AbstractMYCN-amplified RB1 wild-type (MYCNampRB1+/+) retinoblastoma is a rare and aggressive subtype, often resistant to standard therapies. Identifying unique MRI features is crucial for diagnosing this subtype, as biopsy is not recommended. This study aimed to differentiate MYCNampRB1+/+ from the most prevalent RB1-/- retinoblastoma using pretreatment MRI and radiomics.

摘要MYCN扩增的RB1野生型（MYCNampRB1+/+）视网膜母细胞瘤是一种罕见的侵袭性亚型，通常对标准疗法具有抗性。识别独特的MRI特征对于诊断该亚型至关重要，因为不建议进行活检。本研究旨在使用预处理MRI和放射组学将MYCNampRB1+/+与最常见的RB1-/-视网膜母细胞瘤区分开。

Ninety-eight unilateral retinoblastoma patients (19 MYCN cases and 79 matched controls) were included. Tumors on T2-weighted MR images were manually delineated and validated by experienced radiologists. Radiomics analysis extracted 120 features per tumor. Several combinations of feature selection methods, oversampling techniques and machine learning (ML) classifiers were evaluated in a repeated fivefold cross-validation machine learning pipeline to yield the best-performing prediction model for MYCN.

纳入了98例单侧视网膜母细胞瘤患者（19例MYCN病例和79例匹配对照）。T2加权MR图像上的肿瘤由经验丰富的放射科医生手动描绘和验证。放射组学分析提取了每个肿瘤120个特征。在重复的五倍交叉验证机器学习流水线中评估了特征选择方法，过采样技术和机器学习（ML）分类器的几种组合，以产生MYCN性能最佳的预测模型。

The best model used univariate feature selection, data oversampling (duplicating MYCN cases), and logistic regression classifier, achieving a mean AUC of 0.78 (SD 0.12). SHAP analysis highlighted lower sphericity, higher flatness, and greater gray-level heterogeneity as predictive for MYCNampRB1+/+ status, yielding an AUC of 0.81 (SD 0.11).

最佳模型使用单变量特征选择，数据过采样（重复MYCN病例）和逻辑回归分类器，平均AUC为0.78（SD 0.12）。SHAP分析强调了较低的球形度，较高的平坦度和较大的灰度异质性，可预测MYCNampRB1+/+状态，产生0.81（SD 0.11）的AUC。

This study shows the potential of MRI-based radiomics to distinguish MYCNampRB1+/+ and RB1-/- retinoblastoma subtypes..

这项研究显示了基于MRI的放射组学区分MYCNampRB1+/+和RB1-/-视网膜母细胞瘤亚型的潜力。。

IntroductionRetinoblastoma is the most prevalent malignant ocular neoplasm in pediatric patients with an incidence of 1:17,000 live births and is typically diagnosed before the age of five1. The initiation of tumorigenesis primarily involves biallelic inactivation of the RB1 tumor suppressor gene, resulting in RB1-/- retinoblastoma.

引言视网膜母细胞瘤是儿科患者中最常见的恶性眼部肿瘤，发病率为1:17000，通常在五岁之前被诊断出。肿瘤发生的起始主要涉及RB1肿瘤抑制基因的双等位基因失活，导致RB1-/-视网膜母细胞瘤。

It has been established that distinct molecular subtypes of retinoblastoma exist, offering potential avenues for individualized therapeutic interventions2,3,4,5,6,7,8.In 2013 a subtype of retinoblastoma was identified, characterized by a significant amplification of MYCN in the tumor without detectable pathogenic variants in the RB1 alleles(MYCNampRB1+/+).

已经确定存在不同的视网膜母细胞瘤分子亚型，为个体化治疗干预提供了潜在途径2,3,4,5,6,7,8。2013年，鉴定出一种视网膜母细胞瘤亚型，其特征在于肿瘤中MYCN的显着扩增，而RB1等位基因（MYCNampRB1+/+）中没有可检测到的致病变异。

In this subtype, MYCN amplification was identified as the key driver in initiating retinal tumors, observed in approximately 1–2% of retinoblastoma cases9,10,11. Although MYCN amplifications can also be found in RB1-/- tumors, RB1 wild-type (RB1+/+) tumors with MYCN amplification (MYCNampRB1+/+) show a clear inclination and exhibiting unique clinical characteristics12,13.

