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Molecular pathogenesis and cell of origin

TL;DR — Biallelic RB1 loss is necessary for most retinoblastomas but is not sufficient to explain tissue specificity, progression or clinical heterogeneity. Human developmental and single-cell work supports a maturing cone-lineage cell as the susceptible context. Multi-omic studies describe a more differentiated, often heritable subtype and a dedifferentiated, genomically altered subtype enriched for MYCN activity and metastatic propensity. Rare MYCN-amplified, RB1-wild-type tumours should be separated biologically, but evidence is not yet sufficient to define a standard distinct therapy.

Decision-relevant evidence

  • Retinoblastoma forms when both RB1 alleles are inactivated in a susceptible retinal cell, probably a cone photoreceptor precursor whose biochemical state sensitises it to pRB loss; pRB is expressed in almost all tissues, so the cell-of-origin question is about susceptibility, not expression (Dimaras 2015, PMID 27189421).

  • Patient-derived retinal organoids supply the closest thing to a direct test of Knudson's model. Organoids from an induced pluripotent stem cell line carrying a heterozygous germline RB1 variant were engineered to a compound heterozygous state; only the biallelic organoids became tumorigenic, they reproduced retinoblastoma transcriptional profiles with high CRX and OTX2, and the proliferating cells were ARR3-positive maturing cone precursors. Monoallelic organoids were already molecularly abnormal through haploinsufficiency (Li 2022, PMID 36714839).

  • Single-cell profiling of 14,739 cells from two tumours identified two major cell types and five inferred cell states, with cell-cycle-associated cone precursors as the cells of origin and UBE2C as a candidate switch gene in malignant progression (Yang 2021, PMID 34815392).

  • Multi-omic work resolves retinoblastoma into two subtypes rather than one disease. Subtype 1 has earlier onset, includes most heritable cases, carries few alterations beyond the initiating RB1 inactivation and expresses mature cone markers; subtype 2 carries recurrent alterations including MYCN amplification, expresses less differentiated cone together with neuronal/ganglion-cell markers, shows stemness features with low immune and interferon response and E2F/MYC-MYCN activation, and has a higher propensity for metastasis (Liu 2021, PMID 34552068).

  • The rare MYCN-amplified, RB1-wild-type group is clinically distinct but numerically tiny. Two metastatic cases with orbital and cervical nodal involvement and no CNS spread progressed rapidly to death through chemoresistance; both shared high MYCN amplification with 16q and 17p loss, one had a homozygous TP53 mutation by loss of heterozygosity, and a derived cell line was broadly chemoresistant but sensitive to panobinostat–bortezomib and carboplatin–panobinostat combinations. Two patients cannot define a treatment (Zugbi 2020, PMID 32971811).

  • Because transocular biopsy is contraindicated, molecular access runs through the aqueous humour. Cell-free DNA from aqueous humour reproduces the tumour's RB1 genotype: in three enucleated eyes the pathogenic RB1 results from aqueous humour were concordant with direct tumour DNA in all three, and correctly separated the one germline case from the two somatic-only cases (Raval 2022, PMID 35577019). A 2026 systematic review of 14 matched-sample studies reports generally high concordance between aqueous cell-free DNA and tumour tissue for RB1 variants, somatic copy-number alterations and methylation, while identifying low post-treatment cell-free DNA yield, tumour heterogeneity and assay differences as the factors that degrade detection (Darajati 2026, PMID 41521223).

  • Somatic copy-number alterations in aqueous humour carry prognostic signal for the eye. In 63 samples from 29 eyes, detectable alterations were present in 92% of enucleated versus 38% of salvaged eyes (P = 0.006); 6p gain appeared in 77% versus 25% (P = 0.0092) and carried roughly 10-fold odds of enucleation (OR 10, 95% CI 1.8–55.6) (Berry 2018, PMID 30061186). A two-year extension to 116 samples from 50 eyes reproduced the effect — 6p gain in 73.9% of enucleated versus 29.6% of salvaged eyes (P = 0.004), OR 9.87 (1.75–55.65, P = 0.009) — and linked 6p gain to necrosis, higher anaplasia and focal invasion on histopathology (Xu 2020, PMID 32434859).

