Retrospective Evaluation of Somatic Alterations in Cell-Free DNA from Blood in Retinoblastoma

Abramson, David H.; Mandelker, Diana; Francis, Jasmine H.; Dunkel, Ira J.; Brannon, A. Rose; Benayed, Ryma; Berger, Michael F.; Arcila, Maria E.; Ladanyi, Marc; Friedman, Danielle Novetsky; Jayakumaran, Gowtham; Diosdado, Monica; Robbins, Melissa; Haggag-Lindgren, Dianna; Shukla, Neerav; Walsh, Michael F.; Kothari, Prachi; Tsui, Dana

doi:10.1016/j.xops.2021.100015

Cited by 18 publications

(20 citation statements)

References 16 publications

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“…Aqueous humor is a suitable source to obtain cell-free DNA from patients with retinoblastoma, allowing not only the diagnosis of RB1 mutations but also identifying potential genomic markers for the risk of treatment failure [34]. The use of hybridization capture and deep sequencing of around 20,000X raw coverage further improves the sensitivity of this technique, allowing the analysis of RB1 aberrations in cell-free DNA in blood samples [35]. However, deep sequencing techniques are generally not available outside large world-referral institutions.…”

Section: Discussionmentioning

confidence: 99%

Identification of immunosuppressive factors in retinoblastoma cell secretomes and aqueous humor from patients

Cuadrado‐Vilanova

Liu

Paco

et al. 2022

The Journal of Pathology

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The microenvironment of retinoblastoma, the solid malignancy of the developing retina, is immunosuppressive. To study the interactions between tumor‐associated microglia/macrophages (TAMs) and tumor cells in retinoblastomas, we analyzed immunohistochemistry markers in 23 patient samples and characterized 105 secreted cytokines of 11 retinoblastoma cell models in culture. We detected profuse infiltration of CD163+ protumoral M2‐like polarized TAMs in eyes enucleated due to cancer progression. Previous treatment of patients increased the number of TAMs but did not affect M2‐like polarization. M2‐like microglia/macrophages were almost absent in five eyes obtained from children enucleated due to nontumoral causes. CD8+ tumor‐infiltrating lymphocytes (TILs) were moderately abundant in tumor eyes and very scarce in nontumoral ones. The expression of the immune checkpoint molecule PD‐L1 was absent in 95% of the tumor samples, which is concordant with the finding of FOXP3+ Tregs infiltrating tumors. We confirmed the pathology results using single‐cell transcriptome analysis of one tumor. We identified the cytokines extracellular matrix metalloproteinase inducer (EMMPRIN) and macrophage migration inhibitory factor (MIF), both with reported immunosuppressive activity, secreted at high levels in retinoblastoma primary cell cultures. Gene expression analysis of a large retinoblastoma cohort and single‐cell transcriptome analysis confirmed that MIF and EMMPRIN were significantly upregulated in retinoblastomas, which led us to quantify both proteins by immunoassays in liquid biopsies (aqueous humor obtained from more than 20 retinoblastoma patients). We found a significant increase in the concentration of MIF and EMMPRIN in cancer patients, compared to 12 noncancer ones. Finally, we showed that macrophages derived from peripheral blood mononuclear cells increased the expression of markers of M2‐like polarization upon exposure to retinoblastoma‐conditioned medium or recombinant MIF. Overall, our findings suggest that retinoblastoma cell secretions induce the protumoral phenotype of this tumor. Our results might have clinical impact in the fields of biomarkers and treatment. © 2022 The Pathological Society of Great Britain and Ireland.

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Section: Discussionmentioning

confidence: 99%

Identification of immunosuppressive factors in retinoblastoma cell secretomes and aqueous humor from patients

Cuadrado‐Vilanova

Liu

Paco

et al. 2022

The Journal of Pathology

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“…None of the 20 patients with bony disease at diagnosis of stage 4a RB relapsed at the original bony site of involvement, and our nonrandomized data suggest that IFRT may not be necessary in patients with bony metastases noted to be in CR or VGPR post ASCT. More sensitive measures for assessment of residual disease are desirable and emerging plasma cell‐free DNA technologies merit evaluation to risk stratify patients at high risk of relapse 17,18 …”

