the GC/GC genotype, the GC/AT genotype was also significantly associated with increased susceptibility to lung cancer (OR, 1.46; 95% CI, 1.06–2.02; P = 0.046). Our findings suggest that the p73 G4C14‐to‐A4T14 polymorphism contributes to the risk of developing lung cancer in Chinese population. © 2012 Wiley Periodicals, Inc.     

Association of a p73 exon 2 G4C14-to-A4T14 polymorphism with risk of squamous cell carcinoma of the head and neck

p73, a novel p53 homolog, has some p53-like activity and plays an important role in modulating cell-cycle control, apoptosis and cell growth. p73 regulates differentiation of head and neck squamous epithelium, and changes in p73 may lead to the development of squamous cell carcinoma of the head and neck (SCCHN). Two linked non-coding exon 2 polymorphisms (designated as G4C14-to-A4T14) were identified recently but their functional relevance is unknown. We hypothesized that this p73 polymorphism plays a role in the etiology of SCCHN. Therefore, in this hospital-based case-control study of 708 patients newly diagnosed with SCCHN and 1229 cancer-free controls, we evaluated the association between the p73 AT variant allele and risk of SCCHN. The controls were frequency-matched to the cases by age (+/-5 years), sex and smoking status, and all subjects were non-Hispanic whites. Our results showed that the frequencies of variant AT allele and genotypes were more common in the cases than in the controls (P = 0.029 and P = 0.009, respectively). Compared with the GC/GC genotype, the variant genotypes (GC/AT + AT/AT) were associated with a statistically significantly increased risk for SCCHN [odds ratio (OR) = 1.33, 95% confidence interval (CI) = 1.10-1.60]. Further stratification analyses by age, sex, smoking and alcohol status and by cancer sites within the head and neck region indicated that this significantly increased risk was more pronounced in younger (< or =50 years) individuals (adjusted OR = 1.70; 95% CI, 1.19-2.43), women (1.61; 1.09-2.37), current smokers (1.77; 1.25-2.51) and patients with oral cancer (1.54; 1.15-2.07). Our results suggest that this p73 polymorphism may be a risk marker for genetic susceptibility to SCCHN.     

p73 4G14C-4A14T基因多态性与结直肠癌发病风险相关性的系统评价

 目的
系统评价细胞周期调控基因p73 4G14C-4A14T基因多态性与结直肠癌易感性的关系。方法 检索2000-2010年Cochran
图书馆、中国期刊网、中国生物医学文献数据库、维普科技期刊全文数据库、PubMed、Web of science、BIOSIS
Preview、Journal Citation Reports、FMJS、EMMC等数据库,语种不限,获取有关p73 4G14C-4A14T基因多态性与
结直肠癌发病风险相关性的研究结果,分别以病例组和对照组的p73 4G14C-4A14T基因型分布以及比值比(OR)为效
应指标,确定纳入标准,对文献进行评价筛选,异质性检验,然后利用RevMan5.0软件对各研究原始结果进行统计
处理,并计算合并的OR值及其95%可信区间。结果按照纳入标准,最终入选5篇文献,累计病例919例,对照1 234例
。Meta分析p73 4G14C-4A14T基因型GC/GC vs.GC/AT+AT/AT合并OR值为0.84(95%CI:0.71~1.00),Z值为1.95,GC/GC
vs.AT/AT合并OR值为0.50(95%CI:0.35~0.70),Z值为4.00,AT/AT vs.GC/GC+GC/AT 合并OR值为1.94(95%
CI:1.39~2.70),Z值为3.91。结论 我们发现AT/AT基因纯合子可以明显提高结直肠癌的发病风险,差异有统计学意
义,Meta分析结果说明p73 4G14C-4A14T基因多态性与结直肠癌发病风险之间有明显相关性。结果 表明携带p73
4G14C-4A14T多态性是结直肠癌重要的发病因素。     

Genetic variants of the p53 and p73 genes jointly increase risk of second primary malignancies in patients after index squamous cell carcinoma of the head and neck

BACKGROUND:

Because of the structural and biochemical similarities between the antitumor p53 and p73 proteins, the authors hypothesized that individuals who carry high‐risk genotypes of p53 codon 72 and p73 G4C14‐to‐A4T14 polymorphisms have a higher risk of developing second primary malignancy (SPM) after index squamous cell carcinoma of the head and neck (SCCHN).

