Abstract
目的
p53基因是目前研究最广泛的抑癌基因,其生物功能好似“基因组卫士”。既往研究表明大约50%的肿瘤存在P53蛋白功能缺陷,本文旨在回顾性分析p53 rs1625895基因多态性与弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma, DLBCL)患者预后的相关性。
方法
以384例DLBCL患者为研究对象,采用Sanger法测序其p53 rs1625895基因型,分析rs1625895基因多态性与患者临床特征、一线化疗疗效及预后的关系。
结果
所有患者中AA型2例(0.5%),AG型34例(8.9%),GG型348例(90.6%)。rs1625895基因型与患者年龄、性别、B症状[指出现以下任一症状:原因不明反复发热(常在38 ℃以上)、盗汗、原因不明6个月内体质量减少10%]、红细胞沉降率(erythrocyte sedimentation rate,ESR)、国际预后指数(international prognostic index,IPI)评分、分子分型等临床病理学特征均无明显相关性(P > 0.05)。AA/AG与GG型患者的一线化疗总有效率(overall response rate,ORR)分别为82.9%和82.8%,差异无统计学意义(P > 0.05)。AA/AG和GG基因型的5年无进展生存率(progression-free survival rate, PFS)分别为71.8%和62.3%(χ2= 1.351,P = 0.245),5年总生存率(overall survival rate, OS)分别为72.2%和64.1%(χ2= 1.267,P = 0.260),差异均无统计学意义。亚组分析显示,在生发中心(germinal center B-cell, GCB)亚组中,AA/AG和GG基因型患者的5年PFS分别为91.7%和72.7%(χ2= 4.493,P = 0.034);5年OS分别为91.7%和76.7%(χ2= 4.246,P = 0.039),差异均有统计学意义,AA/AG基因型患者预后明显优于GG型患者。而在非生发中心(non-germinal center B-cell, non-GCB)亚组,AA/AG和GG型的5年PFS及OS差异均无统计学意义(P > 0.05)。根据一线方案是否含有利妥昔单抗将患者分为环磷酰胺、多柔比星、长春新碱和泼尼松(cyclophosphoramide, doxorubicin, vincristine, prednisone, CHOP)治疗组及利妥昔单抗联合环磷酰胺、多柔比星、长春新碱和泼尼松(rituximab, cyclophosphoramide, doxorubicin, vincristine, prednisone, R-CHOP)治疗组,结果在不同亚组中,AA/AG和GG型的5年PFS及OS差异也无统计学意义(P > 0.05)。
结论
对于一线接受CHOP方案化疗的DLBCL患者,p53 rs1625895不能预测患者的临床疗效和预后,但在GCB型患者中,rs1625895有可能成为判断预后的预测指标。
Keywords: 弥漫大B细胞淋巴瘤, p53基因, 单核苷酸多态性
Abstract
Objective
p53 gene, as “the guardian of the genome”, is the most widely studied tumor suppressor gene. Previous studies have shown that about 50 percent of tumors have P53 dysfunction. This article aims to retrospectively analyze the correlation between p53 rs1625895 polymorphism and the prognosis of patients with diffuse large B-cell lymphoma (DLBCL).
Methods
PCR combined with Sanger sequencing were used to detect rs1625895 genotype in 384 DLBCL patients. The relationship between rs1625895 polymorphisms and the clinical characteristics, first-line therapeutic effects and the prognosis of the patients were analyzed.
