突变型P53蛋白在肺腺癌中的表达及其临床意义

背景与目的突变型TP53基因不仅丧失了抑癌功能,其编码的突变型P53蛋白还能获得促进细胞增殖、抑制细胞凋亡等功能。目前TP53基因在肺腺癌中突变的临床意义尚不十分明确。本研究旨在探讨突变型P53蛋白在肺腺癌组织中的表达及其临床意义。方法回顾性分析120例肺腺癌手术患者的临床病理资料,应用免疫组化法检测患者组织标本中突变型P53蛋白的表达,采用χ2检验分析突变型P53蛋白表达与各临床病理参数的关系,采用单因素生存分析及多因素生存分析法分析突变型P53蛋白表达与总生存期的关系。结果突变型P53蛋白在肺腺癌组织中的表达率为63.7%,突变型P53蛋白的表达与肿瘤大小（P=0.041）及病理分期（P=0.025）有关。单因素生存分析提示肿瘤大小（P=0.031）、淋巴结转移（P<0.001）、病理分期（P<0.001）以及突变型P53蛋白的表达（P=0.038）与患者总生存期密切相关。多因素生存分析提示仅有淋巴结转移（P=0.014）是患者总生存期的独立影响因素。结论TP53基因突变的肺腺癌患者预后较差,突变型P53蛋白可以作为预测患者预后的分子标志物。     

乳腺导管内增生病变中p53表达与外显子突变的研究

目的：肿瘤抑制基因p53异常是浸润性乳腺癌发生发展中常见事件,而其与包括普通型增生（usualductal hyperplasia,UDH）、不典型增生（atypical ductal hyperplasia,ADH）及导管内原位癌（ductal carcinoma insitu,DCIS）的乳腺导管内增生性病变关系不明。本研究旨在探讨乳腺导管内增生性病变中p53外显子突变及突变型p53蛋白表达情况,以期了解p53突变及蛋白表达在乳腺癌发生发展中的作用。方法：用高分辨率熔解曲线（high-resolution melting,HRM）结合测序研究140例乳腺导管内增生性病变中p53外显子5-8的突变情况。用免疫组化研究240例乳腺导管内增生性病变中突变型p53蛋白表达情况。结果：经过HRM分析,共17例患者DNA熔解曲线与野生型标准品熔解曲线大于阈值结合测序分析结果发现,其中16例出现p53外显子突变。p53在UDH、ADH及DCIS中的突变率为0.0%（0/40）,12.7%（8/63）和21.6%（8/37）,三者间差异显著（P〈0.05）。40例UDH中未出现突变型p53蛋白阳性表达,在14.6%（19/130）的ADH出现阳性表达,在31.4%（22/70）的DCIS中出现阳性表达,三者间差异显著（P〈0.05）。Spearman相关性分析示突变型p53蛋白表达与p53外显子突变呈正相关（r=0.792,P〈0.01）。结论：p53外显子突变及突变型p53蛋白表达发生于乳腺导管内增生性病变中的ADH与DCIS,其可能为乳腺癌发生发展中的早期事件。     

利用GEO及TCGA数据集分析SMARCA1在胃癌中的表达及其临床意义#br#

目的探讨基因表达汇编（GEO）及癌症和肿瘤基因表达图谱（TCGA）数据集中胃癌组织的SMARCA1表达情况及其与胃癌临床病理特征和预后的关系。 方法利用GEO和TCGA数据集汇总胃癌相关数据,下载胃癌组织SMARCA1表达数据及临床病理参数。分析SMARCA1表达与胃癌临床病理学特征和总生存期（OS）的关系;采用基因集富集分析（GSEA）预测SMARCA1相关的基因通路。 结果在GSE62254数据集中,SMARCA1表达与T分期有关（P=0022）,而与TNM分期、性别、年龄和N分期均无关（P＞005）。在TCGA数据集中,SMARCA1表达与T分期、性别、年龄、N分期、TNM分期和组织学分级均无关（P＞005）。GSE62254数据集中,SMARCA1高、中及低表达组胃癌患者的中位OS分别为364个月、894个月和未达（P=0001）;TCGA数据集中,SMARCA1高、中及低表达组胃癌患者的中位OS分别为237个月、294个月和562个月（P=0033）。GSEA结果显示,SMARCA1高表达样本富集了K Ras、Akt、BMI 1和mTOR通路等基因集。 结论胃癌组织中SMARCA1的表达与T分期有关,高表达患者的预后不良,可作为潜在评估胃癌预后的分子标志物。     

