Email Alert | RSS

北京大学学报（医学版） ›› 2019, Vol. 51 ›› Issue (1): 4-5. doi: 10.19723/j.issn.1671-167X.2019.01.002

• 论著 • 上一篇    下一篇

成釉细胞纤维瘤中BRAF突变基因的检测

尤柱1,2,徐丽莉3,李雪芬1,张建运4,杜菁2,孙丽莎1,△()   

  1. 1. 北京大学口腔医学院·口腔医院,中心实验室　国家口腔疾病临床医学研究中心　口腔数字化医疗技术和材料国家工程实验室　口腔数字医学北京市重点实验室, 北京　100081
    2. 山东大学口腔医学院口腔颌面外科, 济南　250012
    3. 北京大学口腔医学院·口腔医院第二门诊部, 北京　100101
    4. 北京大学口腔医学院·口腔医院病理科, 北京　100081
  • 收稿日期:2018-10-11 出版日期:2019-02-18 发布日期:2019-02-26
  • 通讯作者: 孙丽莎 E-mail:lisa_sun@bjmu.edu.cn
  • 基金资助:
    国家自然科学基金(30901680);北京大学医学科技创新平台发展基金(BMU2018PY023)

BRAF gene mutations in ameloblastic fibromas

Zhu YOU1,2,Li-li XU3,Xue-fen LI1,Jian-yun ZHANG4,Jing DU2,Li-sha SUN1,△()   

  1. 1. Department of Central Laboratory, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China
    2. Department of Oral and Maxillofacial Surgery, School of Stomatology, Shandong University, Jinan 250012, China
    3. Second Clinical Division, Peking University School and Hospital of Stomatology, Beijing 100081, China
    4. Department of Oral Pathology, Peking University School and Hospital of Stomatology, Beijing 100081, China
  • Received:2018-10-11 Online:2019-02-18 Published:2019-02-26
  • Contact: Li-sha SUN E-mail:lisa_sun@bjmu.edu.cn
  • Supported by:
    Supported by the National Natural Science Foundation of China(30901680);and the Fund for Fostering Young Scholars of Peking University Health Science Center(BMU2018PY023)

RICH HTML

   

PDF (PC)

摘要：

目的:检测BRAF基因在成釉细胞纤维瘤(ameloblastic fibroma, AF)中的突变情况,进一步分析该突变与AF的临床表现之间的关系,以期为寻求AF的靶向治疗提供新方法。方法:收集2002年1月至2015年12月期间北京大学口腔医院诊断为AF的病例16例。AF石蜡包埋组织经切片后进行苏木精伊红染色,由两名病理科专家确认病例选取的准确性,按照DNA提取试剂盒使用说明提取组织DNA。对BRAF V600E位点进行PCR扩增,采用直接测序的方法进行BRAF V600E的突变检测,并进一步分析16例AF的临床资料。结果:16例AF患者中包括7例男性,9例女性;3例发生于上颌,13例发生于下颌;入院年龄为2~67岁(中位年龄14.5岁)。病变常表现为无痛性肿胀,生长缓慢。16例AF均携带BRAF基因突变,突变率为100%(16/16), 均为15号外显子上V600E突变型(c.1799T>A),导致在氨基酸水平上由缬氨酸变为谷氨酸,从而使胸腺嘧啶转化为腺苷酸。现有病例表明BRAF突变与AF的年龄、性别、发病部位和复发等无相关性。结论:AF中存在BRAF V600E位点的高突变率,提示BRAF V600E突变可能成为AF发生发展的关键事件,同时为AF患者应用BRAF抑制剂进行靶向治疗提供了一定的理论支持,其病理学意义有待进一步研究。

关键词: 成釉细胞纤维瘤, BRAF基因突变, 靶向治疗

Abstract:

Objective: To investigate the BRAF gene mutations in ameloblastic fibroma (AF), and to further analyze the relationship between the BRAF mutation and clinical characteristics so as to provide new reference to the study of AF’s molecular pathology. Methods: Sixteen cases diagnosed as AF at the Department of Oral Pathology, Peking University School of Stomatology between January 1990 and December 2017 were collected. Genomic DNA was extracted from formalin-fixed, paraffin embedded tissues using the QIAamp DNA Mini Kit (Qiagen, Germany) according to the manufacturer’s instructions. Polymerase chain reaction (PCR) and direct sequencings were used to detect the BRAF gene mutations. The clinicopathological data, such as the age, location of the lesion, symptoms and treatments were retrospectively analyzed. Results: The sixteen cases of AF involved nine women and seven men aged 2-67 years. Three lesions occurred in the maxilla and thirteen in the mandible. The most common presenting symptom of AF was a painless slowly enlarging mass with swelling. Ten patients received conservative treatment and the other six patients received radical surgery. Three cases relapsed during the study period. BRAF gene mutation was found in sixteen of all the sixteen samples analyzed (100%). The BRAF mutation was a point mutation with a thymine-adenine transversion at nucleotide 1 799 of 15 exons, resulting in a change at residue 600 that substituted glutamine for valine. This mutation was the strongest activator of the downstream RAS/RAF/MEK/ERK-MAPK signaling pathway. This helped to bring about a gain-of-function mutation due to a V600E substitution. Many studies identified that BRAF regulated survival, apoptosis, and proliferation of cells by inducing MAPK pathways activation. For the existing cases, none of the age, sex, location, recurrence and treatments had a statistically significant correlation with BRAF mutation. Conclusion: Our findings demonstrated high prevalence of BRAF V600E mutation in AF. The pathogenic role remains to be clarified.

Key words: Ameloblastic fibroma, BRAF gene mutation, Targeted therapy

中图分类号: 

  • R739.8

表1

16例成釉细胞纤维瘤的临床资料"

Case No. Age/ years Gender Site Symptoms Treatment Recurrence
1 23 F Left mandible Swelling Curettage Recurrent, 14 years
2 28 F Right mandible Swelling Lost to follow-up Lost to follow up
3 26 M Right mandible Chin swelling
and numbness		 Right mandibular segmental osteo-
tomy and right iliac crest bone graft		 Recurrent, 1 month
4 13 F Right mandible Swelling Right mandibular segmental osteotomy
and right fibula flap repair		 Lost to follow up
5 20 F Left mandible Swelling, firm Left mandibular segmental osteotomy
and left fibula flap repair		 Lost to follow up
6 1 M Right maxilla Swelling Curettage Non recurrent, 3 years
7 6 M Right maxilla Swelling Curettage Lost to follow up
8 13 F Right mandible Swelling, firm Curettage Non recurrent, 3 years
9 2 M Left mandible Swelling Curettage Non recurrent,1 year
10 3 F Right maxilla Swelling Curettage Non recurrent, 7 months
11 12 F Right mandible Cystic neoplasm Curettage Non recurrent, 4 months
12 22 F Left mandible Swelling, firm Curettage Recurrent, 40 months
13 67 M Right mandible Swelling, firm,
adhering to the bone		 Right mandibular segmental osteotomy
and left fibula flap repair		 Non recurrent, 3 years
14 41 M Left mandible Swelling, repeated
decline and growth		 Left mandibular segmental osteotomy
and left fibula flap repair		 Non recurrent,16 months
15 16 M Right mandible Cystic neoplasm Curettage Non recurrent, 21 months
16 6 F Left mandible Swelling Curettage Non recurrent, 6 years

图1

成釉细胞纤维瘤中检测到BRAF突变"