Results
Among all the patients, 2 (0.5%) patients with AA genotype, 34 (8.9%) patients with AG genotype and 348 (90.6%) patients with GG genotype were identified. The patients with different rs1625895 genotypes did not have any difference in terms of age, gender, B symptoms (developing any of the following symptoms: unexplained recurrent fever (often above 38 ℃), night sweats, and unexplained weight loss of 10% within 6 months ), erythrocyte sedimentation rate (ESR), international prognostic index (IPI) and molecular subtype (P>0.05). The overall response rate (ORR) was 82.9% and 82.8% in AA/AG and GG, respectively. There was no significant dif-ference between the first-line therapeutic effects of the two groups (P>0.05). And there was also no difference between A allele carriers and homozygous G allele carriers for the 5-year progression-free survival rate (PFS) (71.8% vs. 62.3%, χ 2 = 1.351, P=0.245) and 5-year overall survival rate (OS) (72.2% vs. 64.1%, χ 2 = 1.267, P = 0.260). But in the subgroup with Germinal Center B-cell (GCB) type, the patients carrying A allele for rs1625895 had an obviously longer PFS (91.7% vs. 72.7%, χ 2 = 4.493,P = 0.034) and OS (91.7% vs. 76.7%, χ2 = 4.246, P = 0.039) compared with the patients homozygous for the G allele. As for the patients with non-GCB subtype, there was no significant difference in PFS and OS between different rs1625895 genotypes (P>0.05). According to whether the first-line regimen contained rituximab or not,the patients were divided into two groups treated with cyclophosphoramide, doxorubicin, vincristine and prednisone (CHOP) or with rituximab and CHOP (R-CHOP). But in both subgroups, there was no significant difference in the 5-year PFS and OS between the AA/AG and GG patients,too (P>0.05).
Conclusion
For DLBCL patients receiving CHOP regimen chemotherapy in the first line, p53 rs1625895 cannot predict the clinical efficacy and prognosis of the patients, but in the patients with GCB subtype, this polymorphism may be a prognostic indicator.
Keywords: Diffuse large B-cell lymphoma, p53 gene, Single nucleotide polymorphism
弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)是非霍奇金淋巴瘤(non-Hodgkin’s lymphoma,NHL)最常见的亚型, 我国2012年统计的数字显示,DLBCL占全部淋巴瘤的 35.75%,占NHL的40.77%[1]。利妥昔单抗联合环磷酰胺、多柔比星、长春新碱和泼尼松(rituximab, cyclophosphoramide, doxorubicin, vincristine, prednisone, R-CHOP)方案作为标准一线治疗方案显著改善了DLBCL的预后[2],但由于DLBCL的异质性,仍有部分人群表现为治疗无效或短期内复发进展。DLBCL预后的评估指标目前仍主要依据国际预后指数(international prognostic index,IPI), 但由于IPI评分仅包含临床特征,不包括患者的分子生物学指标,有相当一部分患者的预后不能被准确评估,因此,从肿瘤分子生物学及细胞遗传学等方面进一步探寻肿瘤发生、发展及耐药机制,寻找DLBCL新的预后指标仍是当前研究的主要任务。