Chromosome 6p Amplification in Aqueous Humor Cell-Free DNA Is a Prognostic Biomarker for Retinoblastoma Ocular Survival

This investigation uses hybridization capture-based next-generation sequencing to deepen our understanding of genetics that underlie retinoblastoma. Eighty-three enucleated retinoblastoma specimens were evaluated using a MSK-IMPACT clinical next-generation sequencing panel to evaluate both somatic and germline alterations. Somatic copy number variations (CNVs) were also identified. Genetic profiles were correlated to clinicopathologic characteristics. RB1 inactivation was found in 79 (97.5%) patients. All specimens had additional molecular alterations. The most common non-RB1 gene alteration was BCOR in 19 (22.9%). Five (11.0%) had pathogenic germline mutations in other non-RB1 cancer predisposition genes. Significant clinicopathologic correlations included: vitreous seeds associated with 1q gains and 16q loss of heterozygosity (BH-corrected p-value = 0.008, 0.004; OR = 12.6, 26.7, respectively). BCOR mutations were associated with poor prognosis, specifically metastases-free survival (MFS) (nominal p-value 0.03). Furthermore, retinoblastoma patients can have non-RB1 germline mutations in other cancer-associated genes. No two specimens had the identical genetic profile, emphasizing the individuality of tumors with the same clinical diagnosis.

Section: Discussioncontrasting

confidence: 99%

Molecular Changes in Retinoblastoma beyond RB1: Findings from Next-Generation Sequencing

Francis

Richards

Mandelker

et al. 2021

“…Retinoblastoma is thought to follow a multistep model for tumor progression [26,27] and bi-allelic inactivation of the RB1 gene alone, though sufficient for retinoblastoma genesis, seems not sufficient for tumor progression, since all our patients show additional CNA. This high number of CNA, as an indicator of increasing genomic instability [26], confirms previous observations reporting CNA in 63% of children with HRPF and 22% in a recent series including nonenucleated eyes [11,20,27]. In addition, our data support a recent observation reporting that age at diagnosis is correlated with the number of CNA in non-metastatic patients with retinoblastoma regardless of laterality [27].…”

Section: Discussionsupporting

confidence: 92%

“…In such studies, other recurrent CNA besides the 13q loss or copy-neutral loss of heterozygosity (CN-LOH), such as gains in chromosomes 1q, 6p, 2p and losses in 16q have been identified in intraocular retinoblastoma, but none has been conclusively related to an increased risk of extraocular relapse. Gain of chromosome 6p, detected during conservative therapy, was identified as a risk factor for enucleation in studies using liquid biopsy from aqueous humor paracentesis [20]. However, despite them being more common in cases with HRPF, their association with extraocular relapse was not established.…”

Section: Introductionmentioning

confidence: 99%

Recurrent Somatic Chromosomal Abnormalities in Relapsed Extraocular Retinoblastoma

Aschero

Francis

Ganiewich

et al. 2021

Most reports about copy number alterations (CNA) in retinoblastoma relate to patients with intraocular disease and features of children with extraocular relapse remain unknown, so we aimed to describe the CNA in this population. We evaluated 23 patients and 27 specimens from 4 centers. Seventeen cases had extraocular relapse after initial enucleation and six cases after an initial preservation attempt. We performed an analysis of CNA and BCOR gene alteration by SNP array (Single Nucleotide Polymorfism array), whole-exome sequencing, IMPACT panel and CGH array (Array-based comparative genomic hybridization). All cases presented CNA at a higher prevalence than those reported in previously published studies for intraocular cases. CNA previously reported for intraocular retinoblastoma were found at a high frequency in our cohort: gains in 1q (69.5%), 2p (60.9%) and 6p (86.9%), and 16q loss (78.2%). Other, previously less-recognized, CNA were found including loss of 11q (34.8%), gain of 17q (56.5%), loss of 19q (30.4%) and BCOR alterations were present in 72.7% of our cases. A high number of CNA including 11q deletions, 17q gains, 19q loss, and BCOR alterations, are more common in extraocular retinoblastoma. Identification of these features may be correlated with a more aggressive tumor warranting consideration for patient management.

“…AH sampling may be combined with eye examination performed under general anesthesia in infants, as well as in combination with intravitreal delivery of chemotherapy. Berry et al demonstrated that a higher AH somatic chromosomal copy number alteration, including 6p gain, was predictive of more advanced and aggressive RBs [97,98]. They found that AH ct-DNA was concordant with ct-DNA providing from a tissue sample of enucleated patients.…”

Section: Retinoblastoma (Rb)mentioning

confidence: 99%

Liquid Biopsy for Solid Ophthalmic Malignancies: An Updated Review and Perspectives

Martel

Baillif²,

Nahon-Estève³

et al. 2020

Tissue biopsy is considered the gold standard when establishing a diagnosis of cancer. However, tissue biopsies of intraocular ophthalmic malignancies are hard to collect and are thought to be associated with a non-negligible risk of extraocular dissemination. Recently, the liquid biopsy (LB) has emerged as a viable, non-invasive, repeatable, and promising way of obtaining a diagnosis, prognosis, and theragnosis of patients with solid tumors. LB refers to blood, as well as any human liquid. The natural history of uveal melanoma (UM) and retinoblastoma (RB) are radically opposed. On the one hand, UM is known to disseminate through the bloodstream, and is, therefore, more accessible to systemic venous liquid biopsy. On the other hand, RB rarely disseminates hematogenous, and is, therefore, more accessible to local liquid biopsy by performing an anterior chamber puncture. In this review, we summarize the current knowledge concerning LB in UM, RB, conjunctival tumors, and choroidal metastases. We also develop the current limitations encountered, as well as the perspectives.