[1] Speight PM, Takata T . New tumour entities in the 4th edition of the World Health Organization Classification of Head and Neck tumours: odontogenic and maxillofacial bonetumours[J]. Virchows Arch, 2018,472(3):331-339.
doi: 10.1007/s00428-017-2182-3 pmid: 28674741
[2] Slootweg PJ . An analysis of the interrelationship of the mixed odontogenic tumors: ameloblastic fibroma, ameloblastic fibro-odontoma, and the odontomas[J]. Oral Surg Oral Med Oral Pathol, 1981,51(3):266-276.
doi: 10.1016/0030-4220(81)90056-6 pmid: 6938886
[3] Davies H, Bignell GR, Cox C , et al. Mutations of the BRAF gene in human cancer[J]. Nature, 2002,417(6892):949-954.
doi: 10.1038/nature00766
[4] Curtin JA, Fridlyand J, Kageshita T , et al. Distinct sets of genetic alterationsin melanoma[J]. N Engl J Med, 2005,353(20):2135-2147.
doi: 10.1007/s11912-006-0064-y pmid: 16291983
[5] Itamura H, Ide M, Sato A , et al. Identification of the BRAF V600E mutation in Japanese patients with hairy cell leukemia and related diseases using a quenching probe method[J]. Int J Hematol, 2018,108(4):416-422.
doi: 10.1007/s12185-018-2506-3
[6] Maria MD, Adamaki M, Vlahopoulos S , et al. Synchronous and metachronous thyroid cancer in relation to Langerhans cell histiocytosis; involvement of V600E BRAF mutation?[J]. Pediatr Blood Cancer, 2015,62(1):173-174.
doi: 10.1002/pbc.25173 pmid: 25156525
[7] Puxeddu E, Moretti S, Elisei R , et al. BRAF(V599E) mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas[J]. J Clin Endocrinol Metab, 2004,89(5):2414-2420.
doi: 10.1210/jc.2003-031425
[8] Philipsen HP, Reichart PA, Praetorius F . Mixed odontogenic tumours and odontomas. Considerations on interrelationship. Review of the literature and presentation of 134 new cases of odontomas[J]. Oral Oncol, 1997,33(2):86-99.
doi: 10.1016/S0964-1955(96)00067-X pmid: 9231165
[9] Chen Y, Wang JM, Li TJ . Ameloblastic fibroma: a review of published studies with special reference to its nature and biological behavior[J]. Oral Oncol, 2007,43(10):960-969.
doi: 10.1016/j.oraloncology.2007.05.009 pmid: 17689135
[10] Buchner A, Vered M . Ameloblastic fibroma: a stage in the deve-lopment of a hamartomatous odontoma or a true neoplasm? Critical analysis of 162 previously reported cases plus 10 new cases[J]. Oral Surg Oral Med Oral Pathol Oral Radiol, 2013,116(5):598-606.
doi: 10.1016/j.oooo.2013.06.039 pmid: 24055148
[11] Trodahl JN . Ameloblastic fibroma. A survey of cases from the Armed Forces Institute of Pathology[J]. Oral Surg Oral Med Oral Pathol, 1972,33(4):547-558.
doi: 10.1016/0030-4220(72)90367-2
[12] Kim SG, Jang HS . Ameloblastic fibroma: report of a case[J]. J Oral Maxillofac Surg, 2002,60(2):216-218.
doi: 10.1053/joms.2002.29829
[13] Hansen LS, Ficarra G . Mixed odontogenic tumors: an analysis of 23 new cases[J]. Head Neck Surg, 1988,10(5):330-343.
doi: 10.1002/hed.2890100508 pmid: 3220774
[14] Bertoni F, Del CG, Bacchini P , et al. Ameloblastic fibrosarcoma of the mandible evolving from a prior ameloblastic fibroma after two years: an unusual finding[J]. Int J Surg Pathol, 2016,24(7):656-659.
doi: 10.1177/1066896916646448 pmid: 27130840
[15] Abughazaleh K, Andrus KM, Katsnelson A , et al. Peripheral ameloblastic fibroma of the maxilla: report of a case and review of the literature[J]. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2008,105(5):e46-e48.
doi: 10.1016/j.tripleo.2008.01.012 pmid: 18299218
[16] Kale SG, Shetty A, Balakrishnan J , et al. Ameloblastic fibro-odontoma with a predominant radiopaque component[J]. Ann Maxillofac Surg, 2017,7(2):304-307.