p53基因是研究最广泛的抑癌基因,其生物学功能好似“基因组卫士”。生理情况下, p53基因在致癌因子、DNA损伤、缺氧、热休克、紫外照射等应激因素刺激下被激活,通过调节其下游靶基因(包括bax、noxa、puma和p21 等),从而调控细胞周期阻滞、DNA损伤修复、细胞凋亡等,以维持细胞正常的生理功能[3]。既往研究表明,大约50%的肿瘤存在P53蛋白功能缺陷[4]。对于DLBCL,已有研究证实p53基因突变与DLBCL预后不良相关[5],某些p53基因单核苷酸多态性(single nucleotide polymorphism,SNP)也对DLBCL患者预后产生影响,比如rs1042522[6],而rs1625895则研究很少。一些研究发现rs1625895与肿瘤易感性及预后相关[7,8,9,10],本文旨在回顾性分析rs1625895与DLBCL患者预后的相关性。
1. 资料与方法
1.1. 研究对象
收集2000年4月12日至2015年9月23日在北京大学肿瘤医院初治的DLBCL患者共384例,均经组织病理学检查诊断明确。所有患者均具有完整的临床病理学及血液学资料,有可进行基因组分析的全血标本,并具备详细的随访信息。排除资料不全、无全血标本及一线未采用环磷酰胺、多柔比星、长春新碱和泼尼松(cyclophosphoramide, doxorubicin, vincristine, prednisone, CHOP)方案治疗的患者。所有标本采集均与患者签署了相关知情同意书。
1.2. 主要试剂和仪器
PCR所用试剂盒(KAPA2G Robust HotStart ReadyMix)购自北京天一辉远生物技术有限公司,DNA提取试剂盒(QIAamp DNA Mini Kit)购自北京泰克生物技术有限公司,扩增rs1625895基因目的片段所用引物的合成及PCR产物测序委托北京天一辉远生物技术有限公司完成,PCR仪(ABI 2720)购自美国Bio-RAD公司。
1.3. DNA提取及p53 rs1625895基因多态性的检测
取患者入院时经乙二胺四乙酸(ethylene dia-mine tetraacetic acid,EDTA)处理的外周血2 mL,按照试剂盒操作步骤提取基因组DNA,稀释成终浓度为30 mg/L的溶液,置于-20 ℃冰箱保存,以备后续实验应用。设计rs1625895引物序列为5'-TGGCCATCTACAAGCAGTCA-3'和5'-TTGCACATCTCATGGGGTTA-3',扩增片段长度是404 bp。PCR体系25 μL包括DNA模版30 ng。扩增条件:94 ℃预变性5 min、94 ℃变性30 s、60 ℃退火20 s、72 ℃ 延伸40 s,共35个循环,之后72 ℃延伸5 min,得到的最终产物委托给北京天一辉远生物技术有限公司测序。
1.4. 治疗方案
所有患者一线分别接受了2~8个周期的化疗,其中118例患者采用CHOP方案,另外266例则采用R-CHOP方案,两种方案均为每3周重复一次,每重复1次视为1个周期。CHOP方案:环磷酰胺(美国百特国际有限公司)750 mg/m2,静脉滴入,第1天;多柔比星(深圳万乐药业有限公司)50 mg/m2,静脉滴入,第1天;长春新碱(深圳万乐药业有限公司)1.4 mg/m2(最大剂量2 mg),静脉滴入,第1天;泼尼松(天津力生制药股份有限公司)100 mg,口服,第1~5天。R-CHOP方案:CHOP方案联合利妥昔单抗(上海罗氏制药有限公司)375 mg/m2持续4~6 h静脉滴入,第1天。
1.5. 疗效判定
每2~3周期治疗后评价疗效1次,疗效评价标准采用《2007年恶性淋巴瘤疗效评价修订标准》[11],分为完全缓解(complete response, CR)、部分缓解(partial response, PR)、疾病稳定(stable disease, SD)和疾病进展(progressive disease, PD),以CR+PR计算总有效率(overall response rate,ORR)。
1.6. 随访
采用查阅门诊、住院病例及电话方式进行随访。治疗结束后第1年每3个月随访1次,第2~3年每6个月随访1次,之后每年随访1次。总生存期(overall survival,OS)定义为从明确诊断至死亡或末次随访的时间,无进展生存期(progression-free survival,PFS)定义为从开始治疗至淋巴瘤进展或任何原因引起死亡的时间。
1.7. 统计学分析
采用SPSS 20.0版软件进行统计学分析。计数资料采用描述分析,组间差异比较采用χ2检验。生存分析采用Kaplan-Meier法,Cox回归模型评价预后因素。检验水准α=0.05(双侧)。
2. 结果
2.1. p53 rs1625895基因型的分布
测序结果显示,384例患者中AA基因型2例(0.5%), AG基因型34例(8.9%), GG基因型348例(90.6%)。经群体遗传学Hardy-Weinberg平衡定律检验各基因型分布的差异无统计学意义(χ2=1.322,P = 0.250), 符合Hardy-Weinberg平衡。
2.2. p53 rs1625895基因多态性与DLBCL患者临床病理学特征的关系
将rs1625895基因型分为AA/AG和GG两组,分别比较不同基因型与患者年龄、性别、B症状[指出现以下任一症状:原因不明反复发热(常在38 ℃以上)、盗汗、原因不明6个月内体质量减少10%]、血清乳酸脱氢酶(lactate dehydrogenase,LDH)、β2微球蛋白(β2-microglobulin,β2-MG)、红细胞沉降率(erythrocyte sedimentation rate,ESR)、分期(根据1989年修订的Ann-Arbor分期标准)、IPI评分、Ki67、美国东部肿瘤协作组(Eastern Cooperative Oncology Group,ECOG)评分、分子分型及治疗的关系,结果差异均无统计学意义(P > 0.05),见表1。
1.
