MYCN amplification levels in primary retinoblastoma tumors analyzed by Multiple Ligation-dependent Probe Amplification

Abstract

Background: Retinoblastoma (Rb) is a childhood tumor of the developing retina where predisposition is caused by RB1 pathogenic variants. MYCN amplification (MYCN^A) has been implicated in around 2% of sporadic unilateral Rb tumors with no detectable RB1 variants. We audited data from tumors collected between 1993 and 2019 to determine if this is the case for patients treated at Barts Health NHS Trust, and how often it occurred alongside RB1 variants. Materials and methods: Screening for MYCN^A was carried out by Multiple Ligation Probe Analysis of tumor and blood samples collected for RB1 genetic screening. The cohort consisted of 149 tumors, of which 114 had matched blood samples. Results: 10/149 (6.7%) tumors were positive for MYCN^A in a population containing a disproportionate number of cases negative for RB1 pathogenic variants. Of 65 unbiased tumors collected from 2014 to 2019, 2 (3.1%) had MYCN^A. All MYCN^A samples were from sporadic, unilateral patients and 3/10 (30%) had RB1 pathogenic variants. MYCN^A was not detected in any blood sample. No MYCN^A tumor had 6p gain which is usually a common alteration in Rbs. Conclusions:MYCN^A occurs in a small fraction of Rbs and can occur in the presence of pathogenic RB1 variants. However, where it occurs alongside RB1 alterations, the age of onset appears to be later. MYCN^A has yet to be seen as a heritable change. In sporadic cases with early diagnosis, Rbs with no RB1 pathogenic variant identified should be tested for MYCN^A. Conversely, tumors with MYCN^A should still be screened for RB1 pathogenic variants.

Keywords: MYCN; RB1; Retinoblastoma; genetic; somatic; sporadic.