METHODS:

A cohort of 1269 patients with index cases of SCCHN was recruited between May 1995 and January 2007 at The University of Texas MD Anderson Cancer Center and followed for SPM development. Patients were genotyped for p53 codon 72 and p73 G4C14‐to‐A4T14 polymorphisms. A log‐rank test and Cox proportional hazard models were used to compare SPM‐free survival and SPM risk among different risk groups with the combined risk genotypes of the 2 polymorphisms.

RESULTS:

The data demonstrated that patients with p53 WP + PP and p73 GC/GC genotypes had a worse SPM‐free survival and an increased SPM risk compared with the corresponding p53 WW and p73 GC/AT + AT/AT genotypes. After combining the 2 polymorphisms, a borderline significantly or significantly reduced SPM‐free survival and increased SPM risk were observed in the medium‐risk group (p53 WW and p73 GC/GC or p53 P carriers and p73 AT carriers) and high‐risk group (p53 P carriers and p73 GC/GC) compared with low‐risk group (p53 WW and p73 AT carriers), respectively.

CONCLUSIONS:

The results suggest an increased risk of SPM after index SCCHN with both p53 and p73 polymorphisms individually and in combination. Cancer 2011;. © 2011 American Cancer Society.     

p73 G4C14-to-A4T14 polymorphism and risk of lung cancer

Genetic variants in genes controlling cellular processes such as cell cycle, DNA repair, and apoptosis may modulate lung cancer risk. p73 has some p53-like activity and plays an important role in modulating these processes. The noncoding region of exon 2 of the p73 gene has two polymorphisms that are in complete linkage disequilibrium with one another, which may alter translation efficiency of the p73 protein. To test the hypothesis that this p73 polymorphism plays a role in the etiology of lung cancer, we conducted a hospital-based case-control study of 1054 patients newly diagnosed with lung cancer and 1139 cancer-free controls and evaluated the association between the p73 variant AT allele and risk of lung cancer. Cancer-free controls were frequency matched to the cases by age (+/-5 years), sex, and smoking status, and all subjects were non-Hispanic whites. The variant AT allele and genotypes were more common among the cases than among the controls (P = 0.0007 and P < 0.001, respectively). Compared with the GC/GC genotype, the variant GC/AT and AT/AT genotypes were associated with a statistically significantly increased risk for lung cancer [adjusted odds ratio (OR) = 1.32, 95% confidence interval (CI), 1.10-1.59 and OR = 1.54, 95% CI, 1.05-2.26, respectively] in an allele dose-effect relationship (trend test: P < 0.001). The risk associated with the AT allele (GC/AT+AT/AT) was more pronounced in younger (相似文献   

p73 G4C14-to-A4T14 polymorphism and risk of human papillomavirus-associated squamous cell carcinoma of the oropharynx in never smokers and never drinkers

BACKGROUND.

The p53 tumor suppressor protein homolog p73 can be inactivated by oncoprotein E6 of human papillomavirus (HPV). Variation in p73 may alter the interaction between the E6 protein and p73 and, thus, alter the risk for HPV‐associated carcinogenesis. It is believed that the p73 G4C14‐to‐A4T14 polymorphism affects p73 function by altering gene expression; however, whether that polymorphism also alters the risk of HPV type 16 (HPV‐16)‐associated squamous cell carcinoma of the oropharynx (SCCOP) is unknown.

METHODS.

The current case‐control study included a case group of 188 non‐Hispanic white patients with newly diagnosed SCCOP and a control group of 349 healthy individuals. Logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for cases and controls stratified by p73 genotype, age, sex, smoking status, alcohol use, and HPV‐16 status. The effects of p73 genotypes on the risk of HPV‐16‐associated SCCOP were explored with further stratification by smoking and drinking status.