rs1625895基因多态性与DLBCL患者临床病理学特征的关系
DLBCL patients’ characteristics and their correlations with the genotype of rs1625895
| Clinical parameters | n | Genotype | χ2 | P | |
| AA/AG | GG | ||||
| DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B-cell; non-GCB, non-germinal center B-cell; ECOG, Eastern Cooperative Oncology Group; IPI, international prognostic index; LDH, lactate dehydrogenase; β2-MG, β2-microglobulin; ESR, erythrocyte sedimentation rate; CHOP, cyclophosphoramide, doxorubicin, vincristine, prednisone; R-CHOP, rituximab, cyclophosphoramide, doxorubicin, vincristine, prednisone; B symptoms, develop any of the following symptoms: unexplained recurrent fever (often above 38 ℃), night sweats, and unexplained weight loss of 10% within 6 months. | |||||
| Age/years | |||||
| ≤60 | 241 | 22 | 219 | 0.046 | 0.830 |
| >60 | 143 | 14 | 129 | ||
| Gender | |||||
| Male | 197 | 18 | 179 | 0.027 | 0.870 |
| Female | 187 | 18 | 169 | ||
| Subtype (no data were available for 39 patients) | |||||
| GCB | 102 | 13 | 89 | 1.693 | 0.193 |
| Non-GCB | 243 | 20 | 223 | ||
| Ki67 (no data were available for 27 patients) | |||||
| ≤75% | 171 | 16 | 155 | 0.062 | 0.803 |
| >75% | 186 | 16 | 170 | ||
| Stage (no data were available for 1 patient) | |||||
| Ⅰ-Ⅱ | 178 | 19 | 159 | 0.635 | 0.426 |
| Ⅲ-Ⅳ | 205 | 17 | 188 | ||
| B symptoms | |||||
| Negative | 252 | 25 | 227 | 0.257 | 0.612 |
| Positive | 132 | 11 | 121 | ||
| ECOG score | |||||
| 0-1 | 344 | 32 | 312 | 0.021 | 0.886 |
| 2-3 | 40 | 4 | 36 | ||
| IPI score | |||||
| 0-2 | 270 | 26 | 244 | 0.069 | 0.792 |
| 3-5 | 114 | 10 | 104 | ||
| LDH (no data were available for 2 patients) | |||||
| ≤240/ IU/L | 221 | 22 | 199 | 0.173 | 0.677 |
| >240/ IU/L | 161 | 14 | 147 | ||
| β2-MG (no data were available for 15 patients) | |||||
| Negative | 272 | 28 | 244 | 0.789 | 0.374 |
| Positive | 97 | 7 | 90 | ||
| ESR (no data were available for 14 patients) | |||||
| Negative | 162 | 12 | 150 | 0.810 | 0.368 |
| Positive | 208 | 21 | 187 | ||
| Treatment | |||||
| CHOP | 118 | 11 | 107 | 0.001 | 0.981 |
| R-CHOP | 266 | 25 | 241 | ||
2.3. p53 rs1625895基因多态性与DLBCL患者一线化疗疗效的关系
384例患者中,378例可评价近期疗效,其中CR 218例,PR 95例,SD 0例,PD 65例。在35例AA/AG基因型患者中,CR 23例,PR 6例,SD 0例,PD 6例;343例GG基因型患者中,CR 195例,PR 89例,SD 0例,PD 59例。rs1625895不同基因型间的疗效差异无统计学意义(P>0.05), 见表2。
2.
