非霍奇金淋巴瘤分子遗传学特征及预后研究进展
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摘要
非霍奇金淋巴瘤(non-Hodgkin's lymphoma,NHL)是常见的淋巴造血系统恶性肿瘤,其病变范围较广,侵袭度在各个分型中差异较大,临床诊断和预后判断较为困难,通常需要结合相关分子靶标的检测。近年来对于NHL分子遗传学的认识已提升到了新的水平,各表型特征性的染色体易位导致原癌基因表达上调,而诸多抑癌基因的缺失使肿瘤细胞过度增殖,基因多态性决定了NHL的易感性、耐药性和预后差异。另外,DNA甲基化、组蛋白修饰、非编码RNA等表观遗传学现象在NHL诊断中的作用日益增大,并且在临床上对于用药选择和在预后的判断中扮演了重要角色。本文就NHL各表型的染色体易位、抑癌基因缺失、基因多态性和表观遗传学最新研究进展作一综述。
Lymphomas are traditionally divided into Hodgkin' s lymphoma and non-Hodgkin' s lymphoma( NHL),the NHL is a common hematological cancer,w hich represents a w ide spectrum of illnesses from the most indolent to the most aggressive malignancies,and the detection of related molecular targets w ill be needed for diagosing each subtype of NHL. Advances in understanding the pathogenesis of NHL have improved the precision of diagnosis and the prognosis evaluation of patients w ith this disorder,such as chromosomal translocation leading to the up-regulation of oncogene expression. Besides,the deletion of several tumor suppressor genes may cause excessive proliferation in tumor cells,and the single nucleotide polymorphism( SNP) determines the differences of susceptibility,drug-resistance and prognosis of NHL. In addition,DNA methylation,histone modification,non-coding RNA and other epigenetic phenomena play an increasingly important role in the diagnosis,selection of clinical drugs and evaluation of prognosis of NHL. In this review,the recent progress of researches on chromosome translocation,deletion of tumor suppression genes,gene polymorphism and epigenetics are summarized.
Lymphomas are traditionally divided into Hodgkin' s lymphoma and non-Hodgkin' s lymphoma( NHL),the NHL is a common hematological cancer,w hich represents a w ide spectrum of illnesses from the most indolent to the most aggressive malignancies,and the detection of related molecular targets w ill be needed for diagosing each subtype of NHL. Advances in understanding the pathogenesis of NHL have improved the precision of diagnosis and the prognosis evaluation of patients w ith this disorder,such as chromosomal translocation leading to the up-regulation of oncogene expression. Besides,the deletion of several tumor suppressor genes may cause excessive proliferation in tumor cells,and the single nucleotide polymorphism( SNP) determines the differences of susceptibility,drug-resistance and prognosis of NHL. In addition,DNA methylation,histone modification,non-coding RNA and other epigenetic phenomena play an increasingly important role in the diagnosis,selection of clinical drugs and evaluation of prognosis of NHL. In this review,the recent progress of researches on chromosome translocation,deletion of tumor suppression genes,gene polymorphism and epigenetics are summarized.
引文
1 Armitage JO,Gascoyne RD,Lunning MA,et al.Non-Hodgkin lymphoma.Lancet,2017;390(10091):298-310.
2辛丽君,杨波,卢学春,等.高龄进展期弥漫大B细胞淋巴瘤分子亚型对预后及治疗影响-1例分析.中国实验血液学杂志,2016;24(2):457-462.
3 Veldman-Jones MH,Lai Z,Wappett M,et al.Reproducible,quantitative and flexible molecular sub-typing of clinical DLBCL samples using the Nano String nCounter system.Clin Cancer Res,2015;21(10):2367-2378.
4 Rosenthal A,Younes A.High grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6:Double hit and triple hit lymphomas and double expressing lymphoma.Blood Rev,2017;31(2):37-42.
5 Kim H,Kim IS,Lee EY,et al.First case of diffuse large B-cell lymphoma subtype of monomorphic post-transplant lymphoproliferative disorder with 3q27 translocation.Ann Lab Med,2016;36(4):380-383.
6 Batmanov K,Wang W,Bjors M,et al.Integrative whole-genome sequence analysis reveals roles of regulatory mutations in BCL6 and BCL2 in follicular lymphoma.Sci Rep,2017;7(1):7040.
7 Kallen ME,Kim Y,Yang L,et al.A Cryptic t(11;14)translocation in mantle cell lymphoma highlights the importance of FISH.JAssoc Genet Technol,2015;41(1):13-16.
8 Du MQ.MALT lymphoma:Genetic abnormalities,immunological stimulation and molecular mechanism.Best Pract Res Clin Haematol,2017;30(1-2):13-23.