RESULTS.

HPV‐16 seropositivity was associated with an increased risk of SCCOP (adjusted OR, 5.98; 95% CI, 3.89‐9.20), especially among never smokers (adjusted OR, 13.8; 95% CI, 5.91‐32.1), never drinkers (adjusted OR, 14.9; 95% CI, 5.24‐42.4), and individuals with p73 variant genotypes (GC/AT and AT/AT; adjusted OR, 7.96; 95% CI, 3.83‐16.5). Moreover, the risk of HPV‐16‐associated SCCOP for individuals who had p73 variant genotypes was particularly high in never smokers and never drinkers.

CONCLUSIONS.

The p73 G4C14‐to‐A4T14 polymorphism may modulate the risk of HPV‐16‐associated SCCOP, and the p73 variant genotypes may be markers of genetic susceptibility to HPV‐16‐associated SCCOP, particularly in never smokers and never drinkers. Cancer 2008. © 2008 American Cancer Society.     

p14ARF genetic polymorphisms and susceptibility to second primary malignancy in patients with index squamous cell carcinoma of the head and neck

BACKGROUND:

p14^ARF, an alternate reading frame (ARF) product of the cyclin‐dependent kinase inhibitor 2A locus, plays a critical role in crosstalk between the tumor protein 53 (p53) and retinoblastoma (Rb) pathways and in cellular anticancer mechanisms. Therefore, the authors of this report investigated the association between single nucleotide polymorphisms (SNPs) of the p14^ARF gene and the risk of developing a second primary malignancy (SPM) after an index squamous cell carcinoma of the head and neck (SCCHN).

METHODS:

The log‐rank test and Cox proportional hazards models were used to assess the association of 2 p14^ARF SNPs (reference SNP [rs]3731217 and rs3088440) with SPM‐free survival and with the risk of developing an SPM among 1287 patients who had SCCHN.

RESULTS:

Patients with either p14^ARF variant genotypes of the 2 polymorphisms had a significantly reduced SPM‐free survival compared with patients with no variant genotypes (log‐rank test; P = .006). Compared with the p14^ARF thymine‐thymine (TT) and guanine‐guanine (GG) genotypes, the variant genotypes of p14^ARF TG/GG and guanine‐adenine (GA)/AA were associated with a significantly moderately increased risk of developing an SPM (p14^ARF rs3731217: adjusted hazard ratio [aHR], 1.48; 95% confidence interval [CI], 1.00‐2.19; p14^ARF rs3088440: aHR, 1.61; 95% CI, 1.07‐2.43). Moreover, after combining the variant genotypes of the 2 SNPs, patients who had variant genotypes were at significantly greater risk of developing an SPM compared with patients who had no variant genotypes (aHR, 3.07; 95% CI, 1.54‐6.12), and the risk was particularly pronounced in several subgroups.

CONCLUSIONS:

The current results suggested that there is a modestly increased risk of developing an SPM after an index SCCHN with each p14^ARF polymorphism, and there is an even greater risk of developing an SPM for patients with combined variant genotypes of the 2 SNPs. Therefore, p14^ARF polymorphisms may be susceptible markers of the risk of developing an SPM in patients with SCCHN. Cancer 2011. © 2010 American Cancer Society.     

Polymorphisms at p53, p73, and MDM2 loci modulate the risk of tobacco associated leukoplakia and oral cancer