rs1625895与DLBCL患者一线CHOP方案临床疗效的关系
Clinical response to CHOP therapy according to the genotype of rs1625895
| Response | n | Genotype | χ2 | P | |
| AA/AG, n(%) | GG, n(%) | ||||
| DLBCL, diffuse large B-cell lymphoma; CHOP, cyclophosphoramide, doxorubicin, vincristine, prednisone; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; OR, overall response. | |||||
| Grouped by CR | |||||
| PR+SD+PD | 160 | 12(34.3) | 148(43.1) | 1.022 | 0.312 |
| CR | 218 | 23(65.7) | 195(56.9) | ||
| Grouped by OR | |||||
| PD+SD | 65 | 6(17.1) | 59(17.2) | 0.000 | 0.993 |
| OR(CR+PR) | 313 | 29(82.9) | 284(82.8) | ||
2.4. p53 rs1625895基因多态性与DLBCL患者的生存关系
所有患者随访2.0~202.6个月,中位随访时间65.7个月。384例患者中79例(20.1%)维持完全缓解状态,163例(42.4%)出现疾病进展或复发,142例(37.0%)死亡。AA/AG和GG基因型的5年PFS分别为71.8%和62.3%(χ2 = 1.351,P=0.245),差异无统计学意义。AA/AG和GG基因型的5年OS分别为72.2%和64.1%(χ2 = 1.267,P = 0.260),差异也无统计学意义。亚组分析显示,在GCB亚组中,AA/AG和GG基因型患者的5年PFS分别为91.7%和72.7%(χ2 = 4.493,P = 0.034);5年OS分别为91.7%和76.7%(χ2 = 4.246,P = 0.039), 差异均有统计学意义,AA/AG基因型患者预后明显优于GG型患者。在non-GCB亚组中,AA/AG和GG型的5年PFS分别为53.3%和55.9%(χ2 = 0.116,P = 0.733), 5年OS分别为55.0%和57.8%(χ2 = 0.050,P = 0.822), 差异均无统计学意义。根据一线方案是否含有利妥昔单抗将患者分为CHOP治疗组及R-CHOP治疗组,结果在CHOP治疗组,AA/AG与GG型患者的5年PFS分别为63.6%和50.6%(χ2 = 0.639,P = 0.424),5年OS分别为63.6%和53.9%(χ2 = 0.667,P = 0.414),差异均无统计学意义;在R-CHOP治疗亚组,AA/AG与GG型患者的5年PFS分别为75.4%和66.7%(χ2 = 0.836,P = 0.360),5年OS分别为76.0%和68.0%(χ2 = 0.724,P = 0.395),差异也无统计学意义。
2.5. Cox多因素分析
单因素分析显示影响DLBCL患者OS的危险因素包括:年龄(HR = 1.427,P = 0.035)、分子分型(HR = 2.203,P = 0.001)、分期(HR = 2.596,P < 0.001)、B症状(HR = 1.687,P = 0.002)、ECOG分级(HR = 1.860,P = 0.009)、IPI评分(HR = 2.391,P < 0.001)、LDH(HR = 2.211,P<0.001)、 血β2-MG(HR = 2.116,P < 0.001)、ESR(HR = 1.500,P = 0.023)、临床疗效(HR = 0.166,P < 0.001)和是否应用利妥昔单抗(HR = 0.640,P = 0.010)。选择有差异的因素和rs1625895基因型进行Cox回归多因素分析,结果显示non-GCB分子分型、β2微球蛋白升高、疗效未达CR及有B症状是预后不良的危险因素(P < 0.05)。rs1625895基因型不是DLBCL患者预后的独立危险因素,见表3。
3.
