Challenges of Genetic Susceptibility Testing for Retinoblastoma

Part of the Essentials in Ophthalmology book series (ESSENTIALS)


Retinoblastoma (RB) has heritable and non-heritable forms. Testing patients with the heritable form of RB has identified different types of germline RB1 mutations in DNA from either all of the leukocytes in a patient’s blood sample or less often, in a subset of the leukocytes (which is called mosaicism). Unusual mechanisms such as inheritance from the paternal allele affecting disease penetrance or the involvement of other genes such as MED4 have been described. Testing patients with the non-heritable form has revealed mechanisms including promoter hypermethylation and loss of heterozygosity in RB1−/− retinoblastomas. The involvement of the MYCN oncogene has been suggested in a small subset of sporadic unilateral tumors in which the RB1 gene is not mutated. As more patients undergo RB1 genetic testing and laboratory methodologies continually improve, the realm of possible results will further expand. Patients with RB and their families should be introduced to the possible results and the potential uses, risks, and limitations prior to undergoing testing. Having contact with genetics professionals at the disclosure of results and in the future is also recommended. Genetic counselors are part of a multidisciplinary team caring for patients with RB. This chapter’s focus is on the role of genetics professionals and the challenges that clinicians face with the interpretation and complexities of germline testing for these patients.


Cancer Gene Genetic counseling Genetic testing Heritable Mosaicism Retinoblastoma RB1 



I want to thank Erin Salo-Mullen, M.S., C.G.C. and Zsofia Stadler, M.D. for their input for the design of this chapter and Richard Benz, M.S., U.S., Peter Fleischut, M.D. and Margaret Sheehan, M.S., C.G.C. for their review of this manuscript.

Compliance with Ethical Requirements

Megan Harlan Fleischut declares that she has no conflict of interest. No animal or human studies were carried out by the author for this article.


