RE: Childhood, adolescent, and young adulthood cancer risk in BRCA1 or BRCA2 pathogenic variant carriers Free

With interest, we read the publication in this issue of the Journal by Li and colleagues¹ who analyzed the cancer risk in children, adolescents, and young adults with BRCA1 or BRCA2 pathogenic variants. These investigators conducted pedigree analyses on 47 117 individuals from 3086 families and found no evidence for an elevated cancer risk before age 18 years.¹ The study had 80% power to detect an approximate 2-fold increased relative cancer risk in children and adolescents combined but not for rare cancer subtypes. Previous studies suggested that pathogenic variants in BRCA2 play a role in the pathogenesis of childhood rhabdomyosarcoma^2,3 and medulloblastoma⁴ and that BRCA1 pathogenic variants are enriched in neuroblastoma.⁵ As these childhood malignancies are exceedingly rare (eg, the annual incidence rate per million is approximately 5 for rhabdomyosarcoma, approximately 5 for medulloblastoma, and approximately 11 for neuroblastoma⁶) and as the previously reported associations were based on cohorts of individuals with these rare cancers, we suggest the study by Li and colleagues¹ was not sufficiently powered to refute these particular associations. For instance, there were only 2 soft tissue sarcomas (rhabdomyosarcoma is a type of soft tissue sarcoma) in the cohort. Notably, one of them was a BRCA2 pathogenic variant carrier. In addition, the study used self-reported childhood cancer data, which may have led to an underestimation of the cancer risk. Survivorship bias may have led to an underestimation of childhood cancer risk, because pathogenic variant carriers who developed childhood or adolescent cancer were less likely to participate in this study.

Nevertheless, the study is important because it confirms that pathogenic variants in both genes are not associated with a high cancer risk in children or adolescents. Therefore, as recently reported, we agree that children or adolescents should not be offered predictive testing of these genes.⁷ This low absolute risk does not exclude low to moderate increases of the relative risk for rare cancer types. Well powered burden testing studies using large cohorts of patients with rare tumors, suitable controls, and identical analytic pipelines are required.⁷ The notion that loss of heterozygosity is uncommonly observed in childhood or adolescent cancers does not exclude a contribution to cancer risk through alternative mechanisms in pediatric cancers.⁷

We propose that more work is needed before testing of children or adolescents with cancer can be recommended in a purely clinical setting. However, in pediatric oncology centers participating in ongoing germline sequencing research studies, we recommend testing BRCA1 and BRCA2 in children and adolescents with cancer to further define the role of these pathogenic variants in this age group. Pathogenic variants in BRCA1 or BRCA2 increase the risk for subsequent neoplasms in survivors of childhood or adolescent cancer, and this risk may further increase the subsequent neoplasm risk conferred by genotoxic cancer treatments.⁷ Thus, the finding of BRCA1 or BRCA2 pathogenic variants in children or adolescents with cancer may influence future treatment decisions and survivor follow-up schedules as research continues to better understand the relationship of BRCA1 and BRCA2 to pediatric cancer.

Acknowledgments

The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Author contributions

Christian Kratz, MD (Conceptualization; Writing—original draft), Sharon Plon, MD (Conceptualization; Writing—review & editing), and Philip Lupo, PhD (Conceptualization; Writing—review & editing).

Funding

C.P.K. has been supported by the BMBF ADDRess (01GM2205A) and by the Deutsche Kinderkrebsstiftung (DKS 2024.03).

Conflicts of interest

None declared.

Data availability

No new data were generated or analyzed for this response.

References