Next-Generation Sequencing of Retinoblastoma Identifies Pathogenic Alterations beyond RB1 Inactivation That Correlate with Aggressive Histopathologic Features.,Ophthalmology

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Next-Generation Sequencing of Retinoblastoma Identifies Pathogenic Alterations beyond RB1 Inactivation That Correlate with Aggressive Histopathologic Features.
Ophthalmology ( IF 13.7 ) Pub Date : 2019-12-12 , DOI: 10.1016/j.ophtha.2019.12.005
Armin R Afshar ₁ , Melike Pekmezci ₂ , Michele M Bloomer ₃ , Nicola J Cadenas ₄ , Meredith Stevers ₅ , Anuradha Banerjee ₆ , Ritu Roy ₇ , Adam B Olshen ₈ , Jessica Van Ziffle ₉ , Courtney Onodera ₉ , W Patrick Devine ₉ , James P Grenert ₉ , Boris C Bastian ₁₀ , David A Solomon ₁₁ , Bertil E Damato ₁₂

Affiliation

Department of Ophthalmology, University of California, San Francisco, San Francisco, California; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
Department of Ophthalmology, University of California, San Francisco, San Francisco, California; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California; Department of Pathology, University of California, San Francisco, San Francisco, California.
Department of Ophthalmology, University of California, San Francisco, San Francisco, California; Department of Pathology, University of California, San Francisco, San Francisco, California.
Cancer Genetics and Prevention Program, University of California, San Francisco, San Francisco, California.
Department of Pathology, University of California, San Francisco, San Francisco, California.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California; Division of Hematology-Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, California.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California; Computational Biology and Informatics, University of California, San Francisco, San Francisco, California.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California; Computational Biology and Informatics, University of California, San Francisco, San Francisco, California; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
Department of Pathology, University of California, San Francisco, San Francisco, California; Clinical Cancer Genomics Laboratory, University of California, San Francisco, San Francisco, California.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California; Department of Pathology, University of California, San Francisco, San Francisco, California; Clinical Cancer Genomics Laboratory, University of California, San Francisco, San Francisco, California; Department of Dermatology, University of California, San Francisco, San Francisco, California.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California; Department of Pathology, University of California, San Francisco, San Francisco, California; Clinical Cancer Genomics Laboratory, University of California, San Francisco, San Francisco, California.
Department of Ophthalmology, University of California, San Francisco, San Francisco, California; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.

PURPOSE To determine the usefulness of a comprehensive, targeted-capture next-generation sequencing (NGS) assay for the clinical management of children undergoing enucleation for retinoblastoma. DESIGN Cohort study. PARTICIPANTS Thirty-two children with retinoblastoma. METHODS We performed targeted NGS using the UCSF500 Cancer Panel (University of California, San Francisco, San Francisco, CA) on formalin-fixed, paraffin-embedded tumor tissue along with constitutional DNA isolated from peripheral blood, buccal swab, or uninvolved optic nerve. Peripheral blood samples were also sent to a commercial laboratory for germline RB1 mutation testing. MAIN OUTCOME MEASURES Presence or absence of germline RB1 mutation or deletion, tumor genetic profile, and association of genetic alterations with clinicopathologic features. RESULTS Germline mutation or deletion of the RB1 gene was identified in all children with bilateral retinoblastoma (n = 12), and these NGS results were 100% concordant with commercial germline RB1 mutation analysis. In tumor tissue tested with NGS, biallelic inactivation of RB1 was identified in 28 tumors and focal MYCN amplification was identified in 4 tumors (2 with wild-type RB1 and 2 with biallelic RB1 inactivation). Additional likely pathogenic alterations beyond RB1 were identified in 13 tumors (41%), several of which have not been reported previously in retinoblastoma. These included focal amplifications of MDM4 and RAF1, as well as damaging mutations involving BCOR, ARID1A, MGA, FAT1, and ATRX. The presence of additional likely pathogenetic mutations beyond RB1 inactivation was associated with aggressive histopathologic features, including higher histologic grade and anaplasia, and also with both unilateral and sporadic disease. CONCLUSIONS Comprehensive NGS analysis reliably detects relevant mutations, amplifications, and chromosomal copy number changes in retinoblastoma. The presence of genetic alterations beyond RB1 inactivation correlates with aggressive histopathologic features.

中文翻译：

视网膜母细胞瘤的下一代测序可确定除与积极的组织病理学特征相关的RB1失活以外的致病性改变。

目的确定全面的，靶向捕获的下一代测序（NGS）测定法对接受去核成视网膜细胞瘤的儿童的临床管理的有效性。设计队列研究。参与者32例视网膜母细胞瘤儿童。方法我们使用UCSF500癌症小组（加利福尼亚大学旧金山分校，加利福尼亚州旧金山分校）对福尔马林固定，石蜡包埋的肿瘤组织以及从外周血，颊拭子或未累及的视神经分离的体质DNA进行了靶向NGS。外周血样品也被送到商业实验室进行种系RB1突变测试。主要观察指标是否存在种系RB1突变或缺失，肿瘤遗传学特征以及遗传改变与临床病理特征的相关性。结果在所有患双侧视网膜母细胞瘤的儿童（n = 12）中均鉴定出胚系突变或RB1基因缺失，这些NGS结果与商业种系RB1突变分析100％一致。在用NGS测试的肿瘤组织中，在28个肿瘤中鉴定出RB1的双等位基因失活，在4个肿瘤中鉴定了局灶性MYCN扩增（2个野生型RB1和2个双等位RB1失活）。在RB1以外的其他可能的致病性改变中，发现了13个肿瘤（41％），其中一些以前在视网膜母细胞瘤中未见报道。这些包括MDM4和RAF1的局部扩增，以及涉及BCOR，ARID1A，MGA，FAT1和ATRX的破坏性突变。除了RB1失活外，其他可能的致病突变也与侵袭性组织病理学特征有关，包括较高的组织学分级和发育不全，以及单侧和散发性疾病。结论全面的NGS分析能够可靠地检测视网膜母细胞瘤中的相关突变，扩增和染色体拷贝数变化。RB1失活以外的遗传改变的存在与侵略性组织病理学特征相关。

更新日期：2019-12-12

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