Abstract
Retinoblastoma research has been fundamental in uncovering the role of tumor suppressor genes in human cancer and lead to Alfred Knudson’s “two hits” model. However, cytogenetic and comparative genomic hybridization studies in retinoblastoma have shown that, in addition to RB1 mutations (M1-M2 events), other recurrent genomic aberrations (M3-Mn events) are present: gains on 6p, 1q and 2p and losses of 16q. In this scenario, the benign lesion called “retinoma” represents a very interesting tissue to investigate the timing of genomic instability in retinoblastoma. We employed array-CGH methodology at high-resolution (25 kb) to analyse 18 eye samples, 10 from bilateral and 8 from unilateral retinoblastoma patients. Interestingly, two unilateral cases also showed areas of retinoma. The highly frequent rearrangements involved chromosomes 1, 2, 6, 9, 11 and 13. In particular, the entire p arm of chromosome 6 was duplicated in 40% of cases. Results also demonstrated that bilateral cases show a lower number of rearrangements respect to unilateral cases, with statistical significance (p = 0.002). As concerns the group of unilateral cases, it can be divided into low and high-level chromosomal instability groups (respectively ≤4 and ≥7 rearrangements), the first presenting with younger age at diagnosis. In one retinoma, ophthalmoscopically diagnosed, array-CGH did not reveal any genomic aberration. In the other case of retinoma, identified by retrospective histopatological examination, array-CGH revealed the presence of five genomic imbalances. Two gene-free rearrangements were retinoma specific; three were in common with adjacent retinoblastoma. One rearrangement (dup5p) was present only in retinoblastoma and included SKP2 as interesting candidate gene for retinoma-retinoblastoma transition. Array-CGH therefore demonstrated that the two retinomas are indeed different molecular entities: the first is a pretumoral lesion while the second one represents a subclone of cells adjacent to another subclone bearing a set of rearrangements with more selective growth advantage.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Balmer A, Munier F, Gailloud C (1991) Retinoma. Cases studies. Ophtalmic Paediatr Genet 12:131–137
Bowles E, Corson TW, Bayani J, Squire JA, Wong N, Lai PB, Gallie BL (2007) Profiling genomic copy number changes in retinoblastoma beyond loss of RB1. Genes Chromosomes Cancer 46:118–129
Brummelkamp TR, Nijman SM, Dirac AM, Bernards R (2003) Loss of the cylindromatosis tumor suppressor inhibits apoptosis by activating NF- kappaB. Nature 424:797–801
Callagy G, Pharoah P, Chin SF, Sangan T, Daigo Y, Jackson L, Caldas C (2005) Identification and validation of prognostic markers in breast cancer with the complementary use of array-CGH and tissues microarrays. J Pathol 205:388–396
Carrano AC, Eytan E, Hershko A, Pagano M (1999) SKP2 is required for ubiquitin- mediated degradation of the CDK inhibitor p27. Nat Cell Biol 1:193–199
Comings DE (1973) A general theory of carcinogenesis. Proc Natl Acad Sci USA 70:3324–3328
Corson TW, Gallie BL (2007) One hit, two hits, three hits, more? Genomic changes in the development of retinoblastoma. Genes Chromosomes Cancer 46(7):617–34
Dimaras H, Khetan V, Halliday W, Orlic M, Prigoda NL, Piovesan B, Marrano P, Corson TW, Eagle RC Jr, Squire JA, Gallie BL (2008) Loss of RB1 induces non-proliferative retinoma: increasing genomic instability correlates with progression to retinoblastoma. Hum Mol Genet 17:1363–1372
Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP (1986) A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323:643–646