doi: 10.4103/ams.ams_84_17 pmid: 29264304
[17] Kobayashi K, Murakami R, Fujii T , et al. Malignant transformation of ameloblastic fibroma to ameloblastic fibrosarcoma: case report and review of the literature[J]. J Craniomaxillofac Surg, 2005,33(5):352-355.
doi: 10.1016/j.jcms.2005.04.006 pmid: 16129612
[18] Vasconcelos BC, Andrade ES, Rocha NS , et al. Treatment of large ameloblastic fibroma: a case report[J]. J Oral Sci, 2009,51(2):293-296.
doi: 10.2334/josnusd.51.293 pmid: 19550100
[19] Yaktapour N, Meiss F, Mastroianni J , et al. BRAF inhibitor-associated ERK activation drives development of chronic lymphocytic leukemia[J]. J Clin Invest, 2014,124(11):5074-5084.
doi: 10.1172/JCI76539 pmid: 25329694
[20] Hou P, Liu D, Xing M . Functional characterization of the T1799-1801del and A1799-1816ins BRAF mutations in papillary thyroid cancer[J]. Cell Cycle, 2007,6(3):377-379.
doi: 10.4161/cc.6.3.3818 pmid: 17297294250
[21] Kurppa KJ, Caton J, Morgan PR , et al. High frequency of BRAF V600E mutations in ameloblastoma[J]. J Pathol, 2014,232(5):492-498.
doi: 10.1002/path.4317 pmid: 4255689
[22] Sweeney RT, Mcclary AC, Myers BR , et al. Identification of recurrent SMO and BRAF mutations in ameloblastomas[J]. Nat Genet, 2014,46(7):722-725.
doi: 10.1038/ng.2986 pmid: 4418232
[23] Brown NA, Rolland D, Mchugh JB , et al. Activating FGFR2-RAS-BRAF mutations in ameloblastoma[J]. Clin Cancer Res, 2014,20(21):5517-5526.
doi: 10.1158/1078-0432.CCR-14-1069 pmid: 24993163
[24] Brunner P, Bihl M, Jundt G , et al. BRAF p.V600E mutations are not unique to ameloblastoma and are shared by other odontogenic tumors with ameloblastic morphology[J]. Oral Oncol, 2015,51(10):e77-e78.
doi: 10.1016/j.oraloncology.2015.07.010 pmid: 26306423
[25] Diniz MG, Gomes CC, Guimaraes BV , et al. Assessment of BRAFV600E and SMOF412E mutations in epithelial odontogenic tumours[J]. Tumour Biol, 2015,36(7):5649-5653.
doi: 10.1007/s13277-015-3238-0 pmid: 25854168
[26] Soltani M, Tabatabaiefar MA, Mohsenifar Z , et al. Genetic study of the BRAF gene reveals new variants and high frequency of the V600E mutation among Iranian ameloblastoma patients[J]. J Oral Pathol Med, 2018,47(1):86-90.
doi: 10.1111/jop.12610 pmid: 28650588
[27] Gultekin SE, Aziz R, Heydt C , et al. The landscape of genetic alterations in ameloblastomas relates to clinical features[J]. Virchows Arch, 2018,472(5):807-814.
doi: 10.1007/s00428-018-2305-5 pmid: 29388014
[28] Kaye FJ, Ivey AM, Drane WE , et al. Clinical and radiographic response with combined BRAF-targeted therapy in stage 4 ameloblastoma[J]. J Natl Cancer Inst, 2015,107(1):378.
[29] Faden DL, Algazi A . Durable treatment of ameloblastoma with single agent BRAFi Re: Clinical and radiographic response with combined BRAF-targeted therapy in stage 4 ameloblastoma[J]. J Natl Cancer Inst, 2017, 109(1): dwj190
[30] Tan S, Pollack JR, Kaplan MJ , et al. BRAF inhibitor treatment of primary BRAF-mutant ameloblastoma with pathologic assessment of response[J]. Oral Surg Oral Med Oral Pathol Oral Radiol, 2016,122(1):e5-e7.
doi: 10.1016/j.oooo.2015.12.016
[1] 黄教悌,胡菁,韩博. 治疗相关神经内分泌前列腺癌机制研究与靶向治疗新进展[J]. 北京大学学报（医学版）, 2024, 56(4): 557-561.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
No Suggested Reading articles found!
ISSN 1671-167X
CN 11-4691/R
主管单位：中华人民共和国教育部
主办单位：北京大学
地址： 北京市海淀区学院路38号 北京大学医学部 《北京大学学报（医学版）》
邮编：100191
电话：010-82801551
Email： xbbjb2@bjmu.edu.cn

《北京大学学报（医学版）》
微信公众号
版权所有 © 2018 《北京大学学报（医学版）》编辑部