影响DLBCL患者预后的Cox多因素分析
Cox multivariate analysis of prognosis of patients with DLBCL
| Variable | B | SE | Wald | df | P | HR | 95%CI |
| DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B-cell; non-GCB, non-germinal center B-cell; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; β2-MG, β2-microglobulin; B symptoms, develop any of the following symptoms: unexplained recurrent fever (often above 38 ℃), night sweats, and unexplained weight loss of 10% within 6 months. | |||||||
| Subtype(non-GCB vs. GCB) | 0.546 | 0.244 | 4.997 | 1 | 0.025 | 1.727 | 1.070-2.787 |
| Response(CR vs. PR+SD+PD) | -1.593 | 0.216 | 54.159 | 1 | <0.001 | 0.203 | 0.133-0.311 |
| B symptoms(positive vs. negative) | 0.424 | 0.194 | 4.810 | 1 | 0.028 | 1.529 | 1.046-2.234 |
| β2-MG(positive vs. negative) | 0.637 | 0.198 | 10.356 | 1 | 0.001 | 1.890 | 1.283-2.785 |
3. 讨论
本研究是一项关于p53 rs1625895基因多态性对DLBCL患者预后影响的回顾性研究,结果发现rs1625895基因多态性与患者的临床病理学特征及一线化疗疗效均无明显相关性。尽管全组的PFS和OS与基因型分布间的差异无统计学意义,但亚组分析显示在GCB型患者中,AA/AG型患者的5年PFS及OS均明显优于GG型患者。
p53基因定位于17p13.1,含有11个外显子和10个内含子,于1979年被发现[12],1989年被确认为是一种抑癌基因[13],而p53基因编码的P53蛋白的主要生物学功能是维持细胞基因组稳定、避免细胞恶性转化。生理情况下,当细胞在多种应激因素(包括紫外线、X、γ等射线、癌基因、烷化剂、丝裂霉素、拓扑异构酶抑制剂等)刺激下发生DNA损伤时,野生型P53蛋白可以促使细胞周期阻滞,诱导损伤的DNA进行修复,或在DNA损伤严重不能修复时诱导细胞凋亡[14],因此,任何P53蛋白功能异常均有可能引起细胞基因组不稳定,导致细胞向恶性转化进而形成肿瘤。
rs1625895位于p53基因第6内含子第61个碱基对上[14],虽然目前还没有研究发现rs1625895与p53基因转录及翻译有关,但有研究却发现rs1625895可以影响P53蛋白表达水平[15],并且rs1625895 G→A的变异可以引起细胞DNA损伤修复及凋亡能力下降[10],从而推测rs1625895 A等位基因可能与肿瘤易感性相关。在一些临床研究中,也确实发现rs1625895 G→A的变异可能诱导了某些肿瘤的发生,比如皮肤癌[7]、乳腺癌[8]和肺癌[10, 16],但进一步的临床研究却表明携带rs1625895 A等位基因患者的预后反而更佳。Galli等[17]研究发现,在头颈部鳞癌患者中,与rs1625895 GG型患者相比,AA/AG型患者的预后更优(HR = 0.51, 95%CI: 0.23-1.16)。在慢性淋巴细胞白血病中,Kochethu等[18]也发现rs1625895 AA基因型与疾病早期、CD38阴性以及治疗前的等待时间延长有关,这些特征均表明AA型患者的生存期可能更长。
对于DLBCL,既往研究并未发现rs1625895基因多态性与DLBCL易感性相关[19],但Voropaeva等[9]却发现在一线接受R-CHOP方案化疗的DLBCL患者当中,rs1625895 AA/AG型患者的预后明显优于GG型患者,AA/AG与GG型患者的5年OS分别为65.4%和42.5%(P=0.014)。在本研究中,我们并没有发现不同基因型患者间的预后存在明显统计学差异,但不论一线治疗方案是否含有利妥昔单抗,仍可看到AA/AG型患者的预后存在一定优势趋势,其5年OS比GG型患者高约10%。比较两个研究我们发现,在Voropaeva的研究中,发生rs1625895 G→A变异的患者占24.5%,而在本研究中这一比例仅为9.4%。综合既往研究,亚洲人群的AA/AG比例在10%左右[20],而高加索人群及非洲裔美国人则在20%~40%[10, 15, 21],这一结果提示rs1625895基因多态性存在明显的种族差异,这可能也是导致不同研究结果不一致的原因。我们将患者进一步分层分析,结果发现在GCB型患者中,AA/AG型患者的5年OS比GG型患者高15%,差异有统计学意义(P = 0.039),而在non-GCB型患者中,不同基因型患者间的PFS及OS基本一致。结合之前Kochethu等[18]在慢性淋巴细胞白血病中的研究,rs1625895 G→A变异对预后的影响可能在早期、预后良好的患者中更有意义。
由于本研究是一项回顾性研究,因此尚存在很多问题:比如由于P53蛋白表达不是DLBCL患者常规检测项目,因此本研究未能分析P53蛋白表达与rs1625895基因多态性之间的关系,而rs1625895基因多态性对DLBCL患者预后的影响很可能是通过P53蛋白表达的差异产生的;另外,由于本组人群AA/AG比例不到10%,造成不同基因型间的患者人数差异过大、比例失衡,导致统计效能下降,结果的可靠性也相应下降,这些都需要后续进一步研究来证实。到目前为止,关于rs1625895与肿瘤易感性及预后的研究仅有十余篇,要想更充分地了解该SNP位点的意义以及是否能够成为肿瘤治疗靶点,还需要研究人员更多的努力。
