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PubMed2025

Detection and Characterization of RB1 Mosaicism in Patients With Retinoblastoma Receiving cfDNA Test.

IMPORTANCE: Plasma cell-free DNA (cfDNA) testing is increasingly used for disease diagnosis and monitoring in retinoblastoma, with RB1 allele fraction in cfDNA actively corresponding to disease status and treatment response. However, while RB1 mosaicism has been reported in retinoblastoma, its clinical implications and potential impact on cfDNA testing remain unclear. OBJECTIVES: To identify RB1 mosaicism using paired plasma and buffy coat (containing lymphocytes, monocytes, granulocytes, and platelets) DNA testing, and to characterize the implications of RB1 mosaicism on cfDNA testing outcomes. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, participants with retinoblastoma underwent testing with MSK-ACCESS (Memorial Sloan Kettering-Analysis of Circulating cfDNA to Examine Somatic Status), a clinical assay that combines plasma cfDNA and buffy coat genomic DNA sequencing, enabling the detection and differentiation of somatic, heterozygous, and mosaic variants, between July 2020 and April 2024 at the Memorial Sloan Kettering Cancer Center. Mosaic findings from MSK-ACCESS were correlated with those from a subgroup of patients who concurrently underwent testing using the MSK-IMPACT germline assay. Data analysis was performed from April to September 2024. EXPOSURE: RB1 mosaicism in retinoblastoma. MAIN OUTCOMES AND MEASURES: The RB1 variant allele fractions in cfDNA and buffy coat genomic DNA were used to detect RB1 mosaicism. RESULTS: A total of 136 consecutive patients with retinoblastoma (median age at diagnosis, 1.0 year [IQR, 0.4-1.7 years]; 74 [54.4%] female; 67 with bilateral disease and 69 with unilateral disease) who underwent testing with the MSK-ACCESS assay were included. RB1 mosaicism was identified in buffy coat DNA from 20 patients (14.7%), with consistent results detected in all 11 participants tested concurrently by the MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) germline assay. Four participants with RB1 mosaicism previously tested negative for germline RB1 variants by external laboratories. Compared with heterozygous participants, participants with RB1 mosaicism had a lower risk of developing bilateral disease (91.7% vs 55.0%, respectively; difference, 36.7% [95% CI, 13.8%-59.6%]; P = .002). In cfDNA, the mosaicism variant was detected both before and after treatment, with variant allele fraction initially decreasing after treatment but then stabilizing at levels consistent with mosaicism, despite the absence of clinical disease. CONCLUSIONS AND RELEVANCE: The accurate detection and quantification of RB1 mosaicism are crucial. RB1 mosaicism should be considered when RB1 variants persist in cfDNA after treatment without evidence of disease; failure to do so may lead to false-positive results and overtreatment in patients with RB1 mosaicism. Identifying RB1 mosaicism may improve patient counseling, inform treatment decisions, and enhance surveillance efforts.

Humans↗

PubMed2026

Bilateral Conversion Risk in Unilateral Retinoblastoma Using Age and Genetic Testing.

IMPORTANCE: Metachronous bilateral conversion in initially unilateral retinoblastoma is uncommon but clinically consequential, potentially requiring intensified treatment and carrying worse prognosis. Clarifying how age at diagnosis refines genetic-risk stratification could enable safer, more efficient surveillance protocols. OBJECTIVE: To estimate the incidence and timing of metachronous bilateral conversion in unilateral retinoblastoma and assess whether age at diagnosis and RB1 testing are associated with bilateral conversion risk. DESIGN, SETTING AND PARTICIPANTS: This was a retrospective cohort study at a tertiary center in Shanghai, China, including 1108 consecutive children with initially unilateral retinoblastoma diagnosed from July 2010 to October 2024 (after exclusions for short follow-up [n = 139], missing data [n = 53], or synchronous bilateral disease [n = 10]). The median (IQR) follow-up was 43.4 (24.2-67.6) months. EXPOSURES: Age at diagnosis and RB1 genetic status/subtypes assessed by next-generation sequencing and multiplex ligation-dependent probe amplification, including penetrance class (high vs low) and mosaic vs germline categorization. MAIN OUTCOMES AND MEASURES: Time to metachronous bilateral conversion; cumulative incidence functions with death as a competing risk; spatial distribution of fellow-eye tumors. RESULTS: Among 1108 patients (median [IQR] age at diagnosis, 22.2 [12.0-31.4] months; 591 [53.3%] male), 24 (2.2%) developed metachronous bilateral disease. At 24 months, cumulative incidence was 2.2% (95% CI, 1.3-3.1) overall. By genetic status, the 24-month cumulative incidence was 24.8% (95% CI, 13.8-35.9) in RB1 variant-positive vs 1.6% (95% CI, 0.0-3.1) in RB1 variant-negative patients. Among RB1 variant-positive patients, risk clustered among those diagnosed before 9 months, whereas no conversions were observed among those diagnosed at older than 9 months. Four RB1 variant-negative patients who were initially diagnosed at notably late ages (20.9, 42.7, 79.6, and 118 months) subsequently converted; these cases likely represent undetected low-level mosaicism, somatic variants below detection thresholds, or rare genomic events not captured by standard sequencing panels. Fellow-eye tumors did not involve macula and showed a nasal-predominant distribution. CONCLUSIONS AND RELEVANCE: The findings in this study suggest that age at diagnosis may refine genetic risk stratification for metachronous bilateral conversion. RB1 variant-positive patients diagnosed at 9 months or later represent a very low-risk subgroup that may warrant surveillance deescalation, while rare late conversions in RB1 variant-negative patients necessitate continued long-term monitoring.