HIF-1α反义寡核苷酸对骨肉瘤MG-63细胞HIF-1α和p53表达的影响

目的：观察缺氧诱导因子HIF-1α反义寡核苷酸（antisense oligonucleotides,ASODN）在缺氧环境下对骨肉瘤MG-63细胞HIF-1α和p53表达的影响。方法：设计针对HIF-1α亚基的mRNA反义和正义寡核苷酸（sense oligodeoxynucleotides,SODN）,并建立骨肉瘤细胞体外缺氧培养模型,观察不同时相5μmol/L的HIF-1αASODN对骨肉瘤MG-63细胞HIF-1α和p53表达的影响。半定量RT-PCR方法检测HIF-1α和p53 mRNA的转录水平,免疫组化SP法和免疫印迹（Western blot）检测HIF-1α和p53蛋白表达情况。结果：与常氧组比较,单纯缺氧组及SODN缺氧组的蛋白表达水平随缺氧时间延长明显升高（P〈0.05）;而p53 mRNA以及蛋白的表达水平较常氧组均显著增强（P〈0.05）。在ASODN缺氧组,HIF-1α蛋白表达水平显著降低（P〈0.05）;p53 mRNA及其蛋白的表达水平也明显减弱（P〈0.05）。结论：缺氧可以通过诱导野生型p53的突变使HIF-1α稳定表达。而ASODN明显抑制HIF-1α的表达,且使突变型p53的表达水平显著下降,这说明HIF-1α可能在缺氧诱导野生型p53突变方面有一定的作用。     

骨肉瘤差异表达基因的生物信息学分析及关键基因筛选

目的筛选成骨型骨肉瘤与正常成骨细胞的差异表达基因, 寻找成骨型骨肉瘤发生、发展的关键基因。方法从Gene Expression Omnibus(GEO)数据库获得正常成骨细胞和骨肉瘤组织的基因表达数据集GSE33382, 采用R语言的limma包筛选正常成骨细胞和成骨型骨肉瘤的差异表达基因, 对差异表达基因进行京都基因与基因组百科全书(KEGG)通路富集分析。采用String数据库构建蛋白交互网络, 应用Cytoscape软件的分子复合物检测(MCODE)插件筛选互作网络中的网络模块, 应用Cytoscape软件中的BiNGO模块对MCODE筛选得到的前3个主要模块所包含的差异表达基因进行基因本体(GO)富集分析。采用MCC算法筛选蛋白互作网络中前10个关键基因。从GEO数据库获得骨肉瘤的基因表达和生存数据集GSE39055, 采用Kaplan-Meier法进行生存分析。选取2005年1月至2015年12月福建医科大学附属第一医院收治的48例成骨型骨肉瘤患者的资料进行验证, 采用免疫组化法测定骨肉瘤组织中STC2蛋白的表达, 结合患者的临床资料进行生存分析。结果从GSE33382数据集...     

基于单细胞RNA测序的膀胱癌预后风险模型的构建与验证

目的基于单细胞RNA测序(scRNA-seq)生物信息学分析的预后相关的差异表达基因构建膀胱癌预后风险模型并验证。方法从基因表达综合(GEO)数据库中下载膀胱癌scRNA-seq数据集GSE135337、GSE129845, 数据更新时间分别为2022年、2019年;下载常规转录组数据集GSE13507(数据更新时间为2020年)中165例膀胱癌样本的表达谱及其生存信息。从癌症基因组图谱(TCGA)数据库中下载414例膀胱癌样本和19例癌旁样本的表达谱数据及405例膀胱癌患者的临床信息。采用R 4.1.2软件对GEO数据库中的10例膀胱癌单细胞样本进行质量控制及降维聚类并对其进行细胞注释;采用CellChat分析GEO数据库中单细胞数据的细胞间通信。采用单因素Cox比例风险模型分析筛选与膀胱癌预后相关的差异表达基因, 并使用LASSO-Cox回归分析构建预后风险模型, 计算风险评分。根据中位风险评分, 以TCGA数据集中膀胱癌患者为训练集, 将患者分为低风险组和高风险组;采用GEO数据库GSE13507数据集为验证集进行验证, 通过Kaplan-Meier分析比较训练集、验证集低风险组...     

