Skip to main content

Advertisement

SpringerLink
Log in

Genetics and Genomics

Cancer in Costello syndrome: a systematic review and meta-analysis

  • Article
  • Published:
British Journal of Cancer Submit manuscript

Abstract

Background

Costello syndrome (CS) is a cancer-predisposition disorder caused by germline pathogenic variants in HRAS. We conducted a systematic review using case reports and case series to characterise cancer risk in CS.

Methods

We conducted a systematic review to identify CS cases to create a retrospective cohort. We tested genotype–phenotype correlations and calculated cumulative incidence and hazard rates (HR) for cancer and cancer-free death, standardised incidence rates (SIR) and survival after cancer.

Results

This study includes 234 publications reporting 621 patients from 35 countries. Over nine percent had cancer, including rhabdomyosarcoma, bladder, and neuroblastoma. The rate of cancer and death associated with p.Gly12Ser were lower when compared to all other variants (P < 0.05). Higher mortality for p.Gly12Cys, p.Gly12Asp, p.Gly12Val and p.Gly60Val and higher malignancy rate for p.Gly12Ala were confirmed (P < 0.05). Cumulative incidence by age 20 was 13% (cancer) and 11% (cancer-free death). HR (death) was 3–4% until age 3. Statistically significant SIRs were found for rhabdomyosarcoma (SIR = 1240), bladder (SIR = 1971), and neuroblastoma (SIR = 60). Survival after cancer appeared reduced.

Conclusions

This is the largest investigation of cancer in CS to date. The high incidence and SIR values found to highlight the need for rigorous surveillance and evidence-based guidelines for this high-risk population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1: PRISMA flowchart.
Fig. 2: Variants in the HRAS gene reported in Costello syndrome literature cases.
Fig. 3: Cumulative incidence accounting for competing risks and annual hazard rates by age.
Fig. 4: Survival after cancer for all cases and stratified by cancer type and variant.

Similar content being viewed by others

Data availability

Data will be made available upon request.

References

  1. Costello JM. A new syndrome: mental subnormality and nasal papillomata. Aust Paediatr J. 1977;13:114–8.

    CAS  PubMed  Google Scholar 

  2. Der Kaloustian VM, Moroz B, McIntosh N, Watters AK, Blaichman S. Costello syndrome. Am J Med Genet. 1991;41:69–73.

    Article  Google Scholar 

  3. Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tidyman WE, Rauen KA. Pathogenetics of the RASopathies. Hum Mol Genet. 2016;25:R123–r32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tidyman WE, Rauen KA. Expansion of the RASopathies. Curr Genet Med Rep. 2016;4:57–64.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Aoki Y, Niihori T, Kawame H, Kurosawa K, Ohashi H, Tanaka Y, et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005;37:1038–40.

    Article  CAS  PubMed  Google Scholar 

  7. Grant AR, Cushman BJ, Cavé H, Dillon MW, Gelb BD, Gripp KW, et al. Assessing the gene-disease association of 19 genes with the RASopathies using the ClinGen gene curation framework. Hum Mutat. 2018;39:1485–93.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Kerr B, Delrue MA, Sigaudy S, Perveen R, Marche M, Burgelin I, et al. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006;43:401–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Estep AL, Tidyman WE, Teitell MA, Cotter PD, Rauen KA. HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. Am J Med Genet A. 2006;140:8–16.

    Article  PubMed  Google Scholar 

  10. Gripp KW, Rauen KA. Costello syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, et al., editors. GeneReviews. University of Washington, Seattle; 1993. https://www.ncbi.nlm.nih.gov/books/NBK1507/.

  11. Jafry M, Sidbury R. RASopathies. Clin Dermatol. 2020;38:455–61.

    Article  PubMed  Google Scholar 

  12. Giannoulatou E, McVean G, Taylor IB, McGowan SJ, Maher GJ, Iqbal Z, et al. Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline. Proc Natl Acad Sci USA. 2013;110:20152–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Abe Y, Aoki Y, Kuriyama S, Kawame H, Okamoto N, Kurosawa K, et al. Prevalence and clinical features of Costello syndrome and cardio-facio-cutaneous syndrome in Japan: findings from a nationwide epidemiological survey. Am J Med Genet A. 2012;158a:1083–94.

    Article  PubMed  Google Scholar 

  14. Gripp KW, Morse LA, Axelrad M, Chatfield KC, Chidekel A, Dobyns W, et al. Costello syndrome: clinical phenotype, genotype, and management guidelines. Am J Med Genet A. 2019;179:1725–44.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kratz CP, Rapisuwon S, Reed H, Hasle H, Rosenberg PS. Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes. Am J Med Genet C Semin Med Genet. 2011;157c:83–9.

    Article  PubMed  Google Scholar 

  16. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Moola SMZ, Tufanaru C, Aromataris E, Sears K, Sfetcu R, Currie M, et al. Systematic reviews of etiology and risk. In: Aromataris E, Munn Z, editor. JBI Manual for Evidence Synthesis. Adelaide, Australia: JBI, Chapter 7, 2020. https://synthesismanual.jbi.global.

  18. Munn Z, Barker TH, Moola S, Tufanaru C, Stern C, McArthur A, et al. Methodological quality of case series studies: an introduction to the JBI critical appraisal tool. JBI Evid Synth. 2020;18:2127–33.

