药物相关性分子靶标检测在儿童恶性实体肿瘤个体化治疗中的初步研究
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摘要
目的初步探讨药物相关性分子靶标检测在儿童恶性实体肿瘤个体化治疗中的临床意义。方法选择2014年2月至2017年3月期间于重庆医科大学附属儿童医院诊治的150例恶性实体肿瘤患儿,取其手术肿瘤组织标本150份,通过免疫组织化学(IHC)或聚合酶链式反应(PCR)测序的方法检测肿瘤药物相关性分子靶标的表达或突变,并根据靶标对应的药物分别比较间叶来源和非间叶来源的肿瘤,霍奇金淋巴瘤(Hodgkin lymphoma,HL)和非霍奇金淋巴瘤(non-Hodgkin lymphoma,NHL),神经母细胞瘤(neuroblastoma,NB)和肝母细胞瘤(hepatoblastoma,HB)对常见化疗药物的敏感性及毒副作用有无差异。结果 (1)共检测肿瘤标本化疗药物相关性分子靶标15个,包括:人切除修复交叉互补基因1(ERCC1),DNA拓扑异构酶I(TOPO I),DNA拓扑异构酶ⅡA(TOPOⅡA),DNA修复蛋白O6-甲基转移酶(MGMT),微管蛋白β3(tubulinβ3),胸苷酸合成酶(TS),CYP2C19~*2,二氢叶酸还原酶[DHFR(C829T)],尿苷二磷酸-葡萄糖醛酸基转移酶(l UGT1A1~*28),CYP2B6~*6,亚甲基四氢叶酸还原酶[MTHFR(C677T)],巯嘌呤甲基转移酶[TPMT(A719G)],TPMT(G238C),二氢嘧啶脱氢酶[DPYD~*2A(14+1G>A)]和DPYD~*9(T85C)基因的表达或多态性。(2)根据靶标对应的相关药物进行分析,得出常用不同化疗药物在儿童恶性实体肿瘤中的总体敏感率及毒副反应情况:甲氨蝶呤敏感占100.0%,替莫唑胺/卡莫司汀/司莫司汀敏感占66.7%,蒽环类/依托泊苷、氟尿嘧啶敏感占52.2%,铂类敏感占52.1%,长春碱类敏感占51.6%,伊立替康/拓扑替康不敏感占81.5%,环磷酰胺不敏感占53.7%;甲氨蝶呤毒副反应弱占90.0%,巯嘌呤毒副反应弱占87.5%,环磷酰胺毒副反应弱占73.8%,氟尿嘧啶毒副反应弱占64.3%,伊立替康/依托泊苷毒副反应弱占55.6%。(3)不同来源、不同病理类型的儿童恶性实体肿瘤对同一化疗药物敏感性的差异比较:间叶源性肿瘤较非间叶源性肿瘤对伊立替康/拓扑替康敏感性较高(P<0.001),NHL较HL对蒽环类/依托泊苷敏感性较高(P<0.001),HB较NB对铂类(P=0.011)和长春碱类敏感性较高(P=0.018),差异均有统计学意义。结论本研究系统性检测了儿童常见恶性实体肿瘤药物相关性分子靶标的表达或多态性,根据检测结果预测药物敏感性及毒副作用,为儿童恶性实体肿瘤化疗方案的制定提供了循证学依据及进一步为个体化用药提供了指导。
Objective To preliminarily explore the clinical significance of drug-related genomic markers for individualized therapy in children with common malignant solid tumors. Methods Surgical specimens in 150 children with malignant solid tumor were collected between February 2014 and March 2017. The drug-related genomic markers were examined by immunohistochemical staining and polymerase chain reaction sequencing. According to identification of genomic markers,we compared the differences of sensitivity and toxicity to common chemotherapeutic agents between mesenchymal and non-mesenchymal tumors,Hodgkin lymphoma( HL) and non-Hodgkin lymphoma( NHL),neuroblastoma( NB) and hepatoblastoma( HB) respectively. Results (1)Fifteen genomic markers of anti-neoplastic agents correlations were examined,including gene expression or mutation of excision repair cross-complementing 1( ERCC1),topoisomerase I( TOPOI),topoisomerase Ⅱ A( TOPO ⅡA),O6-methylguanine-DNA methyltransferase( MGMT),tubulin β3,thymidylate synthase( TS),CYP2 C19 ~* 2,dihydrofolate reductase( DHFR C829T),UDP-glucuronosyltransferase1( UGT1 A1 ~* 28),CYP2B6~* 6,methylene tetrahydrofolate reductase( MTHFR C677T),thiopurine S-methyltransferase( TPMT A719G),TPMT G238C,dihydropyrimidine dehydrogenase( DPYD ~* 2A14 + 1G > A),DPYD ~* 9T85C.(2) Among examined specimens,100% were of methotrexate sensitivity and 66. 7% had temozolomide/carmustine/semustine sensitivity,52. 2% anthracycline/etoposide and fluorouracil sensitivity,52. 1% platinum sensitivity and 51. 6% vincristine sensitivity. While 81. 5% had no sensitivity to irinotecan/topotecan,53. 7% non-sensitivity to cyclophosphamide. 90. 0% weak toxicity to methotrexate,73. 8% weak toxicity to cyclophosphamide,64. 3% weak toxicity to fluorouracil and 55. 6% weak toxicity to irinotecan/etoposide.(3)Mesenchymal tumors had higher sensitivity to irinotecan/topotecan than non-mesenchymal tumors( P = 0. 