| Summary: | 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. <i>RB1</i> inactivation was found in 79 (97.5%) patients. All specimens had additional molecular alterations. The most common non-<i>RB1</i> gene alteration was <i>BCOR</i> in 19 (22.9%). Five (11.0%) had pathogenic germline mutations in other non-<i>RB1</i> cancer predisposition genes. Significant clinicopathologic correlations included: vitreous seeds associated with 1q gains and 16q loss of heterozygosity (BH-corrected <i>p</i>-value = 0.008, 0.004; OR = 12.6, 26.7, respectively). <i>BCOR</i> mutations were associated with poor prognosis, specifically metastases-free survival (MFS) (nominal <i>p</i>-value 0.03). Furthermore, retinoblastoma patients can have non-<i>RB1</i> 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.
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