Gallie BL, Ellsworth RM, Abramson DH, Phillips RA (1982) Retinoma: spontaneous regression of retinoblastoma or benign manifestation of the mutation? Br J Cancer 45:513–521
Gallie BL, Campbell C, Devlin H, Duckett A, Squire JA (1999) Developmental basis of retinal-specific induction of cancer by RB mutation. Cancer Res 59:1731s–1735s
Grasemann C, Gratias S, Stephan H, Schüler A, Schramm A, Klein-Hitpass L, Rieder H, Schneider S, Kappes F, Eggert A, Lohmann DR (2005) Gains and overexpression identify DEK and E2F3 as targets of chromosome 6p gains in retinoblastoma. Oncogene 24:6441–6449
Herzog S, Lohmann DR, Buiting K, Schüler A, Horsthemke B, Rehder H, Rieder H (2001) Marked differences in unilateral isolated retinoblastomas from young and older children studied by comparative genomic hybridization. Hum Genet 108:98–104
Howard RO (1996) Multiple changes in oncogenes and tumor suppressor genes in human retinoblastoma. Trans Am Ophtalmol Soc 94:299–312; discussion 312–314
Hsu T, Trojanowska M, Watson DK (2004) Ets proteins in biological control and cancer. J Cell Biochem 91:896–903
Knudson AJ Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820–823
MacCarty A, Draper GJ, Steliarova-Foucher E, Kingston JE (2006) Retinoblastoma incidence and survival in European children (1978–1997). Report from the Automated Childhood Cancer Information System project. Eur J Cancer 42:2092–2102
Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194:23–28
Nowell PC (1986) Mechanisms of tumor progression. Cancer Res 46:2203–2207
Pinkel D, Segraves R, Sudar D, Clark S, Poole I, Kowb el D, Collins C, Kuo WL, Chen C, Zhai Y, Dairkee SH, Ljung BM, Gray JW, Albertson DG (1998) High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet 20:207–211
Raina D, Kharbanda S, Kufe D (2006) MUC1 oncoprotein blocks nuclear targeting of c-Abl in the apoptotic response to DNA damage. EMBO J 25:3774–3783
Ravichandran KS (2001) Signaling via Shc family adapter proteins. Oncogene 20(44):6322–6330
Sampieri K, Mencarelli MA, Epistolato MC, Toti P, Lazzi S, Bruttini M, De Francesco S, Longo I, Meloni I, Mari F, Acquaviva A, Hadjistilianou T, Renieri A, Ariani F (2008) Genomic differences between retinoma and retinoblastoma. Acta Oncol 47(8):1483–1492
Sampieri K, Amenduni M, Papa FT, Katzaki E, Mencarelli MA, Marozza A, Epistolato MC, Toti P, Lazzi S, Bruttini M, De Filippis R, De Francesco S, Longo I, Meloni I, Mari F, Acquaviva A, Hadjistilianou T, Renieri A, Ariani F (2009) Array comparative genomic hybridization in retinoma and retinoblastoma tissues. Cancer Sci 100(3):465–471; Epub 2009 Jan 29
Scott D (2003) What about prostate cancer? Can Fam Physician 49:1271; author reply 1271–1272
Yendamuri S, Trapasso F, Calin GA (2008) ARLTS1 – a novel tumor suppressor gene. Cancer Lett 264:11–20
Zielinski B, Gratias S, Toedt G, Mendrzyk F, Stange DE, Radlwimmer B, Lohmann DR, Lichter P (2005) Detection of chromosomal imbalances in retinoblastoma by matrix-based comparative genomic hybridization. Genes Chromosomes Cancer 43(3):294–301
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Springer Science+Business Media Dordrecht
About this chapter
Cite this chapter
Amenduni, M., Livide, G., Ariani, F., Renieri, A. (2012). Retinoma and Retinoblastoma: Genomic Hybridisation. In: Hayat, M. (eds) Tumors of the Central Nervous System, Volume 8. Tumors of the Central Nervous System, vol 8. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4213-0_10
Download citation
DOI: https://doi.org/10.1007/978-94-007-4213-0_10
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-007-4212-3
Online ISBN: 978-94-007-4213-0
eBook Packages: MedicineMedicine (R0)