Loss at chromosome arm 16q in retinoblastoma: Confirmation of the association with diffuse vitreous seeding and refinement of the recurrently deleted region

Abstract

In addition to mutations in both alleles of the retinoblastoma gene (RB1) alleles, retinoblastomas frequently show additional alterations including loss of chromosome arm 16q. In a previous study, the presence of 16q alterations was found to be associated with diffuse vitreous seeding of this tumor. This growth pattern is clinically important as it determines therapeutic decisions. The present study was designed to test this association and to narrow down the list of candidate genes in the minimal region of genomic loss on chromosome arm 16q. Our data confirm the association of 16q loss and diffuse vitreous seeding and define a minimal region of genomic loss of 6.6 Mb on 16q containing 86 known genes. As retinoblastoma is an embryonic tumor, we assumed that any gene relevant for its progression is likely to show regulated expression during retinogenesis. Microarray expression analysis of RNA from a continuous developmental series of murine retinas identified murine orthologs with regulated expression and these data helped to narrow the number of candidate genes in minimal region to 35. Analysis of gene expression in retinoblastomas with and without the loss of heterozygosity (LOH) on chromosome 16q further reduced this number to 26 candidate genes. One of these genes is cadherin 13 (CDH13) and notably, downregulation of CHD13 has previously been associated with poorer prognosis in various other cancers.

“Monoallelic germline methylation and sequence variant in the promoter of the RB1 gene: a possible constitutive epimutation in hereditary retinoblastoma”

“…This suggests a biparental germinal contribution of both D13 chromosomes to the Rb phenotype. A biparental-specific share of the alleles of chromosome 16 was also observed, which represents information of additional interest in this family since deletion of the long arm of this chromosome (16q) is related to a particular type of Rb [ 34 ].…”

Intravitreal Chemotherapy in the Management of Vitreous Disease in Retinoblastoma

“…Retinoblastoma has a natural tendency to infiltrate and disseminate and intravitreal seeding is an important characteristic of this tumor. It has been suggested that tumors with local and diffuse intravitreal seeding were genetically distinct and that loss of chromosome 16q was strongly associated with diffuse seeding (14). As the intraretinal tumor grows, necrosis, inflammatory reaction, and increased intratumoral pressure lead to a breach in the internal limiting and posterior hyaloid membranes and result in liquefaction of the neighboring vitreous and tumor herniation (15).…”

Retinoblastoma: Etiology, Modeling, and Treatment

“…Interestingly, the 1q gain and 16q loss in tumors are indicative of increased levels of genomic instability and associated with late diagnosis and non-hereditary retinoblastoma [ 27 , 28 , 31 , 33 ]. 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 ].…”