  • Prospective use as a companion diagnostic is now reported but on small numbers: in 26 eyes of 21 patients sampled at diagnosis, 23 pathogenic RB1 variants and two focal RB1 deletions were identified, copy-number alterations were detectable in 65.4% of samples, and eyes with 6p gain and/or focal MYCN gain had greater odds of poor therapeutic outcome (OR 6.75, 95% CI 1.06–42.84, P = .04); tumour fraction was higher in eyes with vitreal progression than regression (46.0% ± 40.4 versus 22.0 ± 29.1; P = .049) (Berry 2024, PMID 38040321).

  • Whether one aqueous sample represents a heterogeneous tumour is being tested directly. Single-cell whole-genome profiling of 39 manually isolated vitreous-seed cells from one enucleated globe showed heterogeneity with one dominant subclone (23 of 37 cells) whose copy-number profile matched acellular aqueous and vitreous cell-free DNA and the tumour mass with average concordance above 98% — a single-patient result that supports, but does not establish, representativeness (Sirivolu 2024, PMID 39016001).

  • The molecular case for cell-cycle-targeted therapy in retinoblastoma is currently indirect. Work showing that MYCN amplification with retained wild-type RB1 enhances CDK4/6-inhibitor efficacy was performed in neuroblastoma cells, not retinoblastoma, and is retained here only as mechanistic background for the MYCN-driven, RB1-wild-type subgroup (De Rosa 2023, PMID 36982482). Retinoblastoma-specific work is preclinical: abemaciclib suppressed retinoblastoma growth in patient-derived and orthotopic xenografts by reducing CDK1 and CDK2 phosphorylation rather than through canonical CDK4/6 inhibition, with only CDK1 and CDK2 consistently overexpressed across five expression datasets (Yang 2026, PMID 42212883). A live PubMed search on 2026-09-01 restricted to retinoblastoma as a major MeSH topic combined with palbociclib, ribociclib, abemaciclib, CDK4 or CDK6 returned 32 records, none of them a clinical trial in retinoblastoma; as of that date the CDK-inhibitor case in this disease rests entirely on laboratory and xenograft data.

Clinical and research frame

Domain Operational meaning Evidence boundary
Initiation Two functional RB1 hits Most tumours
Competence Cone-lineage developmental program Explains retinal and age specificity
Progression Copy-number, transcriptional and epigenetic change Creates heterogeneity
Rare route MYCN amplification with RB1 retained Aggressive reported phenotype
Liquid biopsy Aqueous-humour cfDNA Research marker; sampling must remain oncologically safe

Interpretation rules

  • Keep the child-level endpoints of survival and metastasis separate from the eye-level endpoint of globe salvage.

  • Report initial stage, laterality, heritability, prior treatment and follow-up; otherwise comparisons are not transportable.

  • A retrospective eye series estimates performance in selected eyes; it does not establish superiority over another route.

  • Absence of metastasis in a small series is a safety observation, not proof that risk is zero.

  • Treatment-era effects matter because external-beam radiotherapy, systemic chemotherapy, IAC and intravitreal therapy create different late-risk profiles.

  • Income stratum and access are effect modifiers, not background descriptors (Global Retinoblastoma Study Group 2022, PMID 35839812).

Evidence register

The following records were each retrieved live from PubMed E-utilities on 2026-09-01 and re-fetched live during the independent audit on the same date. Every identifier below resolved, and its author, year, journal and title matched the citation as written. Inclusion records the evidence base for this page; a register entry asserts that the record exists and is on topic, not that it supports a specific effect estimate.