Polymorphisms at loci controlling cellular processes such as cell cycle, DNA repair, and apoptosis may modulate the risk of cancer. We examined the association of two linked polymorphisms (G4C14–A4T14) at p73 and one polymorphism (309G > T) at MDM2 promoter with the risk of leukoplakia and oral cancer. The p73 and MDM2 genotypes were determined in 197 leukoplakia patients, 310 oral cancer patients and in 348 healthy control subjects. The p73 GC/AT genotype increased the risk of leukoplakia (OR = 1.6, 95% CI = 1.1–2.3) and oral cancer (OR = 2.4, 95% CI = 1.7–3.3) but the 309G > T MDM2 polymorphism independently could not modify the risk of any of the diseases. Stratification of the study population into subgroups with different tobacco habits showed that the risk of the oral cancer is not modified further for the individuals carrying p73 risk genotype. However, leukoplakia patients with smokeless tobacco habit showed increased risk with combined GC/AT and AT/AT (OR = 3.0, 95% CI = 1.3–7.0) genotypes. A combined analysis was done with our previous published data on p53 codon 72 pro/arg polymorphism. Analysis of pair wise genotype combinations revealed increase in risk for specific p73‐MDM2 and p73‐p53 genotype combinations. Finally, the combined three loci analyses revealed that the presence of at least one risk allele at all three loci increases the risk of both leukoplakia and oral cancer. © 2009 Wiley‐Liss, Inc.     

Association of p73 G4C14-to-A4T14 (GC/AT) polymorphism with breast cancer survival

p73 gene shares structural and functional similarities to p53, and plays an important role in modulating cell-cycle arrest and apoptosis. A common non-coding polymorphism of exon 2 of the p73 gene (designated as GC/AT) may affect gene expression, thus, it may lead to functional significance. The correlation of this polymorphism with breast cancer survival has not been investigated. In this study, by using genomic DNA p73 GC/AT polymorphism was detected by PCR-SSCP in 526 breast cancer patients with a median follow-up of 7.3 years. Among the 526 breast cancer patients, 4% of the patients were homozygous for the AT/AT genotype, 39% were heterozygous GC/AT and 57% were homozygous for the GC/GC genotype. We found that patients with the GC/GC genotype had a significantly worse clinical outcome than did patients with the AT Variants (AT/AT or GC/AT genotype) (5-year disease-free survival, 74.2 versus 95.0 or 84.1%, P=0.02; 5-year overall survival, 78.9 versus 95.0 or 87.5%, P=0.01, respectively). As compared with the GC/AT and AT/AT genotypes, the GC/GC genotype remained an independent prognostic indicator of disease-free survival (HR 1.82, P=0.003) and overall survival (HR 1.99, P=0.004) in multivariate analysis. Our results suggest that the GC/GC genotype is significantly associated with poor prognosis in breast cancer and raise the possibility that analysis of p73 polymorphism may provide useful prognostic information for breast cancer patients. Additional independent studies are needed to confirm these findings.     

Association of the p73 Gene G4C14-to-A4T14 Polymorphism with Increased Gastric Cancer Risk in a Northwestern Chinese Population

OBJECTIVE To evaluate the p73 gene G4C14-to-A4T14 double nucleotide polymorphism with both increased gastric cancer(GC) risk and different histological subtypes of GC in a northwestern Chinese population. METHODS Genotyping of the polymorphism of the p73 gene was conducted with PCR-CTPP. RESULTS All 385 GC patients including 305 diffuse-type and 80 intestinal-type cases and 412 healthy controls were investigated.The frequencies of p73 AT/AT,AT/GC,and GC/GC genotypes were 28.1%,47.1%,and 24.8% in the controls,and were 22.0%,45.0%,and 33.0% in GC cases respectively;the GC/GC homozygote frequency was higher in GC cases,mainly in diffuse type compared to the controls with OR=1.71(1.16～2.51) and 1.87 (95%CI,1.24～2.81) respectively.The results showed that carriers of the p73 G4A GC/GC homozygote had a 1.71-time higher risk of GC,especially of the diffuse-type GC compared to the controls. The carriers of the AT/GC heterozygote also had a slightly increased risk of GC cancer,mainly on intestinal-type GC.This is the first report that the p73 G4A double-nucleotide polymorphism is associated with an increased risk of diffuse-type gastric cancer. CONCLUTION The p73 G4A GC/GC genotype is associated with an increased risk of gastric cancer,especially of the GC diffuse-type.     