总之,本研究表明对于一线接受CHOP或R-CHOP方案化疗的DLBCL患者,p53 rs1625895不能预测患者的临床疗效及预后,但在GCB型患者中,rs1625895有可能成为判断预后的预测指标。
References
- 1.李 小秋, 李 甘地, 高 子芬, et al. 中国淋巴瘤亚型分布:国内多中心性病例10002例分析. 诊断学理论与实践. 2012;11(2):111–115. [Google Scholar]
- 2.Shah BK, Bista A, Shafii B. Survival in advanced diffuse large B-cell lymphoma in pre- and post-rituximab eras in the United States. Anticancer Res. 2014;34(9):5117–5120. [PubMed] [Google Scholar]
- 3.Lu TX, Young KH, Xu W, et al. TP53 dysfunction in diffuse large B-cell lymphoma. Crit Rev Oncol Hematol. 2016;97:47–55. doi: 10.1016/j.critrevonc.2015.08.006. [DOI] [PubMed] [Google Scholar]
- 4.Hainaut P, Hollstein M. p53 and human cancer: the first ten thousand mutations. Adv Cancer Res. 2000;77:81–137. doi: 10.1016/s0065-230x(08)60785-x. [DOI] [PubMed] [Google Scholar]
- 5.Zenz T, Kreuz M, Fuge M, et al. TP53 mutation and survival in aggressive B cell lymphoma. Int J Cancer. 2017;141(7):1381–1388. doi: 10.1002/ijc.30838. [DOI] [PubMed] [Google Scholar]
- 6.Liu Y, Wang X, Ding N, et al. TP53 Arg72 as a favorable prognostic factor for Chinese diffuse large B-cell lymphoma patients treated with CHOP. BMC Cancer. 2017;17(1):743. doi: 10.1186/s12885-017-3760-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Mukhammadiyeva GF, Karimov DO, Bakirov AB, et al. TP53 gene polymorphisms and occupational skin cancer risks for workers of glass fiber manufacture. Iran J Public Health. 2017;46(11):1495–1501. [PMC free article] [PubMed] [Google Scholar]
- 8.Gaudet MM, Gammon MD, Bensen JT, et al. Genetic variation of TP53, polycyclic aromatic hydrocarbon-related exposures, and breast cancer risk among women on Long Island, New York. Breast Cancer Res Treat. 2008;108(1):93–99. doi: 10.1007/s10549-007-9573-0. [DOI] [PubMed] [Google Scholar]
- 9.Voropaeva EN, Voevoda MI, Pospelova TI, et al. Prognostic impact of the TP53 rs1625895 polymorphism in DLBCL patients. Br J Haematol. 2015;169(1):32–35. doi: 10.1111/bjh.13237. [DOI] [PubMed] [Google Scholar]
- 10.Wang W, Spitz MR, Yang H, et al. Genetic variants in cell cycle control pathway confer susceptibility to lung cancer. Clin Cancer Res. 2007;13(19):5974–5981. doi: 10.1158/1078-0432.CCR-07-0113. [DOI] [PubMed] [Google Scholar]
- 11.Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579–586. doi: 10.1200/JCO.2006.09.2403. [DOI] [PubMed] [Google Scholar]
