Development of a surrogate liquid biopsy from the aqueous humor in retinoblastoma eyes.

开发视网膜母细胞瘤眼房水替代液体活检。

• 批准号: 10447091
• 负责人: Jesse L Berry
• 金额: $ 22.88万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447091
• 关键词: Anaplasia; Anatomy; Aqueous Humor; Bioinformatics; Biological Assay; Biological Markers; Biopsy; Blindness; Breast; Cancer Patient; Caring; Child; Child Care; Childhood; Chromosomal Gain; Chromosomal Loss; Chromosomes; Clinical; Collection; Copy Number Polymorphism; Cornea; Data; Developing Countries; Development; Diagnosis; Dideoxy Chain Termination DNA Sequencing; Evaluation; Event; Excision; Exons; Eye; Eye Neoplasms; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Markers; Genetic Materials; Genetic Transcription; Genomics; Genotype; Goals; Human; In Situ; Injections; Institutional Review Boards; Knowledge; Liquid substance; Lung; MYCN gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of lung; Methods; Morbidity - disease rate; Mosaicism; Mutation; Oncogenes; Oncologist; Outcome; Outcomes Research; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Phenotype; Physicians; Pilot Projects; Positioning Attribute; Procedures; Prognosis; Prognostic Marker; Prostate; Protocols documentation; Publishing; RB1 Gene Inactivation; RB1 gene; RNA; Recurrence; Reporting; Research; Retinoblastoma; Role; Sampling; Scientist; Shapes; Stage at Diagnosis; Subgroup; Survival Rate; Testing; Time; Tumor Markers; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor Tissue; Tumor stage; Tumor-Derived; aqueous; base; cancer genetics; cancer risk; career; cell free DNA; chemotherapy; clinical database; clinical diagnostics; clinical practice; deep sequencing; demographics; design; genome sequencing; insight; intravitreal injection; lens; liquid biopsy; malignant breast neoplasm; minimally invasive; mortality; next generation sequencing; personalized care; personalized medicine; prognostic; prognostication; response; targeted treatment; treatment response; tumor; tumor DNA; tumor growth; tumor progression; tumorigenesis; virtual; whole genome

Abstract Retinoblastoma is a primary intraocular cancer that develops in the eyes of children. Tumorigenesis is initiated by a mutation in the RB1 gene, which was the first tumor suppressor gene described. Investigating the tumor suppressor pathway regulated by RB1 has provided unprecedented insights into the genetic mechanisms of tumorigenesis, not only for retinoblastoma, but virtually all human cancers. The evaluation of specific mutations, oncogenes and suppressors, tumor markers and gene expression profiles have revolutionized the care of breast, lung, prostate and other cancer patients. However, despite the fact that retinoblastoma-related research launched the field of cancer genetics, leveraging this knowledge to personalize the care for retinoblastoma patients has been elusive in large part because we cannot safely biopsy this tumor due to concerns of extraocular spread. Thus, we currently cannot correlate the genetic and genomic changes at the level of the tumor with clinical outcomes. Identifying these genomic changes, and providing clinical correlation is critically needed for retinoblastoma patients. The objective of this proposal is to develop a surrogate tumor biopsy for retinoblastoma using the aqueous humor, which is the clear fluid in a separate part of the eye from where the tumor forms. Starting in 2012, extractions of aqueous humor have been routinely and safely done as a standard part of the procedure to inject chemotherapy into the vitreous cavity of the eye; no cases of extraocular spread have been reported. Our preliminary data from evaluation of the aqueous revealed that tumor-derived cell-free DNA is present and whole genome sequencing demonstrates a profile of chromosomal gains and losses that corroborate changes in the tumor. The specific aims of this study are designed to test the following hypothesis: the aqueous can serve as a surrogate tumor biopsy – more precisely, the aqueous harbors tumor-derived genetic material which can be assayed and correlated with clinical outcomes. Aim 1 is to define highly recurrent chromosomal changes in the aqueous, such as 2p gain/MYCN amplification, that are known to occur in retinoblastoma tumors. Aim 2 is to identify the specific RB1 mutation(s) that underlie tumorigenesis from the aqueous humor. Finally, Aim 3 will evaluate RNA expression profiles to define subgroups in the aqueous, and correlate these with clinical outcomes such as tumor recurrence. Currently, the only way any of these Aims are possible is from evaluation of tumor tissue, which is only available if an eye is removed (e.g. enucleated). However, by defining these genetic changes in the aqueous we will, for the first time, be able to characterize tumors in situ during therapy. This will allow for the development of prognostic markers for therapeutic response and, in the future, may guide therapy. Use of the aqueous humor as a surrogate tumor biopsy holds tremendous potential, from directly impacting the way we manage retinoblastoma patients, to ultimately allowing for the development of personalized medicine for this blinding childhood cancer. ! !