  1. Abramson DA, Frank CM. Second nonocular tumors in survivors of bilateral retinoblastoma. A possible age effect on radiation-related risk. Ophthalmology. 1998;105(4):573–80.CrossRefPubMedGoogle Scholar
  2. American Society of Clinical Oncology. ASCO slide library. (2004).
  3. BioReference Laboratories. Gene tests laboratory directory. (2014).
  4. Bremner R, Du DC, Connolly-Wilson MJ, et al. Deletion of RB exons 24 and 25 causes low-penetrance retinoblastoma. Am J Hum Genet. 1997;61:556–70.CrossRefPubMedCentralPubMedGoogle Scholar
  5. Canadian Retinoblastoma Society. National retinoblastoma strategy Canadian guidelines for care: stratégie thérapeutique du retinoblastoma guide Clinique canadine. Can J Ophthalmol. 2009;44 Suppl 2:S1–88.Google Scholar
  6. Carlson EA, Desnick RJ. Mutational mosaicism and genetic counseling in retinoblastoma. Am J Med Genet. 1979;4:365–81.CrossRefPubMedGoogle Scholar
  7. Castéra L, Dehainault C, Michaux D, et al. Fine mapping of whole RB1 gene deletions in retinoblastoma patients confirms PCDH8 as a candidate gene for psychomotor delay. Eur J Hum Genet. 2013;21:460–4.CrossRefPubMedCentralPubMedGoogle Scholar
  8. Culver JO, Brinkerhoff CD, Clague J, et al. Variants of uncertain significance in BRCA testing: evaluation of surgical decisions, risk perception and cancer distress. Clin Genet. 2013;84(5):464–72.CrossRefPubMedCentralPubMedGoogle Scholar
  9. Dehainault C, Garancher A, Castéra L, et al. The survival gene MED4 explains low penetrance retinoblastoma in patients with large RB1 deletion. Hum Mol Genet. 2014;23(19):5243–50.CrossRefPubMedGoogle Scholar
  10. Dimaras H, Kimani K, Dimba EA, et al. Retinoblastoma. Lancet. 2012;379:1436–46.CrossRefPubMedGoogle Scholar
  11. Genetic Information Nondiscrimination Act H.R. 493 (2008).Google Scholar
  12. Kleinerman RA, Yu CL, Little MP, et al. Variation of second cancer by family history among long-term survivors. J Clin Oncol. 2012;30:950–7.CrossRefPubMedCentralPubMedGoogle Scholar
  13. Klutz M, Brockmann D, Lohmann DR. A parent-of-origin effect in two families with retinoblastoma is associated with a distinct splice mutation in the RB1 gene. Am J Hum Genet. 2002;71:174–9.CrossRefPubMedCentralPubMedGoogle Scholar
  14. Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971;68:820–3.CrossRefPubMedCentralPubMedGoogle Scholar
  15. Knudson AG. Genetics and the etiology of childhood cancer. Pediatr Res. 1976;10:513–7.CrossRefPubMedGoogle Scholar
  16. Lohmann DR, Brandt B, Höpping W, et al. The spectrum of RB1 germ-line mutations in hereditary retinoblastoma. Am J Hum Genet. 1996;58:940–9.PubMedCentralPubMedGoogle Scholar
  17. Lohmann D, Gerick M, Brandt B, et al. Constitutional RB1 gene mutations in patients with isolated unilateral retinoblastoma. Am J Hum Genet. 1997;61(2):282–94.CrossRefPubMedCentralPubMedGoogle Scholar
  18. Lohmann DR, Gallie BL. Retinoblastoma. Gene Reviews. Funded by the NIH. Developed at the University of Washington, Seattle. (2000, 2013).
  19. Lohmann DR, Gallie BL. Retinoblastoma: revisiting the model prototype of inherited cancer. Am J Med Genet. 2004;129C:23–8.CrossRefPubMedGoogle Scholar
  20. Mitter D, Ullmann R, Muradyan A, et al. Genotype-phenotype correlations in patients with retinoblastoma and interstitial 13q deletions. Eur J Hum Genet. 2011;19:947–58.CrossRefPubMedCentralPubMedGoogle Scholar
  21. National Cancer Institute. US National Institutes of Health (NIH). Cancer Genetics Overview (PDQ®). (2014).
  22. National Society of Genetic Counselors. Genetic Counseling as a Profession. (2005).
  23. Offit K, Davis J, Kohut K, et al. Cancer genetic testing and assisted reproduction. J Clin Oncol. 2006a;24:4775–82.CrossRefPubMedGoogle Scholar
  24. Offit K, Sagi M, Hurley K. Preimplantation genetic diagnosis for cancer syndromes: a new challenge for preventive medicine. JAMA. 2006b;296:2727–30.CrossRefPubMedGoogle Scholar
  25. Offit K, Thom P. Ethicolegal aspects of cancer genetics. Cancer Treat Res. 2010;155:1–14.CrossRefPubMedGoogle Scholar
  26. Otterson CA, Chen WD, Coxon AB, Khleif SN, Kaye FJ. Incomplete penetrance of familial retinoblastoma linked to germ-line mutations that result in partial loss of RB function. Proc Natl Acad Sci U S A. 1997;94:12036–40.CrossRefPubMedCentralPubMedGoogle Scholar
  27. Price EA, Price K, Kolkiewicz K, et al. Spectrum of RB1 mutations identified in 403 retinoblastoma patients. J Med Genet. 2014;51:208–14.CrossRefPubMedGoogle Scholar
  28. Richter S, Vandezande K, Chen N, et al. Sensitive and efficient detection of RB1 gene mutations enhances care for families with retinoblastoma. Am J Hum Genet. 2003;72(2):253–69.CrossRefPubMedCentralPubMedGoogle Scholar
  29. Riley BD, Culver JO, Skrzynia C, et al. Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors. J Genet Couns. 2012;21(2):151–61.CrossRefPubMedGoogle Scholar
  30. Robson ME, Storm CD, Weitzel J, Wollins DS, Offit K. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2010;28(5):893–901.CrossRefPubMedGoogle Scholar
  31. Rushlow D, Piovesan B, Zhang K, et al. Detection of mosaic RB1 mutations in families with retinoblastoma. Hum Mutat. 2009;30:842–51.CrossRefPubMedGoogle Scholar
  32. Rushlow D, Mol BM, Kennett JY, et al. Characterization of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncol. 2013;14(4):327–34.CrossRefPubMedGoogle Scholar
  33. Salo-Mullen EE, Guillem JG. The genetic counselor: an important surgical ally in the optimal care of the cancer patient. Adv Surg. 2012;46:137–53.CrossRefPubMedGoogle Scholar
  34. Sippel KC, Fraioli RE, Smith GD, et al. Frequency of somatic and germ-line mosaicism in retinoblastoma: implications for genetic counseling. Am J Hum Genet. 1998;62:610–9.CrossRefPubMedCentralPubMedGoogle Scholar
  35. Temming P, Viehmann A, Biewald E, Lohmann DR. Sporadic unilateral retinoblastoma or first sign of bilateral disease? Br J Ophthalmol. 2013;97:475–80.CrossRefPubMedGoogle Scholar
  36. Thériault BL, Dimaras H, Gallie BL, Corson TW. The genomic landscape of retinoblastoma: a review. Clin Experiment Ophthalmol. 2014;42:33–52.CrossRefPubMedCentralPubMedGoogle Scholar
  37. Weitzel JN, Blazer KR, Macdonald DJ, Culver JO, Offit K. Genetics, genomics, and cancer risk assessment: state of the art and future directions in the era of personalized medicine. CA Cancer J Clin. 2011;61(5):327–59.PubMedCentralPubMedGoogle Scholar
  38. Xu K, Rosenwaks Z, Beaverson K, et al. Preimplantation genetic diagnosis for retinoblastoma: the first reported live born. Am J Ophthalmol. 2004;137(1):18–23.CrossRefPubMedGoogle Scholar
  39. Zeschnigk M, Böhringer S, Price EA, et al. A novel real-time PCR assay for quantitative analysis of methylated alleles (QAMA): analysis of the retinoblastoma locus. Nucleic Acids Res. 2004;32:e125.CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of MedicineClinical Genetics Service, Memorial Sloan Kettering Cancer CenterNew YorkUSA

Personalised recommendations