Significance of an exon 2 G4C14-to-A4T14 polymorphism in the p73 gene on survival in rectal cancer patients with or without preoperative radiotherapy

Background and purpose

An exon 2 G4C14 → A4T14 polymorphism in the p73 gene was shown to be related to survival in several types of cancers, including colorectal cancer. The purpose was to investigate if this polymorphism was related to survival in rectal cancer patients with or without preoperative radiotherapy.

Materials and methods

DNA extracted from tissue of 138 rectal cancer patients that received preoperative radiotherapy or had surgery alone was typed for the polymorphism by PCR using confronting two-pair primers.

Results

Among patients, 69% had GC/GC genotype, 27% had GC/AT and 4% had AT/AT. In the radiotherapy group, patients carrying the AT (GC/AT + AT/AT) allele had stronger expression of p53 (p = 0.001) and survivin protein (p = 0.03) than those carrying the GC/GC genotype. Further, among patients receiving preoperative radiotherapy the GC/GC genotype tended to be related to better survival (p = 0.20). Patients with GC/GC genotype, along with negative p53 and weak survivin expression showed better survival than the other patients (p = 0.03), even after adjusting for TNM stage and tumor differentiation (p = 0.01, RR, 7.63, 95% CI, 1.50-38.74). In the non-radiotherapy group, the polymorphism was not related to survival (p = 0.74).

Conclusions

Results suggest that the p73 G4C14 → A4T14 polymorphism could be one factor influencing outcome of preoperative radiotherapy in rectal cancer patients.     

Association of a p73 exon 2 G4C14-to-A4T14 polymorphism with risk of hepatocellular carcinoma in a Chinese population

P73, a p53 homolog, has some p53-like activities and plays an important role in modulating cell cycle, apoptosis, and DNA repair. A potentially functional dinucleotide polymorphism, G4C14-to-A4T14, has been identified in the 5′ untranslated region of exon 2 of the p73 gene, which may theoretically form a stem-loop structure and affect gene expression. We hypothesized that genetic variants in p73 may modify individual susceptibility to hepatocellular carcinoma (HCC). To test this hypothesis that these two common variants play a role in HCC susceptibility, we conducted a hospital-based case–control study of 476 HCC patients and 526 cancer-free controls in a Chinese population. The matrix-assisted laser desorption ionization time-of-flight mass spectrometry method was performed to detect these polymorphisms. The results showed that the genotype and allele frequencies of the p73 G4C14-A4T14 did not differ significantly between the HCC patients and the control group (all P values are above 0.05). However, with stratification analysis by age, sex, smoking status, drinking status, HBV carrier state, and family history of cancer, we found that the variant genotypes (GC/AT + AT/AT) of the p73 G4C14-A4T14 was associated with a significant increased risk of HCC among HbsAg-positive individuals (adjusted OR?=?2.19, 95 % CI?=?1.25–3.83) and among women (adjusted OR?=?2.62, 95 % CI?=?1.47, 4.66). These results suggest that the p73 G4C14-to-A4T14 dinucleotide polymorphism may play a role in the development of chronic HBV-infected HCC in the Chinese population, especially among women.     

Combined effects of the p53 codon 72 and p73 G4C14-to-A4T14 polymorphisms on the risk of HPV16-associated oral cancer in never-smokers

