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Clinical and Experimental Ophthalmology 2014; 42: 2–3 doi: 10.1111/ceo.12277
Editorial Genomic landscape of retinoblastoma Retinoblastoma (RB) is the most common primary intraocular malignancy in the paediatric population, affecting 1 in 15 000 children. It is initiated by a mutation of the RB1 gene, which was the first described tumour suppressor gene.1 Early diagnosis and advancements in pharmacological treatment strategies coupled with laser consolidation protocols have allowed RB patients to achieve nearly complete cure rates, with a significant number of patients retaining normal vision in at least one eye.2 If left untreated, however, RB can lead to devastating consequences, including blindness and death. Tumours disseminate to the retina, optic nerve, brain parenchyma and systemically. Historically, genetic counselling for the families of RB patients has been complex and challenging. A parent with bilateral RB has a 45% chance of having a child with RB. Furthermore, all children who develop familial RB, unilateral or bilateral, also have a 45% chance of having a child with RB. Only 5% of children with the RB mutation do not develop RB. Individualized screening protocols that vary depending on risk are an integral part of the practice of an ocular oncologist. Early detection of RB allows for better control of tumours with less comorbidity because small tumours are responsive to laser alone. Recent advancements in the understanding of RB genetics continue to shorten the distance towards developing screening tests and individualized treatments. A recent publication by Thériault et al. described the scientific advancements in RB, including next-generation genomic technologies.3 Recent developments in genomic and epigenetic analysis methodologies now allow for a ‘high-resolution’ view of specific aberrations. There is mounting evidence that MDM4, KIF14, MYCN, DEK, E2F3 and CDh11 are driver oncogenes in the progression of RB.3 A unique second mechanism where the RB gene is intact but has MYCN gene amplification has also been described, and it may be associated with a more aggressive clinical presentation.3 However, because MYCN-positive tumours have a wild-type, functional RB gene, they may not develop secondary tumours. Changes in gene expression of KIF14, MDM4,
MYCN, DEK, E2F3, CDH11, miR-17∼92 and SYK have demonstrated importance in RB progression. These genes could be developed into markers that could be used for screening posttreatment or as target of individualized therapy. The protein coded by the RB gene, pRB, is a transcriptional cofactor that functions primarily as a regulator of gene expression influencing multiple cell processes, including cell proliferation, apoptosis, differentiation and DNA remodelling.4 Different mechanisms leading to pRB loss have also been documented, including genomic instability, defects of the DNA mismatch repair system, alterations of DNA methylation, amplification, histone acetylation/ deacetylation and aneuploidy.5–7 More recently, using the LHBETATAG RB murine model, microarray analysis showed that regional and temporal variations in genomic expression were evident in RB tumours.8 Although RB1 gene loss is the underlying causative mutation in RB, multiple genetic alterations have been reported in association with RB.9 The genomic landscape of RB is becoming increasingly complex with new research technologies. However, functional validation of the data regarding RB genetics needs to occur via large clinical trials because most of the RB genomic studies are based on a small number of clinical samples. Genetic testing of patients with a family history of RB is now available.10 It is most useful when the specific mutation associated with the proband is known because those who do not carry the family’s mutation can avoid repeated invasive surveillance procedures under anaesthesia. However, when the genetic mutation of the family is unknown, a negative test does not imply that the patient does not carry the disease. Therefore, family members from a patient with bilateral or multifocal tumours need independent clinical screening even with a negative RB genetic test. Since the discovery of RB1, there have been profound advances in our understanding of the genetic and molecular dysfunctions underlying the development of RB. A new technology in genomic analysis puts us closer to developing targeted therapy for RB
Competing/conflicts of interest: No stated conflict of interest. Funding sources: No stated funding sources. © 2014 Royal Australian and New Zealand College of Ophthalmologists
Editorial patients. However, breakthrough treatment applications are yet to crystallize. As the breadth of knowledge in the genomic landscape of RB evolves, medicine will be able to offer patients enhanced screening protocols and targeted therapies. Victor M Villegas MD, Aaron S Gold OD, Andrea Wildner CRA, Fiona Ehlies CDOS and Timothy G Murray MD MBA Murray Ocular Oncology and Retina
REFERENCES 1. Friend SH, Bernards R, Rogelj S et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 1986; 323: 643–6. 2. Broaddus E, Topham A, Singh AD. Survival with retinoblastoma in the USA: 1975–2004. Br J Ophthalmol 2009; 93: 24–7. 3. Thériault BL, Dimaras H, Gallie BL, Corson TW. The genomic landscape of retinoblastoma: a review. Clin Experiment Ophthalmol 2013; doi: 10.1111/ceo.12132.