在这种亚型中，MYCN扩增被确定为引发视网膜肿瘤的关键驱动因素，在大约1-2%的视网膜母细胞瘤病例中观察到9,10,11。尽管在RB1-/-肿瘤中也可以发现MYCN扩增，但具有MYCN扩增（MYCNampRB1+/+）的RB1野生型（RB1+/+）肿瘤显示出明显的倾向并表现出独特的临床特征12,13。

A previous study revealed that this MYCNampRB1+/+ retinoblastoma manifests as unilateral large tumors at an early age, displaying distinctive histopathological features characterized by poorly differentiated neuroblastic cells and limited rosette formations9. Moreover, this subtype demonstrated relative resistance to conventional therapeutic interventions14.

先前的一项研究表明，这种MYCNampRB1+/+视网膜母细胞瘤在早期表现为单侧大肿瘤，表现出独特的组织病理学特征，其特征在于分化差的成神经细胞和有限的玫瑰花结形成9。此外，这种亚型表现出对常规治疗干预的相对抗性14。

The diagnosis of retinoblastoma in children under 12 months of age frequently indicates an inherited condition with increased risk of bilateral disease and subsequent significant loss of vision, which enhances efforts to pursue eye-saving therapeutic approaches. However, caution must be exercised when considering eye salvage in this aggressive subtype of retinoblastom.

12个月以下儿童视网膜母细胞瘤的诊断经常表明遗传性疾病，双侧疾病的风险增加，随后视力严重丧失，这加强了寻求挽救眼睛的治疗方法的努力。然而，在考虑这种侵袭性视网膜母细胞亚型的眼部挽救时，必须谨慎行事。

Data Availability

数据可用性

The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request, only if permission of the providing center is obtained.

由于敏感性的原因，支持本研究结果的数据无法公开获得，只有在获得提供中心的许可后，才能根据合理的要求从通讯作者那里获得。

Abbreviations

缩写

RB1

RB1型

-/-

-/-

:

:

Pathogenic variants in the RB1 gene

RB1基因的致病变异

MYCN

MYCN

amp

安培

RB1

RB1型

+/+

+/+

:

:

MYCN-amplified RB1 wild-type

MYCN扩增的RB1野生型

MRI:

MRI：

Magnetic resonance imaging

磁共振成像

STARD:

标准：

Standards for Reporting Diagnostic accuracy studies

诊断准确性研究报告标准

PCA:

主成分分析：

Principal component analysis

主成分分析

RFE-LR:

RFE-LR：

Recursive feature elimination approach using a logistic regression in nested cross-validation

嵌套交叉验证中使用逻辑回归的递归特征消除方法

RFE-RF:

RFE-RF：

Recursive feature elimination approach using random forest in nested cross-validation

嵌套交叉验证中使用随机森林的递归特征消除方法

Univariate:

单变量：

Univariate selection method based on ANOVA testing that retained the top 10 percentile features

基于ANOVA测试的单变量选择方法，保留了前10个百分位数的特征

AUC:

AUC：

Area under the curve

曲线下面积

SD:

标准差：

Standard deviation

标准偏差

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Download referencesFunding Initiation and coordination of this study was funded by Stichting Kinderen Kankervrij (KIKA) (grant no. 342) and the Hanarth Foundation (grant for project titled MRI-based Deep Learning Segmentation and Quantitative Radiomics in Retinoblastoma: A Next Step Toward Personalized Interventions).

下载参考资料本研究的资金启动和协调由Stichting Kinderen Kankervrij（KIKA）（批准号342）和Hanarth基金会（资助项目名为基于MRI的视网膜母细胞瘤深度学习分割和定量放射学：个性化干预的下一步）资助。

Departmental funding was received by Casey Eye Institute, Oregon Health & Science University (A.H.S., A.K.M., and O.E.U.) from the National Institutes of Health (grant P30 EY010572) in addition to unrestricted departmental funding from Research to Prevent Blindness. Departmental funding was received by Emory Eye Center, Ocular Oncology Service (O.E.U., G.B.H., and H.G.) via National Eye Institute core grant P30 EY006360.Author informationAuthors and AffiliationsEuropean Retinoblastoma Imaging Collaboration (ERIC), Amsterdam, The NetherlandsChristiaan M.