Because p53 and p73 are associated with critical cellular processes and can be inactivated or degraded by the human papillomavirus (HPV) E6 oncoprotein, we investigated the combined effects of p53 codon 72 and p73 G4C14-to-A4T14 polymorphisms on the risk of HPV16-associated oral cancer. We analyzed genotype data from 326 patients with squamous cell carcinoma of the oral cavity or oropharynx and 349 cancer-free controls. We found that HPV16 seropositivity was associated with an increased risk of oral cancer [adjusted odds ratio (OR), 3.42; 95% confidence interval (CI), 2.28-5.13], especially among never-smokers (adjusted OR, 8.20; 95% CI, 3.66-18.4) and subjects with variant genotypes [adjusted OR for p53 Arg/Pro + Pro/Pro (Pro carriers), 5.00; 95% CI, 2.72-9.21; adjusted OR for p73 GC/AT + AT/AT (AT carriers), 3.83; 95% CI, 1.98-7.41]. HPV16 seropositivity was also associated with an significantly increased risk of oral cancer in all three risk groups with combined genotypes [adjusted ORs (95% CIs) were 2.28 (1.15-4.54) for p53 Arg/Arg and p73 GC/GC, the low-risk group; 3.97 (2.14-7.36) for p53 Arg/Arg and p73 AT carriers or p53 Pro carriers and p73 GC/GC, the medium-risk group and 5.11 (2.00-13.0) for p53 Pro carriers and p73 AT carriers, the high-risk group]. Moreover, HPV16-seropositive never-smokers in the high-risk group exhibited an approximately 11-fold greater risk of oral cancer (adjusted OR, 11.3; 95% CI, 1.22-106.0) than did HPV16-seronegative never-smokers in the low-risk group. These findings suggest that the combined variants of p53 and p73 significantly increase the risk of HPV16-associated oral cancer, especially among never-smokers.     

Effect of heme oxygenase‐1 gene promoter polymorphism on cancer risk by histological subtype: A prospective study in arseniasis‐endemic areas in Taiwan

Heme oxygenase (HO)?1 is upregulated by many stressful stimuli, including arsenic. A GT‐repeat ((GT)n) polymorphism in the HO‐1 gene promoter inversely modulates the levels of HO‐1 induction. Previous HO‐1 (GT)n polymorphism studies in relation to cancer risk have shown disparate results. We prospectively investigated the associations between HO‐1 (GT)n polymorphism and cancer risk related to arsenic from drinking water. Totally, 1,013 participants from community‐based cohorts of arseniasis‐endemic areas in Taiwan were followed for 13 years. Allelic polymorphisms were classified into long (L, ≥27 (GT)n) and short (S, <27 (GT)n). Newly developed cases were identified through linkage with National Cancer Registry of Taiwan. Multivariate Cox proportional hazard methods were used to evaluate effects of the HO‐1 polymorphism alone or combined with arsenic exposure. Results showed that participants with the S/S genotype had an increased risk of Bowen's disease (HR = 10.49; 95% CI: 2.77–39.7), invasive skin cancer (HR = 2.99; 95% CI: 1.13–7.87), and lung squamous cell carcinoma (HR = 3.39; 95% CI: 1.15–9.95) versus those with L/S or L/L genotype. The S/S genotype combined with high arsenic exposure (>300 μg/L) had a greater risk of skin cancer compared to the genotype alone. Consistent with previous findings, participants with the S‐allele had a reduced risk of lung adenocarcinoma (HR = 0.21; 95% CI: 0.03–0.68) versus those with L/L genotype. There were no significant differences in risk of urothelial carcinoma among the three genotypes. Associations of HO‐1 (GT)n polymorphism with cancer risk differs by histological subtype and the polymorphism should be considered a modifier in the risk assessment of arsenic exposure.     

Association of p73 G4C14-A4T14 polymorphisms with genetic susceptibilities to breast cancer: a case–control study

The aim of this study was to evaluate the association of p73 G4C14-A4T14 polymorphisms with susceptibility to breast cancer in Chongqing women of Han Nationality in China. In a case?Ccontrol study, single-nucleotide polymorphisms of p73 G4C14-A4T14 at exon 2 were genotyped by Sequenom MassArray^? iPLEX GOLD System in 170 patients with breast cancer and 178 healthy controls. Data were analyzed via t test, Chi-square test, and logistic regression analysis. The distribution of p73 genotypes and allelotypes had no significant difference between patients with breast cancer and healthy controls (??²?=?2.750, P?=?0.253; ??²?=?2.195, P?=?0.138). More risk of developing triple negative breast cancer (TNBC) was found in the individuals who carried with GC/GC genotype than individuals carried with GC/AT and AT/AT genotypes (OR?=?2.99; 95?% CI, 1.30?C6.89; P?=?0.010). p73 G4C14-A4T14 polymorphisms are closely associated with the increased risk for TNBC in Chongqing women of Han Nationality in China; GC/GC genotype is susceptible genotype for TNBC in Chongqing women of Han Nationality in China. The patients with breast cancer who carried with GC/GC genotype may have bad prognosis. Additional larger studies are required to confirm these findings.     

