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

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.

Fig. 1. PRISMA flowchart.

PRISMA flowchart showing the study selection process. A total of 2952 studies were identified from publication databases, and 1786 duplicates were initially identified and excluded. References were imported to Covidence. Following the screening of titles and abstracts, 777 references were determined to be irrelevant for review. The full text for the 389 remaining articles was reviewed. One hundred and fifty-five were excluded due to (1) having duplicate cases/cohorts, (2) wrong study design, (3) wrong patient population or (4) presenting aggregate data for cases/determined to have high risk for bias. A total of 234 articles that met inclusion and exclusion criteria were ultimately included. PRISMA Preferred Reporting Items for Systematic reviews and Meta-Analyses, LILACS Literatura Latino-Americana e do Caribe em Ciências da Saúde, WHO GIM World Health Organization Global Index of Medicine, DART Digital Access to Research Theses, NDLTD Networked Digital Library of Theses and Dissertations, OATD Open Access Theses and Dissertations, DTD Document Type Definition.

Fig. 2. Variants in the HRAS gene reported in Costello syndrome literature cases.

Lollipop plot of the HRAS gene with the variants reported in Costello syndrome literature cases.

Fig. 3. Cumulative incidence accounting for competing risks and annual hazard rates by age.

a Cumulative incidence for cancer (blue) and cancer-free death (red) in patients with Costello syndrome and 95% CIs (shaded regions). b Annual hazard rates (incidence rate per year among subjects who are still susceptible) cancer (blue) or cancer-free death (red) and 95% point-wise confidence envelopes (shaded regions) for Costello syndrome.

Fig. 4. Survival after cancer for all cases and stratified by cancer type and variant.

Survival after cancer for: a all cases, b all cases stratified by cancer type (n = >1), c rhabdomyosarcoma cases by variant, and d bladder cancer cases by variant.