000); NHL had higher sensitivity to anthracycline/etoposide than HL( P = 0. 000),HB had higher sensitivity to platinum( P = 0. 011) and vincristine( P = 0. 018) than NB. Based upon the above test results,therapeutic strategies for poor responders were promptly adjusted and then they achieved preliminary effect. Conclusion Genomic markers of drug sensitivity or toxicity are examined in children with malignant solid tumors. It provides rationales of formulating personalized chemotherapeutic regimens.
Objective To preliminarily explore the clinical significance of drug-related genomic markers for individualized therapy in children with common malignant solid tumors. Methods Surgical specimens in 150 children with malignant solid tumor were collected between February 2014 and March 2017. The drug-related genomic markers were examined by immunohistochemical staining and polymerase chain reaction sequencing. According to identification of genomic markers,we compared the differences of sensitivity and toxicity to common chemotherapeutic agents between mesenchymal and non-mesenchymal tumors,Hodgkin lymphoma( HL) and non-Hodgkin lymphoma( NHL),neuroblastoma( NB) and hepatoblastoma( HB) respectively. Results (1)Fifteen genomic markers of anti-neoplastic agents correlations were examined,including gene expression or mutation of excision repair cross-complementing 1( ERCC1),topoisomerase I( TOPOI),topoisomerase Ⅱ A( TOPO ⅡA),O6-methylguanine-DNA methyltransferase( MGMT),tubulin β3,thymidylate synthase( TS),CYP2 C19 ~* 2,dihydrofolate reductase( DHFR C829T),UDP-glucuronosyltransferase1( UGT1 A1 ~* 28),CYP2B6~* 6,methylene tetrahydrofolate reductase( MTHFR C677T),thiopurine S-methyltransferase( TPMT A719G),TPMT G238C,dihydropyrimidine dehydrogenase( DPYD ~* 2A14 + 1G > A),DPYD ~* 9T85C.(2) Among examined specimens,100% were of methotrexate sensitivity and 66. 7% had temozolomide/carmustine/semustine sensitivity,52. 2% anthracycline/etoposide and fluorouracil sensitivity,52. 1% platinum sensitivity and 51. 6% vincristine sensitivity. While 81. 5% had no sensitivity to irinotecan/topotecan,53. 7% non-sensitivity to cyclophosphamide. 90. 0% weak toxicity to methotrexate,73. 8% weak toxicity to cyclophosphamide,64. 3% weak toxicity to fluorouracil and 55. 6% weak toxicity to irinotecan/etoposide.(3)Mesenchymal tumors had higher sensitivity to irinotecan/topotecan than non-mesenchymal tumors( P = 0. 000); NHL had higher sensitivity to anthracycline/etoposide than HL( P = 0. 000),HB had higher sensitivity to platinum( P = 0. 011) and vincristine( P = 0. 018) than NB. Based upon the above test results,therapeutic strategies for poor responders were promptly adjusted and then they achieved preliminary effect. Conclusion Genomic markers of drug sensitivity or toxicity are examined in children with malignant solid tumors. It provides rationales of formulating personalized chemotherapeutic regimens.
引文
1 Blom K,Nygren P,Larsson R,et al.Predictive value of exvivo chemosensitivity assays for individualized cancer chemotherapy[J].SLAS Technol,2017,22(3):306-314.DOI:10.1177/2472630316686297.