COX-2与突变型p53蛋白在乳腺癌组织中的表达及临床意义

目的研究COX-2蛋白和突变型p53蛋白在乳腺癌组织中的表达情况,探讨两者在乳腺癌发生、发展中的作用、相互关系及与临床病理学特征之间的关系。方法运用链霉菌抗生物素蛋白-过氧化物酶免疫组织化学方法（S-P）对99例乳腺癌组织中COX-2蛋白和突变型p53蛋白的表达进行检测。结果99例乳腺癌中COX-2蛋白表达阳性率为69.7%（69/99）,COX-2蛋白表达与患者年龄、原发肿瘤大小、腋淋巴结转移状况、TNM临床分期、激素受体状况均无显著相关（P〉0.05）,而与C-erbB-2蛋白表达呈显著相关（P〈0.05）。99例乳腺癌中突变型p53蛋白表达阳性率为48.5%（48/99）,突变型p53蛋白表达与患者年龄、TNM临床分期、激素受体状况无显著相关（P〉0.05）,而与原发肿瘤大小、腋淋巴结转移状况、C-erbB-2蛋白表达呈显著相关（P〈0.05）。COX-2蛋白表达与突变型p53蛋白在乳腺癌组织中的表达呈正相关（r=0.288,P〈0.05）,两者共表达与肿瘤大小、腋淋巴结转移状况呈显著相关（P〈0.05）。结论COX-2蛋白和突变型p53蛋白在乳腺癌组织中高表达,COX-2蛋白与突变型p53蛋白在乳腺癌组织中的表达呈正相关,两者在乳腺癌的发生、发展中可能起协同作用,是反映乳腺癌生物学行为的重要指标。     

三种鼠不同结构p53minigene瞬时转染H1299细胞对其生长的影响

目的：比较一个位点不同碱基的鼠p53minigene对细胞生长的影响。方法：三种小鼠p53minigene[野生型（Arg）、假野生突变型（Leu)和突变型（His)]真核表达载体,由LipofectAMINE介导转染P53缺失的H1299细胞,在转染后不同时间点收集细胞,利用细胞计数、流式细胞术、蛋白免疫印迹等方法比较三种P53对细胞体外生长的影响。结果：在染后不同时间点,野生型和假野生突变型P53均能诱导细胞凋亡和周期阻滞,并可转录激活Bax,p21^waf1和Mdm-2,突变型则无以上效应。结论：野生型和假野生突变型P53具有诱导肺癌细胞凋亡和引起周期阻滞的功能,。这种作用可能是通过转录激活Bax和p21^WAF1而实现,Mdm-2与野生型和假野 生型P53可以反调节,172Len和172His两种突变表现出截然不同的生物学效应,支持P53基因存在保留野生型抑瘤功能突变方式的观点。     

基于质谱流式细胞技术揭示TP53突变型乙型肝炎病毒相关性肝细胞癌的免疫微环境特征

目的 探讨TP53突变型乙型肝炎病毒（hepatitis B virus，HBV）相关性肝细胞癌（hepatocellular carcinoma，HCC）的肿瘤免疫微环境特征。方法 收集2018—2019年广西医科大学附属肿瘤医院肝胆外科手术切除的38例HCC患者活体组织标本及其配对癌旁组织标本，提取组织DNA，并进行基因突变分析。采用质谱流式细胞术（CyTOF）比较TP53突变组和TP53未突变组中癌组织与癌旁组织以及两组癌组织之间的免疫微环境特点。结果 采用CyTOF鉴定TP53突变组和TP53未突变组所有免疫细胞，结果鉴定为22个细胞亚群，包括CD4⁺T细胞亚群、CD8⁺T细胞亚群、B细胞亚群、树突细胞亚群、自然杀伤（natural killer cell，NK）细胞亚群、NKT细胞亚群、粒细胞亚群和2个未知细胞亚群。其中，TP53突变组癌组织中CD8⁺T细胞和CD4⁺T细胞的表达比例均较未突变组癌组织高（2.26% vs 0.47%，P=0.028；7.53% vs 3.55%，P=0.046）。结论 TP53突变型HBV相关性HCC的肿瘤免疫微环境具有免疫异质性。     