Section: Discussionmentioning

confidence: 99%

Lack of complete response pretransplant is not associated with inferior overall survival for stage 4a metastatic retinoblastoma

Sait

Bernot

Klein

et al. 2022

Pediatric Blood & Cancer

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Background Stage 4a metastatic retinoblastoma (RB) is curable with intensive multimodality therapy including myeloablative chemotherapy with autologous stem cell transplant (HDC‐ASCT) and involved field radiation therapy (IFRT). To our knowledge, no data exist on the impact of (a) pre‐ASCT disease status, and (b) IFRT to sites of metastatic disease post ASCT on survival. Procedure We retrospectively reviewed patients with stage 4a metastatic RB who underwent induction chemotherapy followed by HDC‐ASCT, with or without IFRT, to residual tumor sites at Memorial Sloan Kettering Cancer Center (MSKCC) (n = 24). Results The degree of postinduction response prior to ASCT did not affect outcome, with 5‐year overall survival (OS) of 68% and 86% in patients who achieved complete response (CR) and very good partial response (VGPR)/partial response (PR) prior to ASCT, respectively. IFRT administered post ASCT in patients with possible residual bony metastatic disease increases the likelihood of developing osteosarcoma in the radiation field. Conclusion OS for patients with stage 4a metastatic RB treated with ASCT with VGPR or PR to pretransplant chemotherapy was not significantly different from patients with CR. In addition, IFRT does not seem to be required for bony disease control and increased the likelihood of developing osteosarcoma.

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“…These results are to be interpreted with caution particularly with regard to undetectable cfDNA or VAF thresholds: false-negative results may exist in the presence of active intraocular tumor. 14 An expanded cohort with more regimented collection time points will advance our knowledge further.…”

Section: Discussionmentioning

confidence: 99%

RB1 Circulating Tumor DNA in the Blood of Patients with Unilateral Retinoblastoma

Francis

Gobin

Brannon

et al. 2021

Ophthalmology Science

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Purpose: Circulating tumor DNA (ctDNA) is released by many tumors into the plasma. Its analysis has minimal procedural risk and, in many cancers, has the potential for clinical applications. In retinoblastoma, the clinical correlations of ctDNA in eyes treated without enucleation have not been studied. This purpose of this study was to determine how the ctDNA RB1 variant allele frequency (VAF) changes in patients with unilateral retinoblastoma after intra-arterial chemotherapy (IAC) treatment. Variant allele frequency is a proxy for tumor fraction.Design: Case series from a single tertiary cancer referral center.Participants: Five patients with retinoblastoma with at least 1 measurable ctDNA plasma specimen both at the time of active intraocular retinoblastoma before IAC and after at least 1 IAC cycle.Methods: Circulating tumor DNA RB1 was detected and VAF was measured before and after IAC treatment. Clinical correlations were made using clinical examination, fundus photography, ultrasound, and OCT.Main Outcome Measures: Comparison of ctDNA RB1 VAF before and after IAC treatment for retinoblastoma and concordance of ctDNA RB1 detectability with activity of intraocular disease.Results: Twenty-three ctDNA specimens were included from 5 patients. The 5 baseline RB1 VAFs ranged from 0.27% to 4.23%. In all patients, the subsequent posteintra-arterial RB1 VAF was lower than baseline (0.0%e0.17%). At 4 months (2 months after IAC completion), the ctDNA consistently was negative in the patients who demonstrated clinically inactive intraocular disease.Conclusions: In this small cohort, a decremental decrease in ctDNA RB1 VAF was found after IAC, suggesting that relative VAF changes could be a biomarker of treatment response. Ophthalmology

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Retrospective Evaluation of Somatic Alterations in Cell-Free DNA from Blood in Retinoblastoma

Cited by 18 publications

References 16 publications

Identification of immunosuppressive factors in retinoblastoma cell secretomes and aqueous humor from patients

Identification of immunosuppressive factors in retinoblastoma cell secretomes and aqueous humor from patients

Lack of complete response pretransplant is not associated with inferior overall survival for stage 4a metastatic retinoblastoma

RB1 Circulating Tumor DNA in the Blood of Patients with Unilateral Retinoblastoma

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