9 Schmidt J,Bonzheim I,Steinhilber J,et al.EMMPRIN(CD147)is induced by C/EBPβand is differentially expressed in ALK+and ALK-anaplastic large-cell lymphoma.Lab I Investi,2017;97(9):1095-1102.
10冯江龙,杨文秀,王佳蕊,等.A20基因缺失对弥漫大B细胞淋巴瘤P-gp表达影响.中华肿瘤防治杂志,2017;24(11):750-754.
11 Ma Y,Zhang P,Gao Y,et al.Evaluation of AKT phosphorylation and PTEN loss and their correlation with the resistance of rituximab in DLBCL.Int J Clin Exp Pathol,2015;8(11):14875-14884.
12 Tanaka T,Nakajima-Takagi Y,Aoyama K,et al.Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies.J Exp Med,2017;214(10):2901-2913.
13郭晓静,成志强,金红涛,等.c-myc和Ki-67在结外鼻型NK/T细胞淋巴瘤中的表达及与临床的关系.诊断病理学杂志,2017;24(7):517-520.
14 Li G,Li D.Relationship between IL-10 gene polymorphisms and the risk of non-Hodgkin lymphoma:A meta-analysis.Hum Immunol,2016;77(5):418-425.
15田彩平,廖世奇,袁红霞,等.炎症相关因子基因多态性与弥漫大B细胞淋巴瘤的易感性研究.中国实验血液学杂志,2017;25(2):444-448.
16 Yoon KA,Kim MK,Eom HS,et al.Adverse prognostic impact of vascular endothelial growth factor gene polymorphisms in patients with diffuse large B-cell lymphoma.Leukemia.Lymphoma,2017;58(11):2677-2682.
17 Nedoszytko B,Olszewska B,Roszkiewicz J,et al.The role of polymorphism of interleukin-2,-10,-13 and TNF-αgenes in cutaneous T-cell lymphoma pathogenesis.Adv Dermatol Allergol,2016;33(6):429-434.
18 Liu D,Wu N Sun H,et al.ABCG2 and NCF4 polymorphisms are associated with clinical outcomes in diffuse large B-cell lymphoma patients treated with R-CHOP.Oncotarget,2017;8(35):58292-58303.
19 Delamain MT,Miranda ECM,Lourenco GJ,et al.Through translational prospective study,the GSTP1 Ile105Val polymorphism emerges as prognostic marker in de novo large B-cell lymphoma patients.Blood Cancer J,2017;7(4):e560.
20 Fragkioudaki S,Nezos A,Souliotis VL,et al.MTHFR gene variants and non-MALT lymphoma development in primary Sjogren's syndrome.SCI Rep,2017;7(1):7354.
21高宇,魏楠,李梦洁,等.XRCC1基因多态性与弥漫大B细胞型非霍奇金淋巴瘤预后的关系.浙江医学,2016,38(12):932-935.
22 Bahceci A,Paydas S,Tanriverdi K,et al.DNA repair gene polymorphisms in B cell non-Hodgkin's lymphoma.Tumour Biol,2015;36(3):2155-2161.
23 Hassler MR,Pulverer W,Lakshminarasimhan R,et al.Insights into the pathogenesis of anaplastic large-cell lymphoma through genomewide DNA methylation profiling.Cell Rep,2016;17(2):596-608.
24 Frazzi R,Zanetti E,Pistoni M,et al.Methylation changes of SIRT1,KLF4,DAPK1 and SPG20 in B-lymphocytes derived from follicular and diffuse large B-cell lymphoma.Leuk Res,2017;57:89-96.
25 Ding K,Chen X,Wang Y,et al.Plasma DNA methylation of p16and shp1 in patients with B cell non-Hodgkin lymphoma.Int J Clin Oncol,2017;22(3):585-592.
26 Blakemore SJ,Daigle SR,Mcdonald AA,et al.Preliminary evidence of a molecular predictor of tazemetostat response,beyond EZH2 mutation,in NHL patients via characterization of archive tumor and circulating tumor DNA.Hematol Oncol,2017,35(S2):159-160.
27 Brach D,Johnston-Blackwell D,Drew A,et al.EZH2 inhibition by tazemetostat results in altered dependency on B-cell activation signaling in DLBCL.Mol Cancer Ther,2017;16(11):2586-2597.
28 Lin XJ,Cai LM,Qian ZJ,et al.Increased histone deacetylase 6 expression serves as a favorable prognostic factor for diffuse large B-cell lymphoma.Onco Targets Ther,2017;10:5129-5136.