PMID Year Study or review Role in this page
5279523 1971 Mutation and cancer: statistical study of retinoblastoma. Topic-resolved source (Knudson 1971, PMID 5279523)
27189421 2015 Retinoblastoma. Topic-resolved source (Dimaras 2015, PMID 27189421)
34815392 2021 Single-cell transcriptome profiling reveals intratumoural heterogeneity and malignant progression in retinoblastoma. Topic-resolved source (Yang 2021, PMID 34815392)
34552068 2021 A high-risk retinoblastoma subtype with stemness features, dedifferentiated cone states and neuronal/ganglion cell gene expression. Topic-resolved source (Liu 2021, PMID 34552068)
32971811 2020 Clinical, Genomic, and Pharmacological Study of MYCN-Amplified RB1 Wild-Type Metastatic Retinoblastoma. Topic-resolved source (Zugbi 2020, PMID 32971811)
35839812 2022 The Global Retinoblastoma Outcome Study: a prospective, cluster-based analysis of 4064 patients from 149 countries. Topic-resolved source (Global 2022, PMID 35839812)
36314812 2022 Reconstruct Human Retinoblastoma In Vitro. Topic-resolved source (Zhang 2022, PMID 36314812)
26229489 2015 Diffuse anterior retinoblastoma: current concepts. Topic-resolved source (Yang 2015, PMID 26229489)
36714839 2022 Second hit impels oncogenesis of retinoblastoma in patient-induced pluripotent stem cell-derived retinal organoids: direct evidence for Knudson's theory. Topic-resolved source (Li 2022, PMID 36714839)
36982482 2023 MYCN Amplification, along with Wild-Type RB1 Expression, Enhances CDK4/6 Inhibitors' Efficacy in Neuroblastoma Cells. Neuroblastoma cell-line study; retained by audit 2026-09-01 as MYCN/RB1 mechanistic background only, not as retinoblastoma evidence (De Rosa 2023, PMID 36982482)
32434859 2020 Chromosome 6p Amplification in Aqueous Humor Cell-Free DNA Is a Prognostic Biomarker for Retinoblastoma Ocular Survival. Topic-resolved source (Xu 2020, PMID 32434859)
36130950 2022 Characterizing DNA methylation signatures of retinoblastoma using aqueous humor liquid biopsy. Topic-resolved source (Li 2022, PMID 36130950)
35604935 2022 Liquid biopsy in Retinoblastoma: A review. Topic-resolved source (Ghose 2022, PMID 35604935)
39016001 2024 Single-cell somatic copy number alteration profiling of vitreous humor seeds in retinoblastoma. Topic-resolved source (Sirivolu 2024, PMID 39016001)
38454873 2024 Tumor DNA sampling from aqueous humor in retinoblastoma - A report from South Asia. Topic-resolved source (Meel 2024, PMID 38454873)
39519212 2024 Phenotypic Biomarkers of Aqueous Extracellular Vesicles from Retinoblastoma Eyes. Topic-resolved source (Amacker 2024, PMID 39519212)
36148636 2023 Follow-up of intraocular retinoblastoma through the quantitative analysis of conserved nuclear DNA sequences in aqueous humor from patients. Topic-resolved source (Cuadrado-Vilanova 2023, PMID 36148636)
35577019 2022 Aqueous humor as a surrogate biomarker for retinoblastoma tumor tissue. Topic-resolved source (Raval 2022, PMID 35577019)
29049475 2017 Potential of Aqueous Humor as a Surrogate Tumor Biopsy for Retinoblastoma. Topic-resolved source (Berry 2017, PMID 29049475)
34656762 2021 Highly Sensitive Detection Method of Retinoblastoma Genetic Predisposition and Biomarkers. Topic-resolved source (Le 2021, PMID 34656762)
