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Genetics and Genomics

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



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.


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.


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.


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.

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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.

Data availability

Data will be made available upon request.


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


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.

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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.

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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).

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