Abstract
A small, but unique subgroup of retinoblastoma has been identified with no detectable mutation in the retinoblastoma gene (RB1) and with high levels of MYCN gene amplification. This manuscript investigated alternate pathways of inactivating pRb, the encoded protein in these tumors. We analyzed the mutation status of the RB1 gene and MYCN copy number in a series of 245 unilateral retinoblastomas, and the phosphorylation status of pRb in a subset of five tumors using immunohistochemistry. There were 203 tumors with two mutations in RB1 (RB1 −/−, 83%), 29 with one (RB1 +/−, 12%) and 13 with no detectable mutations (RB1 +/+, 5%). Eighteen tumors carried MYCN amplification between 29 and 110 copies: 12 had two (RB1 −/−) or one RB1 (RB1 +/−) mutations, while six had no mutations (RB1 +/+). Immunohistochemical staining of tumor sections with antibodies against pRb and phosphorylated Rb (ppRb) displayed high levels of pRb and ppRb in both RB1 +/+ and RB1 +/− tumors with MYCN amplification compared to no expression of these proteins in a classic RB1 −/−, MYCN‐low tumor. These results establish that high MYCN amplification can be present in retinoblastoma with or without coding sequence mutations in the RB1 gene. The functional state of pRb is inferred to be inactive due to phosphorylation of pRb in the MYCN‐amplified retinoblastoma without coding sequence mutations. This makes inactivation of RB1 by gene mutation or its protein product, pRb, by protein phosphorylation, a necessary condition for initiating retinoblastoma tumorigenesis, independent of MYCN amplification.
Highlights
In 1971, Alfred Knudson studied a series of cases of retinoblastoma, a childhood-onset ocular tumor, and proposed the “two-h it-model” [1]
The RB1 gene was scanned for the presence of mutations in the coding exons and in the gene promoter region, exonic copy number changes, and methylation status of the RB1 promoter sequence (Table 1 and Table S1)
Rushlow et al reported a class of novel RB1+/+ retinoblastoma with no genetic mutations in RB1, but having a high level of MYCN amplification (>29 copies) [2]
Summary
In 1971, Alfred Knudson studied a series of cases of retinoblastoma, a childhood-onset ocular tumor, and proposed the “two-h it-model” [1]. According to this model, retinoblastoma is caused by biallelic inactivation of a single gene, retinoblastoma (RB1). Retinoblastoma is caused by biallelic inactivation of a single gene, retinoblastoma (RB1) These two “hits” or mutations originally defined the concept of “tumor suppressor” genes. A small subset of retinoblastoma with no detectable mutation in RB1, and amplification of the MYCN gene was identified [2]. It was hypothesized that MYCN amplification initiated retinoblastoma tumorigenesis in the presence of functional pRb protein [2]
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