the identification of the retinoblastoma gene rb1 in 1986   and the discovery of its pivotal role in cell cycle control thrust rb1 and its associated disease , retinoblastoma , to the forefront of cell and cancer biology . inactivation of both alleles of rb1 is a hallmark of retinoblastoma , a rare but aggressive childhood cancer of the retina . today , 26 years since the identification of rb1 , the primary treatment of newly diagnosed retinoblastoma consists of systemic or regional chemotherapy , or enucleation ( surgical removal of the eye ) . the lack of new therapies , despite extensive characterization of the rb1 gene and its manifold functions , is likely to be due to rapid progression of malignancy changes that occur in intraocular retinoblastoma after tumor initiation . as clinicians and pathologists we directly observe a panoply of physical changes occurring inside an eye affected by retinoblastoma . newly arising tumors , usually discovered in the retinas of infants with a family history of the disease , are always the same - small , soft , round , intraretinal , gray - white ' clones ' - as if they were daughter cells arising from a single cell with identical growth characteristics . as these ' clones ' grow , asymmetrical overgrowth appears , which may be due to clonal growth advantages , followed by focal ' nipples ' that shed clumps and strings of cells into the vitreous or subretinal space . this intraocular dispersal of tumor cells is associated with further adjustment to hypoxia , allowing massive tumor growth independently of an obvious vascular supply . eventually , as the eye fills with tumor mass , cells invade both adjacent tissues , the choroid and the optic nerve , signaling to the pathologist an increased risk to the child of metastatic disease . the molecular mechanism(s ) behind these consistently observed phenotypic alterations are not understood . in light of recent findings , however , this may be about to change . in a recent article published in nature , michael dyer and his group were intrigued that retinoblastoma ' ... progresses very quickly following rb1 inactivation ' . to investigate the mechanisms behind this rapid evolution they performed whole genome sequencing ( wgs ) of four retinoblastomas and their corresponding germline dna . they found that the mutation rate in these four tumors was 15-fold less than in adult tumors that have previously been analyzed by wgs . the only gene found to be recurrently mutated ( 13% of 42 retinoblastomas they subsequently studied to validate their findings in a larger cohort ) was the bcl-6 co - repressor gene bcor . as noted by the authors , this is significantly fewer than the number of mutations found in common adult malignancies , where widespread genomic instability and dozens of mutations are the rule . the authors then evaluated epigenetic deregulation as a possible mechanism for the rapid progression of malignancy changes , using an integrative approach involving chromatin immunoprecipitation ( chip ) , dna methylation and gene expression data analysis . of 104 genes that showed differences in expression between fetal retina tissue and retinoblastoma , 15 known cancer genes were shown to have significant differences . among these , syk , which has no known function in eye development , suppression of the syk protein by small molecule inhibitors led to tumor cell death in vitro and in vivo , indicating ' oncogene addiction ' to this kinase in the retinoblastoma cells . the authors concluded that syk could be a promising new therapeutic target for the disease . while the results reported by zhang et al .   are indeed encouraging , syk is unlikely to be the only answer . epigenetic alterations are widespread in many if not most malignancies , pediatric and adult alike , as shown by recent data on adult acute myeloid leukemia and colorectal cancer . in childhood cancer , aberrant methylation of chromosome 11p in wilms ' tumor , embryonal rhabdomyosarcoma , hepatoblastoma and beckwith - wiedemann syndrome ( bws ) is well documented , often a consequence of uniparental disomy . termed loss of heterozygosity ( loh ) , in bws this results in excessive expression of the gene encoding insulin - like growth factor 2 ( igf2 ) as a result of loss of control of imprinting by dna methylation . however , it is important to note that widespread mutation , copy number changes and other regions of loh are also found in these tumors , emphasizing that cancer is a multistep process with many associated genomic alterations . it is also true that genome - wide methylation is aberrant , as documented by the zhang et al . study and as observed , for example , in a subset of highly malignant adult brain tumors , glioblastoma multiforme , where a hypermethylation phenotype has been associated with better prognosis . while dna methylation is one important mechanism in epigenetic regulation of the genome , control of histone methylation and acetylation is also a key epigenetic tool . methylation may regulate entry to gene promoter regions , but histone modifications control access to dna overall ; compact heterochromatin is transcriptionally silent while open euchromatin is active . in the retinoblastoma cases analyzed here , although multiple mutations in any given adult cancer are common , consistent mutation of any specific gene other than tp53 or ras , for example , is uncommon , rarely exceeding 13% . this could suggest that bcor has a key role in retinoblastoma , aside from its known gene expression repressor function related to bcl-6 . in fact , bcor has also been shown to increase methylation of h3k4 and h3k36 , which in turn activates transcription . disabling mutations of bcor , as reported in this study , would presumably broadly impact chromatin remodeling and thus epigenetic control of transcription . but the potential effects on epigenetic control could form the basis of a novel mechanism underlying retinoblastoma . specifically , the reported genome - wide aberrant methylation could well be the result of bcor mutation , or similar mechanisms in those cases with wild - type bcor . beyond epigenetic control mechanisms , there is increasing interest in regulatory functions unrelated to the coding portion of the genome , or exome . zhang and colleagues   documented some hundreds of sequence variants in the non - coding portion of the genome , the impact of which can not be deduced from exome sequencing or rna - seq of poly - a selected mrnas . this ' dark matter ' of the genome is largely intergenic , where these additional mutations were found . in principle , a mutation in a non - coding rna such as h19 , which controls expression of igf2 , could result in the same effect as uniparental disomy and altered methylation . this principle can be extrapolated to the entirety of the transcribed genome , where tens of thousands of additional transcripts have been identified , but whose function is largely unknown . study is a critical defect in the pathogenesis of retinoblastoma , but by no means the only one . cancer is , after all , a multistep process , where many disparate genetic and epigenetic defects lead to a common phenotype . the identification of syk as a potential therapeutic target is an important first step , but hardly the last . bws : beckwith - wiedemann syndrome ; igf2 : insulin - like growth factor 2 ; loh : loss of heterozygosity ; syk : spleen tyrosine kinase .
the role that retinoblastoma has played in our understanding of cancer biology could hardly have been imagined 40 years ago when this disease was a rare curiosity , of interest primarily because of its variable laterality , occasional dominant inheritance , frequent lethality and embyronal origin . 
 the discovery of its cause ( biallelic loss of rb1 ) did not offer insight to improved management . 
 however , the recent discovery of aberrant expression of the gene encoding spleen tyrosine kinase ( syk ) subsequent to widespread methylation abnormalities in retinoblastoma suggests a potential new therapy for the disease . there is more to the story , however .