29 Chen R,Frankel P,Popplewell L,et al.A phase II study of vorinostat and rituximab for treatment of newly diagnosed and relapsed/refractory indolent non-Hodgkin lymphoma.Haematologica,2015;100(3):357.
30 Liu K,Du J,Ruan L.MicroRNA-21 regulates the viability and apoptosis of diffuse large B-cell lymphoma cells by upregulating B cell lymphoma-2.Exp Ther Med,2017;14(5):4489-4496.
31姜丽,朱尊民,周放,等.miR-125b靶向Sema4C调控STAT3信号通路影响非霍奇金淋巴瘤的侵袭迁移.中国免疫学杂志,2017;33(7):1018-1022.
32赵桂敏,刁兰萍,刘丽宏,等.MicroRNA生物合成通路中Gemin3基因单核苷酸多态性与非霍奇金淋巴瘤风险及预后相关性.中国实验血液学杂志,2017;25(4):1053-1057.
33 Kozloski GA,Jiang X,Bhatt S,et al.miR-181a negatively regulates NF-κB signaling and affects activated B-cell-like diffuse large B-cell lymphoma pathogenesis.Blood,2016;127(23):2856-2866.
34 Battistella M,Romero M,Castro-Vega LJ,et al.The high expression of the microRNA 17-92 cluster and its paralogs,and the downregulation of the target gene PTEN,is associated with primary cutaneous B-cell lymphoma progression.J Invest Dermatol,2015;135(6):1659-1667.
35 Blunt MD,Steele AJ.Releasing the brakes on BTK-targeting miR-NA.Blood,2016;128(26):3023-3024.
2辛丽君,杨波,卢学春,等.高龄进展期弥漫大B细胞淋巴瘤分子亚型对预后及治疗影响-1例分析.中国实验血液学杂志,2016;24(2):457-462.
3 Veldman-Jones MH,Lai Z,Wappett M,et al.Reproducible,quantitative and flexible molecular sub-typing of clinical DLBCL samples using the Nano String nCounter system.Clin Cancer Res,2015;21(10):2367-2378.
4 Rosenthal A,Younes A.High grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6:Double hit and triple hit lymphomas and double expressing lymphoma.Blood Rev,2017;31(2):37-42.
5 Kim H,Kim IS,Lee EY,et al.First case of diffuse large B-cell lymphoma subtype of monomorphic post-transplant lymphoproliferative disorder with 3q27 translocation.Ann Lab Med,2016;36(4):380-383.
6 Batmanov K,Wang W,Bjors M,et al.Integrative whole-genome sequence analysis reveals roles of regulatory mutations in BCL6 and BCL2 in follicular lymphoma.Sci Rep,2017;7(1):7040.
7 Kallen ME,Kim Y,Yang L,et al.A Cryptic t(11;14)translocation in mantle cell lymphoma highlights the importance of FISH.JAssoc Genet Technol,2015;41(1):13-16.
8 Du MQ.MALT lymphoma:Genetic abnormalities,immunological stimulation and molecular mechanism.Best Pract Res Clin Haematol,2017;30(1-2):13-23.
9 Schmidt J,Bonzheim I,Steinhilber J,et al.EMMPRIN(CD147)is induced by C/EBPβand is differentially expressed in ALK+and ALK-anaplastic large-cell lymphoma.Lab I Investi,2017;97(9):1095-1102.
10冯江龙,杨文秀,王佳蕊,等.A20基因缺失对弥漫大B细胞淋巴瘤P-gp表达影响.中华肿瘤防治杂志,2017;24(11):750-754.
11 Ma Y,Zhang P,Gao Y,et al.Evaluation of AKT phosphorylation and PTEN loss and their correlation with the resistance of rituximab in DLBCL.Int J Clin Exp Pathol,2015;8(11):14875-14884.
12 Tanaka T,Nakajima-Takagi Y,Aoyama K,et al.Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies.J Exp Med,2017;214(10):2901-2913.
13郭晓静,成志强,金红涛,等.c-myc和Ki-67在结外鼻型NK/T细胞淋巴瘤中的表达及与临床的关系.诊断病理学杂志,2017;24(7):517-520.
14 Li G,Li D.Relationship between IL-10 gene polymorphisms and the risk of non-Hodgkin lymphoma:A meta-analysis.Hum Immunol,2016;77(5):418-425.
15田彩平,廖世奇,袁红霞,等.炎症相关因子基因多态性与弥漫大B细胞淋巴瘤的易感性研究.中国实验血液学杂志,2017;25(2):444-448.