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6王奕,吴晔明,张弛,等.药物相关性分子靶标检测在指导Ⅲ-Ⅳ期儿童神经母细胞瘤治疗中的初步经验[J].中华小儿外科杂志,2016,37(4):277-281.DOI:10.3760/cma.j.issn.0253-3006.2016.04.009.Wang Y,Wu YM,Zhang C,et al.Primary identification of genomic markers of drug sensitivity for individualized therapy in children with neuroblastoma ofⅢ-IV stage[J].Chinese Journal of Pediatric Surgery,2016,37(4):277-281.DOI:10.3760/cma.j.issn.0253-3006.2016.04.009.
7蒋马伟,吴晔明,周仁华,等.药物相关分子靶标检测在儿童颅外恶性实体瘤38例个体化治疗中的应用[J].中华实用儿科临床杂志,2014,29(14):1107-1111.DOI:10.3760/cma.j.issn.2095-428X.2014.14.017.Jiang MW,Wu YM,Zhou RH,et al.Primary identification of genomic markers of drug sensitivity for individualized therapy in 38 children with extra-cranial malignant solid tumors[J].Chinese Journal of Applied Pediatrics,2014,29(14):1107-1111.DOI:10.3760/cma.j.issn.2095-428X.2014.14.017.
8 Modak S,Cheung NK.Neuroblastoma:therapeutic strategies for a clinical enigma[J].Cancer Treat Rev,2010,36(4):307-317.DOI:10.1016/j.ctrv.2010.02.006.
9 Ferrari A,De Salvo GL,Brennan B,et al.Synovial sarcoma in children and adolescents:the European pediatric Soft tissue sarcoma Study Group prospective trial(Ep SSG NRSTS2005)[J].Ann Oncol,2015,26(3):567-572.DOI:10.1093/annonc/mdu562.
10 Katzenstein HM,Furman WL,Malogolowkin MH,et al.Upfront window vincristine/irinotecan treatment of high-risk hepatoblasto-ma:A report from the Children’s Oncology Group AHEP0731 study committee[J].Cancer,2017,123(12):2360-2367.DOI:10.1002/cncr.30591.
11 Thomas A,Tanaka M,Trepel J,et al.Temozolomide in the era of precision medicine[J].Cancer Res,2017,77(4):823-826.DOI:10.1158/0008-5472.CAN-16-2983.
12 Zhang X,Sun B,Lu Z.Evaluation of clinical value of single nucleotide polymorphisms of dihydropyrimidine dehydrogenase gene to predict 5-fluorouracil toxicity in 60 colorectal cancer patients in China[J].Int J Med Sci,2013,10(7):894-902.DOI:10.7150/ijms.5556.
13 Wang W,Huang J,Tao Y,et al.PhaseⅡand UGT1A1polymorphism study of two different irinotecan dosages combined with cisplatin as first-line therapy for advanced gastric cancer[J].Chemotherapy,2016,61(4):197-203.DOI:10.1159/000442787.
14中华医学会儿科学分会血液学组.儿童霍奇金淋巴瘤的诊疗建议[J].中华儿科杂志,2014,52(8):586-589.Hematology Group of Chinese Medical Association.Recommendations on diagnosis and t reatment of Hodgkin’s lymphoma in children[J].Chinese Journal of Pediatrics Surgery,2014,52(8):586-589.
15中华医学会儿科学分会血液学组.儿童非霍奇金淋巴瘤诊疗建议[J].中华儿科杂志,2011,49(3):186-192.Hematology Group of Chinese Medical Association.Diagnosis and treatment of non-Hodgkin's lymphoma in children[J].Chinese Journal of Pediatrics Surgery,2011,49(3):186-192.
16 Yuan X J,Wang HM,Jiang H,et al.Multidisciplinary effort in treating children with hepatoblastoma in China[J].Cancer Lett,2016,375(1):39-46.DOI:10.1016/j.canlet.2016.02.051.
17 Pinto NR,Applebaum MA,Volchenboum SL,et al.Advances in risk classification and treatment strategies for neuroblastoma[J].J Clin Oncol,2015,33(27):3008-3017.DOI:10.1200/JCO.2014.59.4648.
2 Garnett MJ,Edelman EJ,Heidorn SJ,et al.Systematic identification of genomic markers of drug sensitivity in cancer cells[J].Nature,2012,483(7391):570-575.DOI:10.1038/nature11005.
3 Sudhindra A,Ochoa R,Santos ES.Biomarkers,prediction,and prognosis in non-small-cell lung cancer:a platform for personalized treatment[J].Clin Lung Cancer,2011,12(6):360-368.DOI:10.1016/j.cllc.2011.02.003.