不同方法检测K-Ras基因突变与转移性结直肠癌疗效及预后的关系

目的 探讨直接测序法和肽核酸钳制PCR（PNA-PCR）法检测K-Ras基因突变状态与转移性结直肠癌患者疗效及预后的相关性。方法 收集110例转移性结直肠癌患者的石蜡包埋肿瘤组织,采用直接测序法和PNA-PCR法分别检测肿瘤组织的K-Ras基因第2外显子第12、13密码子的突变状态,并分析其与患者预后的关系。结果 直接测序法检测到43例K-Ras基因突变,PNA-PCR法除了检测出这些突变之外,还在直接测序法检测的野生型中发现了10例突变。对K-Ras突变状态与患者的预后分析发现,直接测序法检测的K-Ras野生型及突变型患者的中位生存时间（OS）分别为20.5个月和15.6个月（P=0.067）。PNA PCR法检测的野生型和突变型患者的中位OS分别为21.3个月和15.8个月（P=0.014）。两种方法检测的野生型与突变型的有效率和无病进展时间（PFS）差异均无统计学意义。按照这两种方法的检测结果分为3组,高突变组、低突变组和野生型组,仅高突变组与野生型组的OS差异有统计学意义（15.6个月vs.21.3个月,P=0.040）。Cox多因素分析显示,ECOG评分（HR=2.70,95％CI：1.39～5.25,P=0.003）和K-Ras丰度（HR=1.52,95％CI：1.52～2.19,P=0.026）与患者的预后相关。结论 K-Ras突变不是以伊立替康或奥沙利铂为主方案的疗效预测因子。PNA-PCR法检测的K-Ras突变状态与患者的预后有关。建议用PNA-PCR法确定野生型患者,而突变型患者则用直接测序法来确定。     

基于生物信息学分析ITGA2在胰腺癌组织中的表达及机制

目的:探讨整合素亚基α2（integrin alpha-2,ITGA2）在胰腺癌组织中的表达及作用机制。方法:从GEO基因芯片数据库下载GSE28735的芯片数据分析ITGA2的表达；从TCGA数据库搜索有关ITGA2临床样本表达的数据，分析不同ITGA2表达与胰腺癌临床病理参数的相关性；利用GEPIA在线数据库分析ITGA2对胰腺癌预后的影响；最后，运用基因富集分析探究ITGA2在胰腺癌中的可能作用机制。结果:ITGA2基因在胰腺癌组织中的表达量高于癌旁组织（P＜0.000 1），ITGA2基因的表达与胰腺癌患者年龄、T分期、肿瘤的恶性程度G分级具有相关性（P＜0.05）。ITGA2高表达胰腺癌患者的总体生存期（P＜0.05）和无病生存期（P＜0.05）较差。GSEA结果表明:ITGA2基因主要与顶端连接（P=0.021）、E2F转录途径（P=0.036）、mTORC1信号通路（P=0.018）、糖酵解途径（P=0.032）、PI3K/AKT/mTOR信号通路（P=0.028）、G2/M细胞周期检查点（P=0.034）等信号通路有关。结论:ITGA2在胰腺癌组织中表达上调并且与胰腺癌不良的预后相关，其可以作为胰腺癌有效的预后标志物和潜在治疗靶点。     

TP53 mutations and outcome in osteosarcoma: a prospective, multicenter study.

PURPOSE: Mutations of the TP53 gene have been associated with resistance to chemotherapy as well as poor prognosis in many different malignancies. This is the first prospective study of the prognostic value of somatic TP53 mutations in patients with newly diagnosed extremity osteosarcoma. PATIENTS AND METHODS: One hundred ninety-six patients with high-grade, nonmetastatic osteosarcoma of the extremities were enrolled from seven tertiary care institutions and observed prospectively for tumor recurrence (median follow-up duration, 44 months). All patients received neoadjuvant or adjuvant chemotherapy and surgery. Tumors were analyzed for the presence of TP53 mutations by polymerase chain reaction single-strand conformation polymorphism analysis and direct DNA sequencing. The association of the status of the TP53 gene with the risk of systemic recurrence was examined using survival analyses with traditional and histologic markers as prognostic factors. RESULTS: Patient age was the only factor that varied with TP53 gene status (P = .05). No relationship was identified between TP53 status and systemic relapse (relative risk, 1.24; P = .41). Analyses based on missense or nonsense mutations gave similar results (P > .10). In multivariate analysis, large (> 9 cm) tumor size (relative risk, 1.9; P = .006) and poor histologic response (< or = 90% necrosis) to chemotherapy (relative risk, 2.14; P = .02) were the only significant independent predictors of systemic outcome. CONCLUSION: We found no evidence that TP53 mutations predict for development of metastases in patients with high-grade osteosarcoma. Identification of other genes that influence chemotherapy response and clinical outcome in osteosarcoma is needed to facilitate further improvements in patient outcomes.     

