Top

01-01-2015 | Ophthalmologic cancers | Article

2. Challenges of Genetic Susceptibility Testing for Retinoblastoma

Author: Megan Harlan Fleischut, M.S., C.G.C.

Publisher: Springer International Publishing

Abstract

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.

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.CrossRefPubMed

American Society of Clinical Oncology. ASCO slide library. http://boa.asco.org/virtual-meeting-and-oncology-slide-library (2004).

BioReference Laboratories. Gene tests laboratory directory. https://www.genetests.org/ (2014).

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.CrossRefPubMedCentralPubMed

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.

Carlson EA, Desnick RJ. Mutational mosaicism and genetic counseling in retinoblastoma. Am J Med Genet. 1979;4:365–81.CrossRefPubMed

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.CrossRefPubMedCentralPubMed

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.CrossRefPubMedCentralPubMed

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.CrossRefPubMed

Dimaras H, Kimani K, Dimba EA, et al. Retinoblastoma. Lancet. 2012;379:1436–46.CrossRefPubMed

Genetic Information Nondiscrimination Act H.R. 493 (2008).

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.CrossRefPubMedCentralPubMed

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.CrossRefPubMedCentralPubMed

Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971;68:820–3.CrossRefPubMedCentralPubMed

Knudson AG. Genetics and the etiology of childhood cancer. Pediatr Res. 1976;10:513–7.CrossRefPubMed

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.PubMedCentralPubMed

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.CrossRefPubMedCentralPubMed

Lohmann DR, Gallie BL. Retinoblastoma. Gene Reviews. Funded by the NIH. Developed at the University of Washington, Seattle. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=retinoblastoma (2000, 2013).

Lohmann DR, Gallie BL. Retinoblastoma: revisiting the model prototype of inherited cancer. Am J Med Genet. 2004;129C:23–8.CrossRefPubMed

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.CrossRefPubMedCentralPubMed

National Cancer Institute. US National Institutes of Health (NIH). Cancer Genetics Overview (PDQ®). http://www.cancer.gov/cancertopics/pdq/prevention/overview/HealthProfessional (2014).

National Society of Genetic Counselors. Genetic Counseling as a Profession. http://www.nsgc.org/About/FAQsDefinitions/tabid/97/Default.aspx (2005).

Offit K, Davis J, Kohut K, et al. Cancer genetic testing and assisted reproduction. J Clin Oncol. 2006a;24:4775–82.CrossRefPubMed

Offit K, Sagi M, Hurley K. Preimplantation genetic diagnosis for cancer syndromes: a new challenge for preventive medicine. JAMA. 2006b;296:2727–30.CrossRefPubMed

Offit K, Thom P. Ethicolegal aspects of cancer genetics. Cancer Treat Res. 2010;155:1–14.CrossRefPubMed

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.CrossRefPubMedCentralPubMed

Price EA, Price K, Kolkiewicz K, et al. Spectrum of RB1 mutations identified in 403 retinoblastoma patients. J Med Genet. 2014;51:208–14.CrossRefPubMed

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.CrossRefPubMedCentralPubMed

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.CrossRefPubMed

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.CrossRefPubMed

Rushlow D, Piovesan B, Zhang K, et al. Detection of mosaic RB1 mutations in families with retinoblastoma. Hum Mutat. 2009;30:842–51.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedCentralPubMed

Temming P, Viehmann A, Biewald E, Lohmann DR. Sporadic unilateral retinoblastoma or first sign of bilateral disease? Br J Ophthalmol. 2013;97:475–80.CrossRefPubMed

Thériault BL, Dimaras H, Gallie BL, Corson TW. The genomic landscape of retinoblastoma: a review. Clin Experiment Ophthalmol. 2014;42:33–52.CrossRefPubMedCentralPubMed

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.PubMedCentralPubMed

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.CrossRefPubMed

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.CrossRefPubMedCentralPubMed

Medicine Matters Oncology

Abstract