- 12.Lane DP, Crawford LV. T antigen is bound to a host protein in SV40-transformed cells. Nature. 1979;278(5701):261–263. doi: 10.1038/278261a0. [DOI] [PubMed] [Google Scholar]
- 13.Baker SJ, Fearon ER, Nigro JM, et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science. 1989;244(4901):217–221. doi: 10.1126/science.2649981. [DOI] [PubMed] [Google Scholar]
- 14.Sauka C, Kohut A, Kundrat I, et al. Polymorphism of gene p53 and apoptosis in patients with malignant lung disease: our observation. Klin Onkol. 2008;21(3):98–103. [PubMed] [Google Scholar]
- 15.Pangilinan F, Geiler K, Dolle J, et al. Construction of a high resolution linkage disequilibrium map to evaluate common genetic variation in TP53 and neural tube defect risk in an Irish population. Am J Med Genet A. 2008;146a(20):2617–2625. doi: 10.1002/ajmg.a.32504. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Mechanic LE, Bowman ED, Welsh JA, et al. Common genetic variation in TP53 is associated with lung cancer risk and prognosis in African Americans and somatic mutations in lung tumors. Cancer Epidemiol Biomarkers Prev. 2007;16(2):214–222. doi: 10.1158/1055-9965.EPI-06-0790. [DOI] [PubMed] [Google Scholar]
- 17.Galli P, Cadoni G, Volante M, et al. A case-control study on the combined effects of p53 and p73 polymorphisms on head and neck cancer risk in an Italian population. BMC Cancer. 2009;9:137. doi: 10.1186/1471-2407-9-137. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Kochethu G, Delgado J, Pepper C, et al. Two germ line polymorphisms of the tumour suppressor gene p53 may influence the biology of chronic lymphocytic leukaemia. Leuk Res. 2006;30(9):1113–1118. doi: 10.1016/j.leukres.2005.12.014. [DOI] [PubMed] [Google Scholar]
- 19.Voropaeva EN, Voevoda MI, Pospelova TI, et al. Linkage dis-equilibrium and haplotypes of the rs1042522, rs1625895, and rs1787862 markers of TP53 in patients with diffuse large B-cell lymphoma. Mol Biol (Mosk) 2014;48(5):664–670. [PubMed] [Google Scholar]
- 20.Sun P, Qiu Y, Zhang Z, et al. Association of genetic polymorphisms, mRNA expression of p53 and p21 with chronic benzene poisoning in a Chinese occupational population. Cancer Epidemiol Biomarkers Prev. 2009;18(6):1821–1828. doi: 10.1158/1055-9965.EPI-09-0140. [DOI] [PubMed] [Google Scholar]
- 21.Sagne C, Marcel V, Amadou A, et al. A meta-analysis of cancer risk associated with the TP53 intron 3 duplication polymorphism (rs17878362): geographic and tumor-specific effects. Cell Death Dis. 2013;4:e492. doi: 10.1038/cddis.2013.24. [DOI] [PMC free article] [PubMed] [Google Scholar]