    PubMed  Google Scholar 

  19. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Gelb BD, Cavé H, Dillon MW, Gripp KW, Lee JA, Mason-Suares H, et al. ClinGen’s RASopathy Expert Panel consensus methods for variant interpretation. Genet Med. 2018;20:1334–45.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Rosenberg PS, Greene MH, Alter BP. Cancer incidence in persons with Fanconi anemia. Blood. 2003;101:822–6.

    Article  CAS  PubMed  Google Scholar 

  22. Matthay KK, Maris JM, Schleiermacher G, Nakagawara A, Mackall CL, Diller L, et al. Neuroblastoma. Nat Rev Dis Prim. 2016;2:16078.

    Article  PubMed  Google Scholar 

  23. Kratz CP, Franke L, Peters H, Kohlschmidt N, Kazmierczak B, Finckh U, et al. Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes. Br J Cancer. 2015;112:1392–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Muñoz-Maldonado C, Zimmer Y, Medová M. A comparative analysis of individual RAS mutations in cancer biology. Front Oncol. 2019;9:1088.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33.

    Article  PubMed  Google Scholar 

  26. Chen X, Stewart E, Shelat AA, Qu C, Bahrami A, Hatley M, et al. Targeting oxidative stress in embryonal rhabdomyosarcoma. Cancer Cell. 2013;24:710–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shern JF, Selfe J, Izquierdo E, Patidar R, Chou HC, Song YK, et al. Genomic classification and clinical outcome in rhabdomyosarcoma: a report from an international consortium. J Clin Oncol. 2021;39:2859–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Villani A, Greer MC, Kalish JM, Nakagawara A, Nathanson KL, Pajtler KW, et al. Recommendations for cancer surveillance in individuals with RASopathies and other rare genetic conditions with increased cancer risk. Clin Cancer Res. 2017;23:e83–e90.

    Article  CAS  PubMed  Google Scholar 

  29. Berthold F, Spix C, Erttmann R, Hero B, Michaelis J, Treuner J, et al. Neuroblastoma screening at 1 year of age: the final results of a controlled trial. JNCI Cancer Spectr. 2021;5:pkab041.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Liu L, Toung JM, Jassowicz AF, Vijayaraghavan R, Kang H, Zhang R, et al. Targeted methylation sequencing of plasma cell-free DNA for cancer detection and classification. Ann Oncol. 2018;29:1445–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Page K, Hava N, Ward B, Brown J, Guttery DS, Ruangpratheep C, et al. Detection of HER2 amplification in circulating free DNA in patients with breast cancer. Br J Cancer. 2011;104:1342–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yagyu S, Gotoh T, Iehara T, Miyachi M, Katsumi Y, Tsubai-Shimizu S, et al. Circulating methylated-DCR2 gene in serum as an indicator of prognosis and therapeutic efficacy in patients with MYCN nonamplified neuroblastoma. Clin Cancer Res. 2008;14:7011–9.

    Article  CAS  PubMed  Google Scholar 

  33. Kratz CP, Achatz MI, Brugières L, Frebourg T, Garber JE, Greer MC, et al. Cancer screening recommendations for individuals with Li-Fraumeni syndrome. Clin Cancer Res. 2017;23:e38–e45.

    Article  CAS  PubMed  Google Scholar 

  34. Consul N, Amini B, Ibarra-Rovira JJ, Blair KJ, Moseley TW, Taher A, et al. Li-Fraumeni syndrome and whole-body MRI screening: screening guidelines, imaging features, and impact on patient management. AJR Am J Roentgenol. 2021;216:252–63.

    Article  PubMed  Google Scholar 

  35. Gross AM, Frone M, Gripp KW, Gelb BD, Schoyer L, Schill L, et al. Advancing RAS/RASopathy therapies: an NCI-sponsored intramural and extramural collaboration for the study of RASopathies. Am J Med Genet A. 2020;182:866–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the contribution of Nathan Appel and Jeremy Miller from the Institute of Mathematical Statistics.

Funding

This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, the National Cancer Institute, and the National Institutes of Health.

Author information

Authors and Affiliations

  1. Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA

    Esteban Astiazaran-Symonds, Gina M. Ney, Cecilia Higgs, Leatrisse Oba, Radhika Srivastava & Douglas R. Stewart

  2. Department of Medicine, College of Medicine–Tucson, University of Arizona, Tucson, AZ, USA

    Esteban Astiazaran-Symonds

  3. NIH Library, Office of Research Services, Office of the Director, National Institutes of Health, Bethesda, MD, USA

    Alicia A. Livinski

  4. Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA

    Philip S. Rosenberg

Authors
  1. Esteban Astiazaran-Symonds
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gina M. Ney
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cecilia Higgs
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leatrisse Oba
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Radhika Srivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alicia A. Livinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Philip S. Rosenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Douglas R. Stewart
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors confirm contribution to the paper as follows: study conception and design: AAL, DRS, EAS and PRS; data collection: AAL, CH, EAS, GMN, LO and RS.; analysis and interpretation of results: DRS, EAS, GMN and PRS; draft manuscript preparation: AAL, DRS, EAS, GMN and PRS. All authors reviewed the results and approved the final version of the manuscript.

Corresponding author

Correspondence to Douglas R. Stewart.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

No Institutional Review Board review or approval was necessary for the conduct of this systematic review, and consent was not required.

Consent for publication

Not applicable.

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

Astiazaran-Symonds, E., Ney, G.M., Higgs, C. et al. Cancer in Costello syndrome: a systematic review and meta-analysis. Br J Cancer 128, 2089–2096 (2023). https://doi.org/10.1038/s41416-023-02229-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-023-02229-7

  • Springer Nature Limited

Search

Navigation