俄勒冈州健康与科学大学凯西眼科研究所（A.H.S.，A.K.M。和O.E.U.）从美国国立卫生研究院（grant P30 EY010572）获得了部门资金，此外还从预防失明的研究中获得了不受限制的部门资金。部门资金由埃默里眼科中心，眼科肿瘤服务（O.E.U.，G.B.H。和H.G.）通过国家眼科研究所核心拨款P30 EY006360获得。作者信息作者和附属机构欧洲视网膜母细胞瘤成像合作组织（ERIC），阿姆斯特丹，荷兰。

de Bloeme , Robin W. Jansen, Liesbeth Cardoen, Sophia Göricke, Sabien van Elst, Philippe Maeder, Mériam Koob, Selma Sirin, Hervé J. Brisse, Paolo Galluzzi, Marcus C. de Jong & Pim de GraafCancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The NetherlandsChristiaan M. de Bloeme , Robin W. Jansen, Sabien van Elst, Charlotte J.

de Bloeme、Robin W.Jansen、Liesbeth Cardoen、Sophia Göricke、Sabien van Elst、Philippe Maeder、Mériam Koob、Selma Sirin、HervéJ.Brisse、Paolo Galluzzi、Marcus C.de Jong、阿姆斯特丹Pim de Graaf癌症中心、阿姆斯特丹影像学和生物标志物、荷兰克里斯蒂安·M·de Bloemes、Robin W.Jansen、Sabien van Elst、Charlotte J。

Dommering, Matthijs Cysouw, Ronald Boellaard, Josephine C. Dorsman, Annette C. Moll, Marcus C. de Jong & Pim de GraafDepartment of Radiology and Nuclear Medicine, UMC location Vrije Universiteit Amsterdam, Amsterdam, 1007 MB, The NetherlandsChristiaan M. de Bloeme , Robin W. Jansen, Sabien van Elst, Matthijs Cysouw, Ronald Boellaard, Marcus C.

Dommering，Matthijs Cysouw，Ronald Boellaard，Josephine C.Dorsman，Annette C.Moll，Marcus C.de Jong，Pim de Graaf放射科和核医学系，UMC地点阿姆斯特丹VU大学，阿姆斯特丹，1007 MB，The Netherlands Christiaan M.de Bloeme，Robin W.Jansen，Sabien van Elst，Matthigs Cysouw。

de Jong & Pim de GraafImaging department Institut Curie, France and Paris-Siences-et-Lettres University, Paris, FranceLiesbeth Cardoen & Hervé J. BrisseDepartment of Diagnostic and Interventional Radiology and Neuroradiolo.

de Jong＆Pim de GraafImaging department Institut Curie，FranceLiesbeth Cardoen＆HervéJ.BrisseDepartment of Diagnostic and Interventional Radiology and Neuroradio，法国和巴黎Siences et Lettres大学，巴黎。

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PubMed Google ScholarConsortiaEuropean Retinoblastoma Imaging CollaborationContributions Guarantors of integrity of entire study, C.M.d.B., R.W.J., P.M., P.d.G. ; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, C.M.d.B., R.W.J., A.H.S., P.M., S.

PubMed Google ScholarConsortiaEuropean视网膜母细胞瘤成像合作贡献整个研究完整性的保证人，C.M.d.B.，R.W.J.，P.M.，P.d.G；研究概念/研究设计或数据采集或数据分析/解释，所有作者；重要知识内容的稿件起草或稿件修订，所有作者；批准提交稿件的最终版本，所有作者；同意确保所有作者适当解决与工作相关的任何问题；文学研究，C.M.d.B.，R.W.J.，A.H.S.，P.M.，S。

Sirin., J.D. ; clinical studies, C.M.d.B., J.L.J., A.H.S., A.K.M., P.M., O.E.U., H.G., R.C.B., S. Sen, M.K., S. Sirin, H.J.B., P.G., C.J.D., M.C., A.C.M., P.d.G. ; experimental studies, C.M.d.B., R.W.J., S.v.E., S. Sen, M.C., R.B., J.D. ; statistical analysis, C.M.d.B., R.W.J., M.C., M.C.d.J. ; and manuscript editing, C.M.d.B., R.W.J., L.C., S.G., S.v.E., J.L.J., A.R., A.H.S., A.K.M., P.M., O.E.U., G.B.H., H.G., H.C.B., K.E.N., R.C.B., S.

