Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Frequency of low-level and high-level mosaicism in sporadic retinoblastoma: genotype–phenotype relationships

Journal of Human Genetics volume 65, pages 165–174 (2020)Cite this article

Subjects

Abstract

Somatic mutational mosaicism is a common feature of monogenic genetic disorders, particularly in diseases such as retinoblastoma, with high rates of de novo mutations. The detection and quantification of mosaicism is particularly relevant in these diseases, since it has important implications for genetic counseling, patient management, and probably also on disease onset and progression. In order to assess the rate of somatic mosaicism (high- and low-level mosaicism) in sporadic retinoblastoma patients, we analyzed a cohort of 153 patients with sporadic retinoblastoma using ultra deep next-generation sequencing. High-level mosaicism was detected in 14 out of 100 (14%) bilateral patients and in 11 out of 29 (38%) unilateral patients in whom conventional Sanger sequencing identified a pathogenic mutation in blood DNA. In addition, low-level mosaicism was detected in 3 out of 16 (19%) unilateral patients in whom conventional screening was negative in blood DNA. Our results also reveal that mosaicism was associated to delayed retinoblastoma onset particularly in unilateral patients. Finally we compared the level of mosaicism in different tissues to identify the best DNA source to identify mosaicism in retinoblastoma patients. In light of these results we recommended analyzing the mosaic status in all retinoblastoma patients using accurate techniques such as next-generation sequencing, even in those cases in which conventional Sanger sequencing identified a pathogenic mutation in blood DNA. Our results suggest that a significant proportion of those cases are truly mosaics that could have been overlooked. This information should be taking into consideration in the management and genetic counseling of retinoblastoma patients and families.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Dimaras H, Corson TW, Cobrinik D, White A, Zhao J, Munier FL, et al. Retinoblastoma. Nat Rev Dis Prim. 2015;1:15021.

    Article  Google Scholar 

  2. Dimaras H, Kimani K, Dimba EA, Gronsdahl P, White A, Chan HS, et al. Retinoblastoma. Lancet 2012;379:1436–46.

    Article  Google Scholar 

  3. Lohmann D. Retinoblastoma. Adv Exp Med Biol. 2010;685:220–7.

    Article  CAS  Google Scholar 

  4. Valverde J, Alonso J, Palacios I, Pestana A. RBI gene mutation up-date, a meta-analysis based on 932 reported mutations available in a searchable database. BMC Genet. 2005;6:53.

    Article  Google Scholar 

  5. Alonso J, Garcia-Miguel P, Abelairas J, Mendiola M, Sarret E, Vendrell M, et al. Spectrum of germline RB1 gene mutations in Spanish retinoblastoma patients: phenotypic and molecular epidemiological implications. Hum Mutat 2001;17:412–22.

    Article  CAS  Google Scholar 

  6. Bremner R, Du DC, Connolly-Wilson MJ, Bridge P, Ahmad KF, Mostachfi H, et al. Deletion of RB exons 24 and 25 causes low-penetrance retinoblastoma. Am J Hum Genet. 1997;61:556–70.

    Article  CAS  Google Scholar 

  7. Albrecht P, Ansperger-Rescher B, Schuler A, Zeschnigk M, Gallie B, Lohmann DR. Spectrum of gross deletions and insertions in the RB1 gene in patients with retinoblastoma and association with phenotypic expression. Hum Mutat. 2005;26:437–45.

    Article  CAS  Google Scholar 

  8. Abouzeid H, Schorderet DF, Balmer A, Munier FL. Germline mutations in retinoma patients: relevance to low-penetrance and low-expressivity molecular basis. Mol Vision. 2009;15:771–7.

    CAS  Google Scholar 

  9. Zhu XP, Dunn JM, Phillips RA, Goddard AD, Paton KE, Becker A, et al. Preferential germline mutation of the paternal allele in retinoblastoma. Nature. 1989;340:312–3.

    Article  CAS  Google Scholar 

  10. Biesecker LG, Spinner NB. A genomic view of mosaicism and human disease. Nat Rev Genet. 2013;14:307–20.

    Article  CAS  Google Scholar 

  11. Sippel KC, Fraioli RE, Smith GD, Schalkoff ME, Sutherland J, Gallie BL, et al. Frequency of somatic and germ-line mosaicism in retinoblastoma: implications for genetic counseling. Am J Hum Genet. 1998;62:610–9.