抽象的 视网膜母细胞瘤是一种在儿童眼中发生的原发性眼内癌症，肿瘤发生开始。 RB1 基因突变，这是第一个研究肿瘤的抑癌基因。 RB1 调节的抑制途径为人们对遗传机制提供了前所未有的见解 肿瘤发生，不仅针对视网膜母细胞瘤，而且几乎针对所有人类癌症。 突变、癌基因和抑制基因、肿瘤标志物和基因表达谱彻底改变了 然而，尽管事实上与视网膜母细胞瘤有关，但乳腺癌、肺癌、前列腺癌和其他癌症患者的护理。 研究启动了癌症遗传学领域，利用这些知识来个性化护理 视网膜母细胞瘤患者在很大程度上难以捉摸，因为我们无法安全地对这种肿瘤进行活检，因为 因此，我们目前无法将遗传和基因组变化联系起来。 识别这些基因组变化并提供临床相关性。 视网膜母细胞瘤患者迫切需要该药物，该提案的目的是开发替代肿瘤。 使用房水进行视网膜母细胞瘤活检，房水是眼睛的一个单独部分中的透明液体 从 2012 年开始，房水提取已常规且安全地进行。 将化疗药物注射到眼睛玻璃体腔的标准程序；没有病例； 我们对房水评估的初步数据显示， 存在肿瘤来源的无细胞 DNA，并且全基因组测序显示了染色体的概况 证实肿瘤变化的增益和损失本研究的具体目的旨在测试。 以下假设：房水可以作为替代肿瘤活检——更准确地说，房水 含有可进行检测并与临床结果相关的肿瘤衍生遗传物质。 定义房水中高度反复发生的染色体变化，例如 2p 增益/MYCN 扩增， 目标 2 是确定视网膜母细胞瘤中发生的特定 RB1 突变。 最后，Aim 3 将评估 RNA 表达谱来定义。 房水中的亚组，并将其与肿瘤复发等临床结果相关联。 实现这些目标的唯一方法是对肿瘤组织进行评估，而这只有在眼睛处于正常状态时才可用。 然而，通过定义水中的这些遗传变化，我们首先将其去除。 时间，能够在治疗期间原位表征肿瘤，这将有助于制定预后。 治疗反应的标志物，并且在未来可能指导房水作为治疗的使用。 替代肿瘤活检具有巨大的潜力，直接影响我们治疗视网膜母细胞瘤的方式 患者，最终允许针对这种致盲的儿童癌症开发个性化医疗。 ！ ！

项目成果

Simultaneous Copy Number Alteration and Single-Nucleotide Variation Analysis in Matched Aqueous Humor and Tumor Samples in Children with Retinoblastoma.

• DOI: 10.3390/ijms24108606
• 发表时间: 2023-05-11
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Schmidt, Michael J.;Prabakar, Rishvanth K.;Pike, Sarah;Yellapantula, Venkata;Peng, Chen-Ching;Kuhn, Peter;Hicks, James;Xu, Liya;Berry, Jesse L.
• 通讯作者: Berry, Jesse L.

High-risk Pathologic Features Based on Presenting Findings in Advanced Intraocular Retinoblastoma: A Multicenter, International Data-Sharing American Joint Committee on Cancer Study.