16 Yoon KA,Kim MK,Eom HS,et al.Adverse prognostic impact of vascular endothelial growth factor gene polymorphisms in patients with diffuse large B-cell lymphoma.Leukemia.Lymphoma,2017;58(11):2677-2682.
17 Nedoszytko B,Olszewska B,Roszkiewicz J,et al.The role of polymorphism of interleukin-2,-10,-13 and TNF-αgenes in cutaneous T-cell lymphoma pathogenesis.Adv Dermatol Allergol,2016;33(6):429-434.
18 Liu D,Wu N Sun H,et al.ABCG2 and NCF4 polymorphisms are associated with clinical outcomes in diffuse large B-cell lymphoma patients treated with R-CHOP.Oncotarget,2017;8(35):58292-58303.
19 Delamain MT,Miranda ECM,Lourenco GJ,et al.Through translational prospective study,the GSTP1 Ile105Val polymorphism emerges as prognostic marker in de novo large B-cell lymphoma patients.Blood Cancer J,2017;7(4):e560.
20 Fragkioudaki S,Nezos A,Souliotis VL,et al.MTHFR gene variants and non-MALT lymphoma development in primary Sjogren's syndrome.SCI Rep,2017;7(1):7354.
21高宇,魏楠,李梦洁,等.XRCC1基因多态性与弥漫大B细胞型非霍奇金淋巴瘤预后的关系.浙江医学,2016,38(12):932-935.
22 Bahceci A,Paydas S,Tanriverdi K,et al.DNA repair gene polymorphisms in B cell non-Hodgkin's lymphoma.Tumour Biol,2015;36(3):2155-2161.
23 Hassler MR,Pulverer W,Lakshminarasimhan R,et al.Insights into the pathogenesis of anaplastic large-cell lymphoma through genomewide DNA methylation profiling.Cell Rep,2016;17(2):596-608.
24 Frazzi R,Zanetti E,Pistoni M,et al.Methylation changes of SIRT1,KLF4,DAPK1 and SPG20 in B-lymphocytes derived from follicular and diffuse large B-cell lymphoma.Leuk Res,2017;57:89-96.
25 Ding K,Chen X,Wang Y,et al.Plasma DNA methylation of p16and shp1 in patients with B cell non-Hodgkin lymphoma.Int J Clin Oncol,2017;22(3):585-592.
26 Blakemore SJ,Daigle SR,Mcdonald AA,et al.Preliminary evidence of a molecular predictor of tazemetostat response,beyond EZH2 mutation,in NHL patients via characterization of archive tumor and circulating tumor DNA.Hematol Oncol,2017,35(S2):159-160.
27 Brach D,Johnston-Blackwell D,Drew A,et al.EZH2 inhibition by tazemetostat results in altered dependency on B-cell activation signaling in DLBCL.Mol Cancer Ther,2017;16(11):2586-2597.
28 Lin XJ,Cai LM,Qian ZJ,et al.Increased histone deacetylase 6 expression serves as a favorable prognostic factor for diffuse large B-cell lymphoma.Onco Targets Ther,2017;10:5129-5136.
29 Chen R,Frankel P,Popplewell L,et al.A phase II study of vorinostat and rituximab for treatment of newly diagnosed and relapsed/refractory indolent non-Hodgkin lymphoma.Haematologica,2015;100(3):357.
30 Liu K,Du J,Ruan L.MicroRNA-21 regulates the viability and apoptosis of diffuse large B-cell lymphoma cells by upregulating B cell lymphoma-2.Exp Ther Med,2017;14(5):4489-4496.
31姜丽,朱尊民,周放,等.miR-125b靶向Sema4C调控STAT3信号通路影响非霍奇金淋巴瘤的侵袭迁移.中国免疫学杂志,2017;33(7):1018-1022.
32赵桂敏,刁兰萍,刘丽宏,等.MicroRNA生物合成通路中Gemin3基因单核苷酸多态性与非霍奇金淋巴瘤风险及预后相关性.中国实验血液学杂志,2017;25(4):1053-1057.
33 Kozloski GA,Jiang X,Bhatt S,et al.miR-181a negatively regulates NF-κB signaling and affects activated B-cell-like diffuse large B-cell lymphoma pathogenesis.Blood,2016;127(23):2856-2866.
34 Battistella M,Romero M,Castro-Vega LJ,et al.The high expression of the microRNA 17-92 cluster and its paralogs,and the downregulation of the target gene PTEN,is associated with primary cutaneous B-cell lymphoma progression.J Invest Dermatol,2015;135(6):1659-1667.
35 Blunt MD,Steele AJ.Releasing the brakes on BTK-targeting miR-NA.Blood,2016;128(26):3023-3024.