    Article  CAS  Google Scholar 

  12. Waldman L, Mahon SM. Mosaicism: implications for genetic counseling and medical management. Clin J Oncol Nurs. 2017;21:428–32.

    PubMed  Google Scholar 

  13. Rohlin A, Wernersson J, Engwall Y, Wiklund L, Bjork J, Nordling M. Parallel sequencing used in detection of mosaic mutations: comparison with four diagnostic DNA screening techniques. Hum Mutat. 2009;30:1012–20.

    Article  CAS  Google Scholar 

  14. Rushlow D, Piovesan B, Zhang K, Prigoda-Lee NL, Marchong MN, Clark RD, et al. Detection of mosaic RB1 mutations in families with retinoblastoma. Hum Mutat. 2009;30:842–51.

    Article  CAS  Google Scholar 

  15. Cohen AS, Wilson SL, Trinh J, Ye XC. Detecting somatic mosaicism: considerations and clinical implications. Clin Genet. 2015;87:554–62.

    Article  CAS  Google Scholar 

  16. Pagnamenta AT, Lise S, Harrison V, Stewart H, Jayawant S, Quaghebeur G, et al. Exome sequencing can detect pathogenic mosaic mutations present at low allele frequencies. J Hum Genet. 2012;57:70–2.

    Article  CAS  Google Scholar 

  17. Beicht S, Strobl-Wildemann G, Rath S, Wachter O, Alberer M, Kaminsky E, et al. Next generation sequencing as a useful tool in the diagnostics of mosaicism in Alport syndrome. Gene. 2013;526:474–7.

    Article  CAS  Google Scholar 

  18. Chen Z, Moran K, Richards-Yutz J, Toorens E, Gerhart D, Ganguly T, et al. Enhanced sensitivity for detection of low-level germline mosaic rb1 mutations in sporadic retinoblastoma cases using deep semiconductor sequencing. Hum Mutat. 2014;35:384–91.

    Article  CAS  Google Scholar 

  19. Amitrano S, Marozza A, Somma S, Imperatore V, Hadjistilianou T, De Francesco S, et al. Next generation sequencing in sporadic retinoblastoma patients reveals somatic mosaicism. Eur J Hum Genet. 2015;23:1523–30.

    Article  CAS  Google Scholar 

  20. Li WL, Buckley J, Sanchez-Lara PA, Maglinte DT, Viduetsky L, Tatarinova TV, et al. A rapid and sensitive next-generation sequencing method to detect RB1 mutations improves care for retinoblastoma patients and their families. J Mol Diagn. 2016;18:480–93.

    Article  CAS  Google Scholar 

  21. Dehainault C, Golmard L, Millot GA, Charpin A, Lauge A, Tarabeux J, et al. Mosaicism and prenatal diagnosis options: insights from retinoblastoma. Eur J Hum Genet. 2017;25:381–3.

    Article  CAS  Google Scholar 

  22. Imperatore V, Pinto AM, Gelli E, Trevisson E, Morbidoni V, Frullanti E, et al. Parent-of-origin effect of hypomorphic pathogenic variants and somatic mosaicism impact on phenotypic expression of retinoblastoma. Eur J Hum Genet. 2018;26:1026–37.

    Article  CAS  Google Scholar 

  23. Alonso J, Garcia-Miguel P, Abelairas J, Mendiola M, Pestana A. A microsatellite fluorescent method for linkage analysis in familial retinoblastoma and deletion detection at the RBI locus in retinoblastoma and osteosarcoma. Diagnostic Mol Pathol. 2001;10:9–14.

    Article  CAS  Google Scholar 

  24. Dehainault C, Michaux D, Pages-Berhouet S, Caux-Moncoutier V, Doz F, Desjardins L, et al. A deep intronic mutation in the RB1 gene leads to intronic sequence exonisation. Eur J Hum Genet. 2007;15:473–7.

    Article  CAS  Google Scholar 

  25. Kleinerman RA, Yu CL, Little MP, Li Y, Abramson D, Seddon J, et al. Variation of second cancer risk by family history of retinoblastoma among long-term survivors. J Clin Oncol. 2012;30:950–7.