3 4. Burkhart DL, Sage J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer 2008; 8: 671–82. doi: 10.1038/nrc2399. 5. Mastrangelo D, De Francesco S, Di Leonardo A, Lentini L, Hadjistilianou T. Retinoblastoma epidemiology: does the evidence matter? Eur J Cancer 2007; 43: 1596–603. 6. Chakraborty S, Khare S, Dorairaj SK, Prabhakaran VC, Prakash DR, Kumar A. Identification of genes associated with tumorigenesis of retinoblastoma by microarray analysis. Genomics 2007; 90: 344–53. 7. Ganguly A, Nichols KE, Grant G, Rappaport E, Shields C. Molecular karyotype of sporadic unilateral retinoblastoma tumors. Retina 2009; 29: 1002–12. 8. Houston SK, Pina Y, Clarke J et al. Regional and temporal differences in gene expression of LH(BETA)T (AG) retinoblastoma tumors. Invest Ophthalmol Vis Sci 2011; 52: 5359–68. 9. Sachdeva UM, O’Brien JM. Understanding pRb: toward the necessary development of targeted treatments for retinoblastoma. J Clin Invest 2012; 122: 425– 34. 10. Rushlow D, Piovesan B, Zhang K et al. Detection of mosaic RB1 mutations in families with retinoblastoma. Hum Mutat 2009; 30: 842–51.
© 2014 Royal Australian and New Zealand College of Ophthalmologists
Clinical and Experimental Ophthalmology 2014; 42: 2–3 doi: 10.1111/ceo.12277
Editorial Genomic landscape of retinoblastoma Retinoblastoma (RB) is the most common primary intraocular malignancy in the paediatric population, affecting 1 in 15 000 children. It is initiated by a mutation of the RB1 gene, which was the first described tumour suppressor gene.1 Early diagnosis and advancements in pharmacological treatment strategies coupled with laser consolidation protocols have allowed RB patients to achieve nearly complete cure rates, with a significant number of patients retaining normal vision in at least one eye.2 If left untreated, however, RB can lead to devastating consequences, including blindness and death. Tumours disseminate to the retina, optic nerve, brain parenchyma and systemically. Historically, genetic counselling for the families of RB patients has been complex and challenging. A parent with bilateral RB has a 45% chance of having a child with RB. Furthermore, all children who develop familial RB, unilateral or bilateral, also have a 45% chance of having a child with RB. Only 5% of children with the RB mutation do not develop RB. Individualized screening protocols that vary depending on risk are an integral part of the practice of an ocular oncologist. Early detection of RB allows for better control of tumours with less comorbidity because small tumours are responsive to laser alone. Recent advancements in the understanding of RB genetics continue to shorten the distance towards developing screening tests and individualized treatments. A recent publication by Thériault et al. described the scientific advancements in RB, including next-generation genomic technologies.3 Recent developments in genomic and epigenetic analysis methodologies now allow for a ‘high-resolution’ view of specific aberrations. There is mounting evidence that MDM4, KIF14, MYCN, DEK, E2F3 and CDh11 are driver oncogenes in the progression of RB.3 A unique second mechanism where the RB gene is intact but has MYCN gene amplification has also been described, and it may be associated with a more aggressive clinical presentation.3 However, because MYCN-positive tumours have a wild-type, functional RB gene, they may not develop secondary tumours. Changes in gene expression of KIF14, MDM4,