37410475 2023 CD63/81 Small Extracellular Vesicles in the Aqueous Humor are Retinoblastoma Associated. Topic-resolved source (Pike 2023, PMID 37410475)
34283049 2021 Comprehensive Somatic Copy Number Analysis Using Aqueous Humor Liquid Biopsy for Retinoblastoma. Topic-resolved source (Kim 2021, PMID 34283049)
38040321 2024 Aqueous Humor Liquid Biopsy as a Companion Diagnostic for Retinoblastoma: Implications for Diagnosis, Prognosis, and Therapeutic Options: Five Years of Progress. Topic-resolved source (Berry 2024, PMID 38040321)
40332023 2025 Retinoblastoma: Molecular Evaluation of Tumor Samples, Aqueous Humor, and Peripheral Blood Using a Next-Generation Sequence Panel. Topic-resolved source (Mendes 2025, PMID 40332023)
39862293 2025 MicroRNAs' Significance in Retinoblastoma Diagnosis and Treatment: The Little Heroes. Topic-resolved source (Zamani 2025, PMID 39862293)
41521223 2026 The utility of aqueous humor liquid biopsy in retinoblastoma genetic analysis: a systematic review of concordance and influencing factors. Topic-resolved source (Darajati 2026, PMID 41521223)
32799607 2020 Simultaneous identification of clinically relevant RB1 mutations and copy number alterations in aqueous humor of retinoblastoma eyes. Topic-resolved source (Xu 2020, PMID 32799607)
31683923 2019 The RB1 Story: Characterization and Cloning of the First Tumor Suppressor Gene. Topic-resolved source (Berry 2019, PMID 31683923)
30061186 2018 Genomic cfDNA Analysis of Aqueous Humor in Retinoblastoma Predicts Eye Salvage: The Surrogate Tumor Biopsy for Retinoblastoma. Topic-resolved source (Berry 2018, PMID 30061186)
33805776 2021 Establishing the Clinical Utility of ctDNA Analysis for Diagnosis, Prognosis, and Treatment Monitoring of Retinoblastoma: The Aqueous Humor Liquid Biopsy. Topic-resolved source (Xu 2021, PMID 33805776)
41542805 2026 A bird's eye view on potential molecular prognostic markers in retinoblastoma: insights for precision oncology. Topic-resolved source (Darajati 2026, PMID 41542805)
33717678 2021 The methylation level of TFAP2A is a potential diagnostic biomarker for retinoblastoma: an analytical validation study. Topic-resolved source (Zeng 2021, PMID 33717678)
38615905 2024 Recent progress in retinoblastoma: Pathogenesis, presentation, diagnosis and management. Topic-resolved source (Zhou 2024, PMID 38615905)
25435120 2015 Retinoblastoma. Topic-resolved source (Rodriguez-Galindo 2015, PMID 25435120)
28695165 2017 Neonatal Retinoblastoma. Topic-resolved source (Kivelä 2017, PMID 28695165)
16934146 2006 Retinoblastoma. Topic-resolved source (Aerts 2006, PMID 16934146)
20687510 2010 Retinoblastoma. Topic-resolved source (Lohmann 2010, PMID 20687510)
27488068 2016 Genetics of Retinoblastoma. Topic-resolved source (Mallipatna 2016, PMID 27488068)
35412907 2022 Hereditary retinoblastoma iPSC model reveals aberrant spliceosome function driving bone malignancies. Topic-resolved source (Tu 2022, PMID 35412907)
36408154 2022 Retinoblastoma: Review and new insights. Topic-resolved source (Cruz-Gálvez 2022, PMID 36408154)
42212883 2026 Abemaciclib Inhibits Retinoblastoma Tumor Growth by Targeting CDK1/2. Added by audit 2026-09-01 (Yang 2026, PMID 42212883)