    Article  Google Scholar 

  26. Kleinerman RA, Tucker MA, Abramson DH, Seddon JM, Tarone RE, Fraumeni JF Jr. Risk of soft tissue sarcomas by individual subtype in survivors of hereditary retinoblastoma. J Natl Cancer Inst. 2007;99:24–31.

    Article  Google Scholar 

  27. Wong JR, Morton LM, Tucker MA, Abramson DH, Seddon JM, Sampson JN, et al. Risk of subsequent malignant neoplasms in long-term hereditary retinoblastoma survivors after chemotherapy and radiotherapy. J Clin Oncol. 2014;32:3284–90.

    Article  Google Scholar 

  28. Temming P, Viehmann A, Arendt M, Eisele L, Spix C, Bornfeld N, et al. Pediatric second primary malignancies after retinoblastoma treatment. Pediatr Blood Cancer. 2015;62:1799–804.

    Article  Google Scholar 

Download references

Acknowledgements

This work has been supported by grants from the Instituto de Salud Carlos III (PI12/00816; PI16CIII/00026); Asociación Pablo Ugarte (TPY-M 1149/13; TRPV 205/18), ASION (TVP 141/17), and Fundación Sonrisa de Alex & Todos somos Iván (TVP 1324/15). CRM was supported by contracts from the Ministry of Economy and Competitiveness (PTA2012-7562-I), and Asociación Pablo Ugarte. SM was supported by a contract from the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER-ISCIII).

Author information

Author notes

  1. These authors contributed equally: Carlos Rodríguez-Martín, Cristina Robledo, Gema Gómez-Mariano

Authors and Affiliations

  1. Unidad de Tumores Sólidos Infantiles, Instituto de Investigación de Enfermedades Raras, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain

    Carlos Rodríguez-Martín, Cristina Robledo & Javier Alonso

  2. Instituto de Investigación de Enfermedades Raras, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain

    Gema Gómez-Mariano, Beatriz Martínez-Delgado & Manuel Posada

  3. Bioinformatics Unit, Core Scientific and Technical Units, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain

    Sara Monzón & Isabel Cuesta

  4. University Hospital La Paz, Madrid, Spain

    Ana Sastre & Jose Abelairas

  5. Pediatric Oncohematology Deparment, Vall d’Hebron Hospital, Barcelona, Spain

    Constantino Sábado

  6. Pediatric Ophthalmology Department, Vall d’Hebron Hospital, Barcelona, Spain

    Nieves Martín-Begué

  7. Parc Taulí Hospital Universitari. Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain

    Joan Carles Ferreres

  8. Pediatric Onco-Hematology Unit, Hospital Universitario Virgen Macarena, Sevilla, Spain

    Ana Fernández-Teijeiro

  9. Department of Anatomic Pathology, Hospital Universitario Virgen Macarena, Sevilla, Spain

    Ricardo González-Campora & María José Rios-Moreno

  10. Genomics Unit, Core Scientific and Technical Units, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain

    Ángel Zaballos

  11. Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III (CB06/07/1009; CIBERER-ISCIII), Majadahonda, Madrid, Spain

    Beatriz Martínez-Delgado, Manuel Posada & Javier Alonso

Authors
  1. Carlos Rodríguez-Martín
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cristina Robledo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gema Gómez-Mariano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sara Monzón
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ana Sastre
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jose Abelairas
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Constantino Sábado
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nieves Martín-Begué
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Joan Carles Ferreres
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ana Fernández-Teijeiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ricardo González-Campora
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. María José Rios-Moreno
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ángel Zaballos
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Isabel Cuesta
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Beatriz Martínez-Delgado
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Manuel Posada
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Javier Alonso
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Javier Alonso.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This project was approved by the institutional ethics committee of the Instituto de Salud Carlos III (PI 17_2012-v2) and written consent were obtained from all patients.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rodríguez-Martín, C., Robledo, C., Gómez-Mariano, G. et al. Frequency of low-level and high-level mosaicism in sporadic retinoblastoma: genotype–phenotype relationships. J Hum Genet 65, 165–174 (2020). https://doi.org/10.1038/s10038-019-0696-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s10038-019-0696-z

This article is cited by

Search

Advanced search

Quick links