Molecular and Clinical Genetics of Retinoblastoma

Retinoblastoma (RB) is the most common intraocular cancer in children affecting all populations. Prognosis is highly dependent on the timing of diagnosis. Late presentation with extraocular spread is often fatal. In contrast, early-staged diseases are mostly curable using systemic plus focal therapy. Therefore, early presymptomatic diagnosis and even prenatal diagnosis are crucial to improve the clinical outcome. In recent years extensive studies on the RB1 gene and other RB-related genes have contributed to the better understanding of the disease mechanism. Inactivation of both copies of the RB1 gene on chromosome 13q14, due to loss-of-function mutations, is a prerequisite for tumorigenesis in RB. Secondary genetic alterations, such as lesions in another gene, are necessary to precipitate tumour development. We have found in Hong Kong Chinese about 19% of RB patients carry a germ-line RB1 mutation with no methylation at the RB1 promoter. We detected inactivation of the RB1 gene by loss-of-function mutations and loss of heterozygosity (LOH), but rarely by promoter hypermethylation, in Chinese sporadic RB. Promoter hypermethylation that silences gene expressions in the tumour suppressor gene RASSF1A and the DNA repair genes MGMT and MLH1 is a causative factor of retinoblastoma. We have also revealed the presence of microsatellite instability and recurrent loss of heterozygosity at multiple chromosomal regions in the retinoblastoma genome, showing genes other than RB1 as primary or secondary cause of retinoblastoma. Recently, we are working on extraocular regulation of RB development. Our studies on Chinese RB samples have led to useful information in the RB genome and cell biology for novel design of therapeutic modalities for RB.