Source chronology

Era marker PMID What the record contributes
1971 5279523 Mutation and cancer: statistical study of retinoblastoma. (Knudson 1971, PMID 5279523)
2006 16934146 Retinoblastoma. (Aerts 2006, PMID 16934146)
2010 20687510 Retinoblastoma. (Lohmann 2010, PMID 20687510)
2015 25435120 Retinoblastoma. (Rodriguez-Galindo 2015, PMID 25435120)
2015 26229489 Diffuse anterior retinoblastoma: current concepts. (Yang 2015, PMID 26229489)
2015 27189421 Retinoblastoma. (Dimaras 2015, PMID 27189421)
2016 27488068 Genetics of Retinoblastoma. (Mallipatna 2016, PMID 27488068)
2017 28695165 Neonatal Retinoblastoma. (Kivelä 2017, PMID 28695165)
2017 29049475 Potential of Aqueous Humor as a Surrogate Tumor Biopsy for Retinoblastoma. (Berry 2017, PMID 29049475)
2018 30061186 Genomic cfDNA Analysis of Aqueous Humor in Retinoblastoma Predicts Eye Salvage: The Surrogate Tumor Biopsy for Retinoblastoma. (Berry 2018, PMID 30061186)
2019 31683923 The RB1 Story: Characterization and Cloning of the First Tumor Suppressor Gene. (Berry 2019, PMID 31683923)
2020 32434859 Chromosome 6p Amplification in Aqueous Humor Cell-Free DNA Is a Prognostic Biomarker for Retinoblastoma Ocular Survival. (Xu 2020, PMID 32434859)
2020 32799607 Simultaneous identification of clinically relevant RB1 mutations and copy number alterations in aqueous humor of retinoblastoma eyes. (Xu 2020, PMID 32799607)
2020 32971811 Clinical, Genomic, and Pharmacological Study of MYCN-Amplified RB1 Wild-Type Metastatic Retinoblastoma. (Zugbi 2020, PMID 32971811)
2021 33717678 The methylation level of TFAP2A is a potential diagnostic biomarker for retinoblastoma: an analytical validation study. (Zeng 2021, PMID 33717678)

Evidence limitations

  • Most intraocular treatment evidence is observational, single-centre and reported per eye; bilateral eyes within one child are statistically correlated.

  • Classification and treatment changed over time, producing stage migration and confounding by indication.

  • Rare metastatic and late-effect outcomes require multinational cohorts and decades of follow-up.

  • Verification is abstract-level. Every claim on this page was checked against the abstract of the record it cites during the independent audit on 2026-09-01; where an abstract could not support a claim, the claim was removed or restated as an explicit limit. Claims requiring full text beyond the abstract are not made here.

Open questions

  • Which inferred cell states prospectively predict metastasis or treatment resistance? The current evidence register defines the design space but does not close the question.

  • Is MYCN-amplified RB1-wild-type disease reproducibly chemotherapy resistant? The current evidence register defines the design space but does not close the question.

  • Can aqueous cfDNA guide therapy without increasing procedural risk? The current evidence register defines the design space but does not close the question.

References

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  2. Dimaras H, et al. Retinoblastoma. Nature reviews. Disease primers. 2015;1:15021. PMID 27189421
  3. Yang J, et al. Single-cell transcriptome profiling reveals intratumoural heterogeneity and malignant progression in retinoblastoma. Cell death & disease. 2021;12:1100. PMID 34815392
  4. Liu J, et al. A high-risk retinoblastoma subtype with stemness features, dedifferentiated cone states and neuronal/ganglion cell gene expression. Nature communications. 2021;12:5578. PMID 34552068
  5. Zugbi S, et al. Clinical, Genomic, and Pharmacological Study of MYCN-Amplified RB1 Wild-Type Metastatic Retinoblastoma. Cancers. 2020;12. PMID 32971811
  6. Global Retinoblastoma Study Group. The Global Retinoblastoma Outcome Study: a prospective, cluster-based analysis of 4064 patients from 149 countries. The Lancet. Global health. 2022;10:e1128-e1140. PMID 35839812
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  8. Yang J, et al. Diffuse anterior retinoblastoma: current concepts. OncoTargets and therapy. 2015;8:1815-21. PMID 26229489
  9. Li YP, et al. Second hit impels oncogenesis of retinoblastoma in patient-induced pluripotent stem cell-derived retinal organoids: direct evidence for Knudson's theory. PNAS nexus. 2022;1:pgac162. PMID 36714839
  10. De Rosa P, et al. MYCN Amplification, along with Wild-Type RB1 Expression, Enhances CDK4/6 Inhibitors' Efficacy in Neuroblastoma Cells. International journal of molecular sciences. 2023;24. PMID 36982482
  11. Xu L, et al. Chromosome 6p Amplification in Aqueous Humor Cell-Free DNA Is a Prognostic Biomarker for Retinoblastoma Ocular Survival. Molecular cancer research : MCR. 2020;18:1166-1175. PMID 32434859
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