目的：探究RB1基因的突变类型对遗传性视网膜母细胞瘤（RB）第二原发性恶性肿瘤（SPM）发生的影响。方法：从2000年到2010年，本研究共纳入在院就诊的经治疗后存活的98例RB患者，所有患者都进行了RB1基因突变的检测。出院后随访10年，探究RB1基因突变的类型、放射治疗（放疗）及其他因素对SPM发生的影响。结果：98例RB患者中有10例患者在随访中发生SPM。分别有78例和20例患者有RB蛋白表达突变和RB蛋白缺失突变，在COx多因素危险因素模型中，行放疗（HR=1.78，95%CI=1.19~3.28，P=0.022）和RB蛋白缺失的基因突变类型（HR=1.83，95%CI=1.12~2.97，P=0.025）是SPM发生的独立危险因素。所有入组患者中RB蛋白表达突变类型患者的10年累计发病率为6.7%，而RB蛋白缺失突变类型患者的10年累计发病率为12.3%，两组差异具有统计学意义（P=0.024）。对放疗和未放疗患者进行亚组分析，两种突变类型患者在放疗亚组中差异无统计学意义（P=0.853），而在未放疗亚组中，RB产生的突变的SPM发病率要显著低于RB缺失的发病率（P=0.015）。结论：RB1变异的不同类型与儿童RB治疗后SPM的发生风险之间存在显著的相关性，能够导致RB蛋白缺失的突变类型会显著增加患者SPM的发生，此外，放疗对RB治疗后SPM发生有显著的影响，在RB治疗时应优先选择其他治疗方法。

[1] FERNANDES A G, POLLOCK B D, RABITO F A.Retinoblastoma in the United States:a 40-year incidence and survival analysis[J]. J Pediatr Ophthalmol Strabismus, 2017, 55(3):1-7.
[2] 黄东生, 张谊.儿童视网膜母细胞瘤[J]. 中国实用儿科杂志, 2018, 33(10):757-762.
[3] 陆烨, 童剑萍.视网膜母细胞瘤的发生机制及诊断和治疗进展[J]. 现代肿瘤医学, 2016, 24(6):1007-1014.
[4] MEHYAR M, MOSALLAM M, TBAKHI A, et al. Impact of RB1 gene mutation type in retinoblastoma patients on clinical presentation and management outcome[J]. Hematol Oncol Stem Cell Ther, 2020, 13(3):152-159.
[5] KIET N C, KHUONG L T, MINH D D, et al. RB1 Spectrum of mutations in the gene in Vietnamese patients with retinoblastoma[J]. Mol Vis, 2019, 25(4):215-221.
[6] DENG X Y, IWAGAWA T, FUKUSHIMA M, et al. Characterization of human-induced pluripotent stem cells carrying homozygous RB1 gene deletion[J]. Genes Cells, 2020, 25(7):510-517.
[7] SHINOHARA E T, DEWEES T, PERKINS S M.Subsequent malignancies and their effect on survival in patients with retinoblastoma[J]. Pediatr Blood Canc, 2014, 61(1):116-119.
[8] TEMMING P, ARENDT M, VIEHMANN A, et al. How eye-preserving therapy affects longterm overall survival in heritable retinoblastoma survivors[J]. J Clin Oncol, 2016, 34(26):3183-3188.
[9] 罗彩怡, 罗婷, 向中正.视网膜母细胞瘤诊疗进展[J]. 华西医学, 2017, 32(9):1459-1463.
[10] Jiménez I, Laé M, Tanguy M L, et al. Craniofacial second primary tumors in patients with germline retinoblastoma previously treated with external beam radiotherapy:a retrospective institutional analysis[J]. Pediatr Blood Cancer, 2020, 67:e28158.
[11] TEMMING P, ARENDT M, VIEHMANN A, et al. Incidence of second cancers after radiotherapy and systemic chemotherapy in heritable retinoblastoma survivors:a report from the German reference center[J]. Pediatr Blood Canc, 2017, 64(1):71-80.
[12] CHAUSSADE A, MILLOT G, WELLS C, et al. Correlation between RB1germline mutations and second primary malignancies in hereditary retinoblastoma patients treated with external beam radiotherapy[J]. Eur J Med Genet, 2019, 62(3):217-223.
[13] 孟庆娱, 黄旅珍, 王斌, 等.基因捕获技术在视网膜母细胞瘤患者RB1基因突变筛选的应用[J]. 中华眼科杂志, 2017, 53(6):455-459.
[14] KAMIHARA J, BOURDEAUT F, FOULKES W D, et al. Retinoblastoma and neuroblastoma predisposition and surveillance[J]. Clin Canc Res:an Off J Am Assoc Cancer Res, 2017, 23(13):e98-e106.
[15] WOOD M E, REHMAN H T, BEDROSIAN I.Importance of family history and indications for genetic testing[J]. Breast J, 2020, 26(1):100-104.
[16] KLEINERMAN R A, YU C L, LITTLE M P, et al. Variation of second cancer risk by family history of retinoblastoma among long-term survivors[J]. J Clin Oncol, 2012, 30(9):950-957.
[17] SIPPEL K C, FRAIOLI R E, SMITH G D, et al. Frequency of somatic and germ-line mosaicism in retinoblastoma:implications for genetic counseling[J]. Am J Hum Genet, 1998, 62(3):610-619.
[18] YOUSEF Y A, MOHAMMAD M, JARADAT I, et al. Prognostic factors for eye globe salvage by external beam radiation therapy for resistant intraocular retinoblastoma[J]. Oman J Ophthalmol, 2020, 13(3):123-128.