Sirin。，J、 D；临床研究，C.M.d.B.，J.L.J.，A.H.S.，A.K.M.，P.M.，O.E.U.，H.G.，R.C.B.，S.Sen，M.K.，S.Sirin，H.J.B.，P.G.，C.J.d.，M.C.，A.C.M.，P.d.G；；统计分析，C.M.d.B.，R.W.J.，M.C.，M.C.d.J；和手稿编辑，C.M.d.B.，R.W.J.，L.C.，S.G.，S.v.E.，J.L.J.，A.R.，A.H.S.，A.K.M.，P.M.，O.E.U.，G.B.H.，H.G.，H.C.B.，K.E.N.，R.C.B.，S。

Sen, M.K. S. Sirin, H.J.B., P.G., C.J.D., M.C., R.B., J.D., A.C.M., M.C.d.J., P.d.G.Corresponding authorCorrespondence to.

Sen，M.K.S.Sirin，H.J.B.，P.G.，C.J.D.，M.C.，R.B.，J.D.，A.C.M.，M.C.D.J.，P.D.G.通讯作者回复。

Christiaan M. de Bloeme .Ethics declarations

克里斯蒂安·德·布洛姆。伦理声明

Conflict of interests

利益冲突

C.M.d.B.  No relevant relationships.  R.W.J. No relevant relationships.  L.C.  No relevant relationships.  S.G.  No relevant relationships.  S.v.E.  No relevant relationships.  J.L.J.  No relevant relationships.  A.R.  No relevant relationships.  A.H.S. No relevant relationships. A.K.M.  No relevant relationships.  P.M.

C、 M.d.B.无相关关系。R.W.J.无相关关系。L.C.无相关关系。S.G.无相关关系。S.v.E.无相关关系。J.L.J.无相关关系。A.R.无相关关系。A.H.S.无相关关系。A、 K.M.没有相关关系。下午。

No relevant relationships.  O.E.U.  No relevant relationships.  G.B.H.  No relevant relationships.  H.G.  No relevant relationships.  H.C.B.  No relevant relationships.  K.E.N.  No relevant relationships.  R.C.B.  Consultant for Aileron Therapeutics.  S. Sen No relevant relationships.  M.K.  No relevant relationships.  S.

没有相关关系。O.E.U.无相关关系。G.B.H.无相关关系。H.G.无相关关系。H.C.B.无相关关系。K.E.N.无相关关系。R.C.B.副翼治疗顾问。S.Sen没有相关关系。M.K.没有相关关系。S。

Sirin No relevant relationships.  H.J.B.  No relevant relationships.  P.G.  No relevant relationships.  C.J.D.  No relevant relationships.  M.C.  No relevant relationships.  R.B.  No relevant relationships.  J.D.  No relevant relationships.  A.C.M.  No relevant relationships.  M.C.d.J.  No relevant relationships.  P.d.G.

。H.J.B.无相关关系。P.G.无相关关系。C.J.D.无相关关系。M.C.无相关关系。R.B.无相关关系。J.D.无相关关系。A.C.M.无相关关系。M.C.d.J.无相关关系。P.d.G。

No relevant relationships..

无相关关系。。

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Reprints and permissionsAbout this articleCite this articlede Bloeme , C.M., Jansen, R.W., Cardoen, L. et al. Differentiating MYCN-amplified RB1 wild-type retinoblastoma from biallelic RB1 mutant retinoblastoma using MR-based radiomics: a retrospective multicenter case–control study.

转载和许可本文引用本文de Bloeme，C.M.，Jansen，R.W.，Cardoen，L。等人。使用基于MR的放射组学区分MYCN扩增的RB1野生型视网膜母细胞瘤和双等位基因RB1突变型视网膜母细胞瘤：一项回顾性多中心病例对照研究。

Sci Rep 14, 25103 (2024). https://doi.org/10.1038/s41598-024-76933-6Download citationReceived: 16 May 2024Accepted: 17 October 2024Published: 23 October 2024DOI: https://doi.org/10.1038/s41598-024-76933-6Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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KeywordsRetinoblastoma MRI; radiomics

关键词视网膜母细胞瘤MRI；放射组学

MYCN-amplification

MYCN扩增