EGR1在乳腺癌组织中的表达及临床意义

目的:探究早期生长反应基因1（early growth response 1,EGR1）在乳腺癌组织中的表达及临床意义。方法:下载并提取TCGA数据库中EGR1的表达数据;购买乳腺癌组织芯片（HBreD090CS01）,并采用免疫组织化学法检测EGR1在乳腺癌中的表达;利用Kaplan-Meier Plotter数据库分析EGR1在乳腺癌中的预后价值;利用TIMER数据库分析乳腺癌中EGR1表达与免疫细胞浸润的关系。结果:相较于癌旁组织,EGR1 mRNA在乳腺癌中的表达显著下调（P＜0.001）;EGR1蛋白在45例乳腺癌组织中有18例呈低表达,27例呈高表达,在45例癌旁组织中有9例呈低表达,36例呈高表达,差异具有统计学意义（P=0.038）;EGR1表达与乳腺癌分化程度相关（P=0.003）,与患者年龄、肿瘤大小、N分期、临床分期等无关（P＞0.05）;EGR1低表达的乳腺癌患者,其无复发生存率显著低于EGR1高表达的患者（P＜0.001）,但EGR1表达与乳腺癌患者的总生存率无明显相关性（P＞0.05）;乳腺癌组织中EGR1表达与B细胞浸润水平呈负相关（P＜0.001）,与CD8+T细胞、CD4+T细胞、巨噬细胞、中性粒细胞、树突状细胞浸润水平呈正相关（P＜0.001）。结论:EGR1在乳腺癌组织中的表达较癌旁组织低,且与肿瘤分化程度、预后及免疫浸润有关,有望成为乳腺癌预后评估的分子标志物及治疗的潜在靶点。     

High-risk Stage III colon cancer patients identified by a novel five-gene mutational signature are characterized by upregulation of IL-23A and gut bacterial translocation of the tumor microenvironment

The heterogeneities of colorectal cancer (CRC) lead to staging inadequately of patients’ prognosis. Here, we performed a prognostic analysis based on the tumor mutational profile and explored the characteristics of the high-risk tumors. We sequenced 338 colorectal carcinomas as the training dataset, constructed a novel five-gene (SMAD4, MUC16, COL6A3, FLG and LRP1B) prognostic signature, and validated it in an independent dataset from The Cancer Genome Atlas (TCGA). Kaplan–Meier and Cox regression analyses confirmed that the five-gene signature is an independent predictor of recurrence and prognosis in patients with Stage III colon cancer. The mutant signature translated to an increased risk of death (hazard ratio = 2.45, 95% confidence interval = 1.15–5.22, p = 0.016 in our dataset; hazard ratio = 4.78, 95% confidence interval = 1.33–17.16, p = 0.008 in TCGA dataset). RNA and bacterial 16S rRNA sequencing of high-risk tumors indicated that mutations of the five-gene signature may lead to intestinal barrier integrity, translocation of gut bacteria and deregulation of immune response and extracellular related genes. The high-risk tumors overexpressed IL23A and IL1RN genes and enriched with cancer-related bacteria (Bacteroides fragilis,Peptostreptococcus, Parvimonas, Alloprevotella and Gemella) compared to the low-risk tumors. The signature identified the high-risk group characterized by gut bacterial translocation and upregulation of interleukins of the tumor microenvironment, which was worth further researching.     

Influence of TP53 gene alterations and c-erbB-2 expression on the response to treatment with doxorubicin in locally advanced breast cancer