4 Langer CJ.Individualized therapy for patients with nonsmall cell lung cancer:Emerging trends and challenges[J].Crit Rev Oncol Hematol,2012,83(1):130-144.DOI:10.1016/j.critrevonc.2011.09.004.
5 Guo CB,Wang S,Deng C,et al.Relationship between matrix metalloproteinase 2 and lung cancer progression[J].Mol Diagn Ther,2007,11(3):183-192.
6王奕,吴晔明,张弛,等.药物相关性分子靶标检测在指导Ⅲ-Ⅳ期儿童神经母细胞瘤治疗中的初步经验[J].中华小儿外科杂志,2016,37(4):277-281.DOI:10.3760/cma.j.issn.0253-3006.2016.04.009.Wang Y,Wu YM,Zhang C,et al.Primary identification of genomic markers of drug sensitivity for individualized therapy in children with neuroblastoma ofⅢ-IV stage[J].Chinese Journal of Pediatric Surgery,2016,37(4):277-281.DOI:10.3760/cma.j.issn.0253-3006.2016.04.009.
7蒋马伟,吴晔明,周仁华,等.药物相关分子靶标检测在儿童颅外恶性实体瘤38例个体化治疗中的应用[J].中华实用儿科临床杂志,2014,29(14):1107-1111.DOI:10.3760/cma.j.issn.2095-428X.2014.14.017.Jiang MW,Wu YM,Zhou RH,et al.Primary identification of genomic markers of drug sensitivity for individualized therapy in 38 children with extra-cranial malignant solid tumors[J].Chinese Journal of Applied Pediatrics,2014,29(14):1107-1111.DOI:10.3760/cma.j.issn.2095-428X.2014.14.017.
8 Modak S,Cheung NK.Neuroblastoma:therapeutic strategies for a clinical enigma[J].Cancer Treat Rev,2010,36(4):307-317.DOI:10.1016/j.ctrv.2010.02.006.
9 Ferrari A,De Salvo GL,Brennan B,et al.Synovial sarcoma in children and adolescents:the European pediatric Soft tissue sarcoma Study Group prospective trial(Ep SSG NRSTS2005)[J].Ann Oncol,2015,26(3):567-572.DOI:10.1093/annonc/mdu562.
10 Katzenstein HM,Furman WL,Malogolowkin MH,et al.Upfront window vincristine/irinotecan treatment of high-risk hepatoblasto-ma:A report from the Children’s Oncology Group AHEP0731 study committee[J].Cancer,2017,123(12):2360-2367.DOI:10.1002/cncr.30591.
11 Thomas A,Tanaka M,Trepel J,et al.Temozolomide in the era of precision medicine[J].Cancer Res,2017,77(4):823-826.DOI:10.1158/0008-5472.CAN-16-2983.
12 Zhang X,Sun B,Lu Z.Evaluation of clinical value of single nucleotide polymorphisms of dihydropyrimidine dehydrogenase gene to predict 5-fluorouracil toxicity in 60 colorectal cancer patients in China[J].Int J Med Sci,2013,10(7):894-902.DOI:10.7150/ijms.5556.
13 Wang W,Huang J,Tao Y,et al.PhaseⅡand UGT1A1polymorphism study of two different irinotecan dosages combined with cisplatin as first-line therapy for advanced gastric cancer[J].Chemotherapy,2016,61(4):197-203.DOI:10.1159/000442787.
14中华医学会儿科学分会血液学组.儿童霍奇金淋巴瘤的诊疗建议[J].中华儿科杂志,2014,52(8):586-589.Hematology Group of Chinese Medical Association.Recommendations on diagnosis and t reatment of Hodgkin’s lymphoma in children[J].Chinese Journal of Pediatrics Surgery,2014,52(8):586-589.
15中华医学会儿科学分会血液学组.儿童非霍奇金淋巴瘤诊疗建议[J].中华儿科杂志,2011,49(3):186-192.Hematology Group of Chinese Medical Association.Diagnosis and treatment of non-Hodgkin's lymphoma in children[J].Chinese Journal of Pediatrics Surgery,2011,49(3):186-192.
16 Yuan X J,Wang HM,Jiang H,et al.Multidisciplinary effort in treating children with hepatoblastoma in China[J].Cancer Lett,2016,375(1):39-46.DOI:10.1016/j.canlet.2016.02.051.
17 Pinto NR,Applebaum MA,Volchenboum SL,et al.Advances in risk classification and treatment strategies for neuroblastoma[J].J Clin Oncol,2015,33(27):3008-3017.DOI:10.1200/JCO.2014.59.4648.