Humans↗

PubMed2025

Genetic Newborn Screening for Retinoblastoma: A Belgian Initiative Baby Detect.

Baby Detect Project, started in September 2022, aimed to create a newborn screening test using targeted next-generation sequencing for all early-onset, treatable, and serious conditions. The elaborated gene panel covers 405 genes, associated with 165 genetic conditions, and includes RB1, linked to retinoblastoma, the only oncological disease tested for. Germline RB1 mutations concern around 50% of all retinoblastoma cases and 100% of the most severe, bilateral cases. Ninety percent of them occur de novo, which delays the diagnosis by about a year with subsequent loss of vision and sometimes the eye itself. Detecting children with germline RB1 mutation at birth would greatly improve functional and anatomic outcomes, limiting invasive treatments and general anesthesias through early childhood. We discuss herein the novel approach of population screening, the rationale for newborn testing for RB1 mutations, the incidence of expected cases, the reliability of the test and its costs. The next step is to move to a nation-scale population; this initiative marks a landmark in retinoblastoma patients' care.

Humans↗

PubMed2026

Bibliometric analysis of retinoblastoma research over the past decade.

BACKGROUND: Retinoblastoma (RB), the most prevalent primary intraocular malignancy in children, has emerged as a model disease for exploring the molecular underpinnings of pediatric cancer. Over the past decade, research in this field has accelerated, propelled by advances in genomics, diagnostic imaging, targeted therapies, and global scientific collaboration. METHODS: This study systematically retrieved RB-related publications from 2015 to 2024 using the Web of Science Core Collection. A total of 4990 articles were included. CiteSpace and VOSviewer were employed to perform bibliometric and visual analyses across multiple dimensions, including countries, institutions, authors, journals, and thematic evolution. RESULTS: The United States and China were identified as the leading contributors, jointly accounting for over 40.55% of all publications. US-based journals led in both publication volume and citation impact, underscoring their global influence. Cluster analysis revealed 4 major research domains: clinical diagnosis, treatment, and prognosis; molecular mechanisms and signaling pathways; gene and protein function studies; and research methodologies and experimental models. CONCLUSION: RB research is transitioning into an era of precision oncology, characterized by molecular subtyping, novel therapeutic targets, and individualized treatment approaches. While diagnostic and therapeutic outcomes have markedly improved in high-income countries, significant disparities persist in low- and middle-income regions due to limited access to early detection and comprehensive care. Future priorities should include the refinement of preclinical models, investigation of drug resistance mechanisms, and promotion of international collaboration to standardize diagnostic and therapeutic strategies. These efforts are critical to improving global outcomes for children with RB.

Retinoblastoma↗

PubMed2024

ALDH1A1 promotes immune escape of tumor cells through ZBTB7B-glycolysis pathway.

The primary impediment to the success of immunotherapy lies in the immune evasion orchestrated by tumors, contributing to the suboptimal overall response rates observed. Despite this recognition, the intricacies of the underlying mechanisms remain incompletely understood. Through preliminary detection of clinical patient tissues, we have found that ALDH1A1 was a key gene for the prognosis of cancer patients and tumor glycolysis. In vitro experiments and tumor formation in nude mice suggested that targeting ALDH1A1 could inhibit tumor growth. Through further analysis of xenograft tumor models in immune-normal mice and flow cytometry, we found that deficiency in ALDH1A1 could promote immune system suppression of tumors in vivo. Specifically, RNA-seq analysis, combined with qPCR and western blot, identified the transcription factor ZBTB7B as downstream of ALDH1A1. The binding sites of the transcription factor ZBTB7B on the LDHA promoter region, which is responsible for regulating the rate-limiting enzyme gene LDHA in glycolysis, were determined using luciferase reporter gene detection and Chip-qPCR, respectively. In addition, the increased SUMOylation of ZBTB7B stabilized its transcriptional activity. Further in vivo and in vitro experiments confirmed that the combination of targeting ALDH1A1 and ZBTB7B with immune checkpoint inhibitors could synergistically inhibit tumors in vivo. Finally, after conducting additional verification of patient tissue and clinical data, we have confirmed the potential translational value of targeting ALDH1A1 and ZBTB7B for tumor immunotherapy. These results emphasize the potential translational significance of targeting ALDH1A1 and ZBTB7B in the realm of tumor immunotherapy. The convergence of ALDH1A1 inhibition and immune checkpoint blockade, particularly with PD-L1/PD-1 mAb, presents a compelling avenue for curtailing tumor immune escape.

Animals↗

PubMed2026

HoT auto-blinking probes enable real-time, super-resolution chromatin imaging in live cells and tissues.

Single-molecule localization microscopy (SMLM) enables visualization of chromatin architecture at nanoscale resolution. However, high-performance DNA probes suitable for SMLM in both live cells and tissues remain limited. We developed Hoechst-6-Carboxytetramethylrhodamine (6-TAMRA) derivative (HoT) probes-rhodamine-based derivatives conjugated to a Hoechst moiety-through structural fine-tuning of rhodamine spirocyclization. HoTs are self-assembling, auto-blinking probes with excellent photostability and high temporal resolution. They permeate live cells, enabling long-term, real-time nanoscopic chromatin imaging in live and fixed cells and in tissue sections. In live cells, we identified nanoscale features in the 3D organization of chromatin and quantified DNA fiber kinetics at high resolution. We quantified DNA compaction in single cells within retinal and colon cancer sections. OligoSTORM (stochastic optical reconstruction microscopy)-labeled gene loci can be visualized and measured within their HoT-labeled chromatin footprints. Our work provides powerful tools for investigating chromatin structure and functions in living cells and tissues, with applications ranging from cancer diagnosis to retinal regeneration.

Chromatin↗