Association of variants in the interleukin‐27 and interleukin‐12 gene with nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is multifactorial, and the genetic background may be a crucial etiologic factor. Interleukin‐12 (IL‐12) is a multifunctional cytokine that induces interferon (IFN)‐gamma secretion and plays an important role in antitumor immunity. Interleukin‐27 (IL‐27) is a novel IL‐12 family member, the present studies demonstrate that IL‐27 mediates potent antitumor activity. Variations in the DNA sequence in the IL‐12 and IL‐27 gene may lead to altered cytokines production and/or activity, and so this can modulate an individual's susceptibility to NPC. To test this hypothesis, we investigated the relationship of IL‐12 and IL‐27 gene polymorphisms and NPC in a Chinese population. We analyzed single nucleotide polymorphisms (SNPs) of IL‐12 gene 16974 A/C and IL‐27 gene ?964 A/G, 2905 T/G, 4730 T/C in 302 patients with NPC and 310 age‐ and sex‐matched controls, using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and DNA sequencing methods. There were significant differences in the genotype and allele distribution of 16974 A/C polymorphism of the IL‐12 gene among cases and controls. The 16974 CC and AC genotypes were associated with a significantly increased risk of NPC as compared with the 16974 AA genotypes (OR = 2.225, 95% CI 1.395–3.549, P = 0.001 and OR = 1.834, 95% CI 1.239–2.716, P = 0.002, respectively). The 16974 C allele was associated with a significantly increased risk of NPC as compared with the 16974 A allele (OR = 1.334, 95% CI 1.065–1.670, P = 0.012). However, genotype and allele frequencies of the IL‐27 gene ?964 A/G, 2905 T/G, 4730 T/C polymorphisms in NPC patients were not significantly different than that in healthy controls (P > 0.05). Our data suggest that IL‐12 gene may play a role in the development of NPC. © 2009 Wiley‐Liss, Inc.     

Reduced disease‐specific survival following a diagnosis of multiple primary cutaneous malignant melanomas—a nationwide,population‐based study

Outcome data comparing patients with multiple primary invasive cutaneous malignant melanomas (MPMs) to single primary invasive cutaneous malignant melanomas (SPMs) show conflicting results. We have analyzed differences in disease‐specific survival between these patients in a nationwide population‐based setting. From the Swedish Melanoma Register, 27,235 patients were identified with a first invasive cutaneous malignant melanoma (CMM) between 1990 and 2007, followed‐up through 2013. Of these, 700 patients developed MPMs. Cox proportional hazard regression was used for adjusted cause‐specific hazard ratios (HRs). An interval of ≤5 years between CMM diagnoses was significantly correlated to a decreased CMM‐specific survival in Stage I–II MPM‐ vs. SPM‐patients (HR 1.32; 95% CI 1.04–1.67; p = 0.02). MPM‐patients with longer time interval between diagnoses experienced similar risk of CMM‐death as SPM‐patients. The risk of CMM‐death increased by almost 50% above the expected outcome according to stage of the index CMM by the diagnosis of a second CMM (HR 1.48; 95% CI 1.19–1.85; p < 0.001). MPM vs. SPM‐patients had a worse outcome (HR 1.38; 95% CI 1.05–1.83; p = 0.001). This emphasizes the importance of prevention efforts in SPM‐patients to decrease the risk of subsequent CMMs and has implications for more vigilant follow‐up in MPM‐patients.     