• DOI: 10.1016/j.ophtha.2022.04.006
• 发表时间: 2022-08
• 期刊: OPHTHALMOLOGY
• 影响因子: 13.7
• 作者: Tomar, Ankit Singh;Finger, Paul T.;Gallie, Brenda;Kivela, Tero T.;Mallipatna, Ashwin;Zhang, Chengyue;Zhao, Junyang;Wilson, Matthew W.;Brennan, Rachel C.;Burges, Michala;Kim, Jonathan;Berry, Jesse L.;Jubran, Rima;Khetan, Vikas;Ganesan, Suganeswari;Yarovoy, Andrey;Yarovaya, Vera;Kotova, Elena;Volodin, Denis;Yousef, Yacoub A.;Nummi, Kalle;Ushakova, Tatiana L.;Yugay, Olga, V;Polyakov, Vladimir G.;Ramirez-Ortiz, Marco A.;Esparza-Aguiar, Elizabeth;Chantada, Guillermo;Schaiquevich, Paula;Fandino, Adriana;Yam, Jason C.;Lau, Winnie W.;Lam, Carol P.;Sharwood, Phillipa;Moorthy, Sonia;Long, Quah Boon;Essuman, Vera Adobea;Renner, Lorna A.;Semenova, Ekaterina;Catala-Mora, Jaume;Correa-Llano, Genoveva;Carreras, Elisa
• 通讯作者: Carreras, Elisa

Potential of Aqueous Humor as a Liquid Biopsy for Uveal Melanoma.

• DOI: 10.3390/ijms23116226
• 发表时间: 2022-06-02
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Im, Deborah H.;Peng, Chen-Ching;Xu, Liya;Kim, Mary E.;Ostrow, Dejerianne;Yellapantula, Venkata;Bootwalla, Moiz;Biegel, Jaclyn A.;Gai, Xiaowu;Prabakar, Rishvanth K.;Kuhn, Peter;Hicks, James;Berry, Jesse L.
• 通讯作者: Berry, Jesse L.

Diagnostic Aqueous Humor Proteome Predicts Metastatic Potential in Uveal Melanoma.

• DOI: 10.3390/ijms24076825
• 发表时间: 2023-04-06
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Peng, Chen-Ching;Sirivolu, Shreya;Pike, Sarah;Kim, Mary E.;Reiser, Bibiana;Li, Hong-Tao;Liang, Gangning;Xu, Liya;Berry, Jesse L.
• 通讯作者: Berry, Jesse L.

Retinoblastoma seeds: impact on American Joint Committee on Cancer clinical staging.

• DOI: 10.1136/bjophthalmol-2021-318892
• 发表时间: 2023-01
• 期刊: BRITISH JOURNAL OF OPHTHALMOLOGY
• 影响因子: 4.1
• 作者: Tomar, Ankit Singh;Finger, Paul T.;Gallie, Brenda;Kivela, Tero;Mallipatna, Ashwin;Zhang, Chengyue;Zhao, Junyang;Wilson, Matthew;Brennan, Rachel;Burges, Michala;Kim, Jonathan;Berry, Jesse L.;Jubran, Rima;Khetan, Vikas;Ganeshan, Suganeswari;Yarovoy, Andrey;Yarovaya, Vera;Kotova, Elena;Volodin, Denis;Yousef, Yacoub;Nummi, Kalle;Ushakova, Tatiana L.;Yugay, Olga, V;Polyakov, Vladimir G.;Antonio Ramirez-Ortiz, Marco;Esparza-Aguiar, Elizabeth;Chantada, Guillermo L.;Schaiquevich, Paula;Fandino, Adriana C.;Yam, Jason C.;Lau, Winnie W.;Lam, Carol P.;Sharwood, Phillipa;Moorthy, Sonia;Long, Quah Boon;Essuman, Vera Adobea;Renner, Lorna A.;Semenova, Ekaterina;Catala-Mora, Jaume;Correa Llano, Maria;Carreras, Elisa
• 通讯作者: Carreras, Elisa