Variability in retinoblastoma genome stability is driven by age and not heritability

Abstract

Retinoblastoma (RB) is a childhood intraocular cancer initiated by biallelic inactivation of the RB tumor suppressor gene (RB1−/−). RB can be hereditary (germline RB1 pathogenic allele is present) or non‐hereditary. Somatic copy number alterations (SCNAs) contribute to subsequent tumorigenesis. Previous studies of only enucleated RB eyes have reported associations between heritability status and the prevalence of SCNAs. Herein, we use an aqueous humor (AH) liquid biopsy to investigate RB genomic profiles in the context of germline RB1 status, age, and International Intraocular Retinoblastoma Classification (IIRC) clinical grouping for both enucleated and salvaged eyes. Between 2014 and 2019, AH was sampled from a total of 54 eyes of 50 patients. Germline RB1 status was determined from clinical blood testing, and cell‐free DNA from AH was analyzed for SCNAs. Of the 50 patients, 23 (46.0%; 27 eyes) had hereditary RB, and 27 (54.0%, 27 eyes) had non‐hereditary RB. Median age at diagnosis was comparable between hereditary (13 ± 10 months) and non‐hereditary (13 ± 8 months) eyes (P = 0.818). There was no significant difference in the prevalence or number of SCNAs based on (1) hereditary status (P > 0.56) or (2) IIRC grouping (P > 0.47). There was, however, a significant correlation between patient age at diagnosis, and (1) number of total SCNAs (r[52] = 0.672, P < 0.00001) and (2) number of highly‐recurrent RB SCNAs (r[52] = 0.616, P < 0.00001). This evidence does not support the theory that specific molecular or genomic subtypes exist between hereditary and non‐hereditary RB; rather, the prevalence of genomic alterations in RB eyes is strongly related to patient age at diagnosis.

Recurrent Somatic Chromosomal Abnormalities in Relapsed Extraocular Retinoblastoma

“…In this report of the genomic alterations of a large cohort (considering its infrequency) of patients with relapsed extraocular retinoblastoma, we identified CNA at higher frequency than those reported for intraocular patients ( Table 2). 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].…”

“…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].…”

Clinical, Genomic, and Pharmacological Study of MYCN-Amplified RB1 Wild-Type Metastatic Retinoblastoma

“…However, because there are currently no specific clinical patterns aiding for the differential diagnosis of MYCN RB1 cases, it would be difficult to clinically identify this subtype. Access to aqueous humor sampling could provide the tool to genotype and tailor therapy in these patients [ 24 , 25 ]. Of note, our patients were diagnosed at 17 and 30 months, while the median age at diagnosis previously reported was 4.5 months [ 6 ]; thus, it is possible that delay in diagnosis played a role as a determinant for extraocular dissemination, potentially allowing for the acquisition of additional genomic features, as reported for RB1 tumors [ 24 ].…”

Retinoblastoma: Etiology, Modeling, and Treatment

“…Recurrent loss of 16q is believed to impair candidate suppressor genes and is implicated in advanced disease [ 34 , 35 , 36 ]. MYCN gain/amplification occurs in approximately 8% of retinoblastoma and is included in the most common focal genomic aberration [ 24 , 37 , 38 ]. A copy number of MYCN greater than 28 is considered high amplification and is associated with RB1 +/+ or RB1 +/− retinoblastoma [ 37 , 39 ].…”

“…Therefore, well-differentiated tumors develop first, and if diagnosed late or left untreated, may transform and become less differentiated. Less differentiated tumors that appear to lose the cone signature and genomic integrity are commonly found in older patients in contrast to younger patients carrying tumors with a high degree of differentiation [ 33 , 38 , 45 , 51 , 52 ] ( Table 2 ). This also indicates that delayed diagnosis/enucleation significantly affects progression.…”