MYCN, DEK, E2F3, CDH11, miR-17∼92 and SYK have demonstrated importance in RB progression. These genes could be developed into markers that could be used for screening posttreatment or as target of individualized therapy. The protein coded by the RB gene, pRB, is a transcriptional cofactor that functions primarily as a regulator of gene expression influencing multiple cell processes, including cell proliferation, apoptosis, differentiation and DNA remodelling.4 Different mechanisms leading to pRB loss have also been documented, including genomic instability, defects of the DNA mismatch repair system, alterations of DNA methylation, amplification, histone acetylation/ deacetylation and aneuploidy.5–7 More recently, using the LHBETATAG RB murine model, microarray analysis showed that regional and temporal variations in genomic expression were evident in RB tumours.8 Although RB1 gene loss is the underlying causative mutation in RB, multiple genetic alterations have been reported in association with RB.9 The genomic landscape of RB is becoming increasingly complex with new research technologies. However, functional validation of the data regarding RB genetics needs to occur via large clinical trials because most of the RB genomic studies are based on a small number of clinical samples. Genetic testing of patients with a family history of RB is now available.10 It is most useful when the specific mutation associated with the proband is known because those who do not carry the family’s mutation can avoid repeated invasive surveillance procedures under anaesthesia. However, when the genetic mutation of the family is unknown, a negative test does not imply that the patient does not carry the disease. Therefore, family members from a patient with bilateral or multifocal tumours need independent clinical screening even with a negative RB genetic test. Since the discovery of RB1, there have been profound advances in our understanding of the genetic and molecular dysfunctions underlying the development of RB. A new technology in genomic analysis puts us closer to developing targeted therapy for RB
Competing/conflicts of interest: No stated conflict of interest. Funding sources: No stated funding sources. © 2014 Royal Australian and New Zealand College of Ophthalmologists
Editorial patients. However, breakthrough treatment applications are yet to crystallize. As the breadth of knowledge in the genomic landscape of RB evolves, medicine will be able to offer patients enhanced screening protocols and targeted therapies. Victor M Villegas MD, Aaron S Gold OD, Andrea Wildner CRA, Fiona Ehlies CDOS and Timothy G Murray MD MBA Murray Ocular Oncology and Retina
REFERENCES 1. Friend SH, Bernards R, Rogelj S et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 1986; 323: 643–6. 2. Broaddus E, Topham A, Singh AD. Survival with retinoblastoma in the USA: 1975–2004. Br J Ophthalmol 2009; 93: 24–7. 3. Thériault BL, Dimaras H, Gallie BL, Corson TW. The genomic landscape of retinoblastoma: a review. Clin Experiment Ophthalmol 2013; doi: 10.1111/ceo.12132.
3 4. Burkhart DL, Sage J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer 2008; 8: 671–82. doi: 10.1038/nrc2399. 5. Mastrangelo D, De Francesco S, Di Leonardo A, Lentini L, Hadjistilianou T. Retinoblastoma epidemiology: does the evidence matter? Eur J Cancer 2007; 43: 1596–603. 6. Chakraborty S, Khare S, Dorairaj SK, Prabhakaran VC, Prakash DR, Kumar A. Identification of genes associated with tumorigenesis of retinoblastoma by microarray analysis. Genomics 2007; 90: 344–53. 7. Ganguly A, Nichols KE, Grant G, Rappaport E, Shields C. Molecular karyotype of sporadic unilateral retinoblastoma tumors. Retina 2009; 29: 1002–12. 8. Houston SK, Pina Y, Clarke J et al. Regional and temporal differences in gene expression of LH(BETA)T (AG) retinoblastoma tumors. Invest Ophthalmol Vis Sci 2011; 52: 5359–68. 9. Sachdeva UM, O’Brien JM. Understanding pRb: toward the necessary development of targeted treatments for retinoblastoma. J Clin Invest 2012; 122: 425– 34. 10. Rushlow D, Piovesan B, Zhang K et al. Detection of mosaic RB1 mutations in families with retinoblastoma. Hum Mutat 2009; 30: 842–51.
© 2014 Royal Australian and New Zealand College of Ophthalmologists