TP53 status [mutations, immunostaining, and loss of heterozygosity (LOH)], expression of c-erbB-2, bcl-2, and histological grading were correlated to the response to doxorubicin monotherapy (14 mg/m2) administered weekly to 90 patients with locally advanced breast cancer. Mutations in the TP53 gene, in particular those affecting or disrupting the loop domains L2 or L3 of the p53 protein, were associated with lack of response to chemotherapy (P = 0.063 for all mutations and P = 0.008 for mutations affecting L2/L3, respectively). Similarly, expression of c-erbB-2 (P = 0.041), a high histological grade (P = 0.023), and lack of expression of bcl-2 (P = 0.018) all predicted chemoresistance. No statistically significant association between either p53 immunostaining or TP53 LOH and response to therapy was recorded, despite the finding that both were associated with TP53 mutation status (p53 immunostaining, P < 0.001; LOH, P = 0.021). Lack of immunostaining for p53 despite mutation of the TP53 gene was particularly seen in tumors harboring nonsense mutations or deletions/splices (7 of 10 negative for staining compared with 4 of 16 with missense mutations). TP53 mutations (total/affecting L2/L3 domains) were associated with expression of c-erbB-2 (P < 0.001 for both), high histological grade (P = 0.001 and P = 0.025), and bcl-2 negativity (P = 0.003 and P = 0.002). TP53 mutations, histological grade, and expression of bcl-2 (but not LOH or c-erbB-2 expression) all predicted for relapse-free as well as breast cancer-specific survival in univariate analysis (Ps between <0.0001 and 0.0155), but only tumor grade was found to be predictive in multivariate analysis (P = 0.01 and P = 0.0007, respectively). Our data are consistent with the hypothesis that certain TP53 mutations predict for resistance to doxorubicin in breast cancer patients. However, the observation that the majority of patients with TP53 mutations affecting or disrupting the L2/L3 domains with LOH in addition (n = 12) obtained a partial response (n = 4) or stabilization of disease (n = 5) during chemotherapy suggests redundant mechanisms to compensate for loss of p53 function. Our findings are consistent with the hypothesis that other defects may act in concert with loss of p53 function, causing resistance to doxorubicin in breast cancers.     

Impact of alterations affecting the p53 pathway in bladder cancer on clinical outcome, assessed by conventional and array-based methods.

This study was designed to define the potential clinical relevance of identifying alterations affecting p53 pathway in bladder cancer and to test a new, low-cost, high-throughput, and array-based TP53 sequencing technology. Tumor samples from 140 evaluable patients with bladder cancer were analyzed with two methods to detect TP53 gene mutations, including single-stranded conformational polymorphism followed by direct sequencing and an oligonucleotide array-based sequencing method. Immunohistochemistry was used to assess patterns of expression of p53, p21/WAF1, and mdm2. Median follow-up time was 27.6 months. Results from the above analyses were correlated with clinicopathological parameters and outcome. Combining the mutation-detection assays, 79 cases (56.4%) were found to harbor TP53 gene mutations. Direct sequencing identified 66 point mutations and five frameshift mutations. The p53 oligonucleotide array detected 65 point mutations and four splice site mutations in different exons but missed all five frameshift mutations. p53 nuclear overexpression was observed in 71 cases (50.7%), lack of p21 nuclear expression was found in 81 cases (57.9%), and mdm2 nuclear overexpression was seen in 64 cases (45.7%). In multivariate analysis, 17 patients (12.1%) had an altered p53 pathway, defined by the detection of mutant TP53 and/or p53 nuclear overexpression, loss of p21 nuclear expression, and mdm2 nuclear overexpression, and exhibited the worst clinical outcome in the observation period (P = 0.015), and it appears to be a significant prognostic factor associated with patient survival.     

Frequency of TP53 mutations in relation to Arg72Pro genotypes in non small cell lung cancer.

Mutations in the TP53 gene are important events during human lung carcinogenesis. The TP53 gene harbors several polymorphisms, and functional studies have shown that the Arg72Pro polymorphism alters both wild-type and mutant p53 protein activity. Thus, we hypothesized that certain Arg72Pro genotypes may influence the frequency and pattern of somatic mutations in TP53. We therefore examined the status of the Arg72Pro polymorphism and TP53 mutations in 260 non-small-cell lung cancer cases. Here we report a significant trend toward lower frequency of TP53 mutations with increasing number of Pro72 alleles (P = 0.02). Overall, Pro72 allele carriers had significantly lower frequency of TP53 mutations compared with Arg72 homozygotes (P = 0.02). In addition, carriage of the Pro72 variant was related to a lower frequency of mutations affecting the hotspot codon 273. Mutations at codon 273 accounted for 10.6% of the mutations in Arg72 homozygotes and 1.7% of the mutations in Pro72 allele carriers. Our results suggest that the genotype of the Arg72Pro polymorphism may modulate the frequency of TP53 mutations in non-small-cell lung cancer.