Polymorphism of the p73 gene in relation to colorectal cancer risk and survival

The results regarding a GC/AT polymorphism in the p73 gene in relation to cancer risk are inconsistent, and the significance of loss of heterozygosity (LOH) of the gene is unclear. In the present study, we investigated whether this polymorphism was related to the risk of colorectal cancer, and whether there were relationships between the polymorphism and LOH, protein expression or clinicopathological variables. 179 patients with colorectal cancer and 260 healthy controls were genotyped for the polymorphism by PCR-restriction fragment length polymorphism (RFLP). Fifty informative cases were examined for LOH in tumours. Immunohistochemistry was performed on distant (n = 42) and adjacent normal mucosa (n = 33), primary tumour (n = 6 9) and lymph node metastasis (n = 12). The frequencies of the genotypes were 63% for wild-type (GC/GC), 30% for heterozygotes (GC/AT) and 7% for variants (AT/AT) in patients, and 62, 36 and 2% in controls, respectively. The frequencies of the genotypes in the patients and controls were significantly different (P = 0.02). The patients carrying the AT allele had a better prognosis than those with the GC/GC genotype (OR = 0.42, 95% CI = 1.15-5.02, P = 0.02). No LOH was observed at the p73 locus. Expression of p73 protein was increased from normal mucosa to primary tumours (P = 0.02), but was not significantly changed between primary tumours and metastases (P = 1.0). In conclusion, the AT/AT homozygotes may have a greater risk of developing colorectal cancer, while the patients who carried the AT allele had a better prognosis.     

Dinucleotide polymorphism of p73 gene is associated with a reduced risk of lung cancer in a Chinese population

p73, a structural and functional homologue of p53, shares some p53-like tumor suppressor activity but also possesses oncogenic activity. Therefore, p73 plays an important role in modulating cell-cycle control and apoptosis. A potentially functional dinucleotide polymorphism, G4C14-to-A4T14, has been identified in the 5' untranslated region (UTR) of exon 2 of the p73 gene, which may theoretically form a stem-loop structure and affect gene expression. To test the hypothesis that these 2 common variants play a role in lung cancer susceptibility, we conducted a case-control study of 425 lung cancer patients and 588 cancer-free controls frequency-matched to the cases on age and sex in a Chinese population. The results showed that these 2 polymorphisms were in complete linkage disequilibrium and the frequencies of variant p73 AT haplotype (A4T14) were less common in the cases (0.225) than in the controls (0.287) (p = 0.0018), suggesting that this AT haplotype was protective against lung cancer. Compared to the p73 GC/GC homozygotes, both the AT/AT variant homozygotes and GC/AT heterozygotes were associated with a significantly decreased risk (adjusted OR: 0.45, 95% CI: 0.26-0.80 and OR: 0.70, 95% CI: 0.53-0.92, respectively). These results suggest that this p73 dinucleotide polymorphism may have a role in lung cancer susceptibility in our study population. Further studies are needed to elucidate potential functional relevance of the p73 AT variant allele.     

p73基因多态性与食管癌、贲门癌遗传易感性的关系

背景与目的:p73作为一种抑癌基因,其第二外显子非编码区存在两个单核苷酸多态性(G4C14-A4T14),可以形成茎环结构而影响基因表达。本研究旨在探讨河北省食管癌高发区人群中这两个连锁多态性与食管癌、贲门癌易感性的关系。方法:采用病例-对照研究,以聚合酶链反应-限制性片段长度多态性方法,分析348例食管癌患者、259例贲门癌患者和630例健康对照者的p73基因多态性。结果:具有上消化道肿瘤家族史可明显增加食管癌和贲门癌的发病风险,经性别、年龄和吸烟状况校正的OR值分别1.68(95%CI=1.28～2.20)和1.68(95%CI=1.24～2.26)。p73G4C14-A4T14基因型及等位基因型在食管癌患者、贲门癌患者和健康对照中总体分布差异无显著性。在根据吸烟状况和上消化道肿瘤家族史进行分层分析,发现在无上消化道肿瘤家族史亚组中,携带GC/AT基因型明显增加贲门癌的发病风险(OR=1.71,95%CI=1.14～2.57),而其他亚组中未见p73G4C14-A4T14多态性增加食管癌、贲门癌的发病风险。结论:p73G4C14-A4T14多态性中,携带GC/AT基因型明显增加河北省食管癌高发区无上消化道肿瘤家族史人群贲门癌的发病风险。