Reply to Li and Colleagues

We thank Dr Li and colleagues (1) for their correspondence in which the following point related to our publication entitled “Heterozygous BRCA1 and BRCA2 and mismatch repair gene pathogenic variants in children and adolescents with cancer” is raised:

The frequency of BRCA2 pathogenic variant (PV) carriers in the population (including controls) decreases with age, due to the primarily cancer related death of carriers. This factor leads to an overestimation of the childhood cancer risk of BRCA2 PV carriers in the presented analysis.

This is a valid argument. However, the use of an extreme phenotype case–control design (eg, by using healthy elderly controls to search for cancer associated genes) has been successfully employed to maximize power (2).

Nevertheless, our literature review and combined meta-analysis and case–control study has several methodological limitations acknowledged in the discussion. Therefore, the analysis represents an early step, and reported findings require independent validation using a more appropriate design (including matched controls as well as identical pipelines to call PVs in cases and controls).

In addition to our findings that were at least in part confirmed in a validation cohort and a supplementary analysis, there is growing evidence from childhood cancer sequencing studies suggesting that PVs in genes like BRCA1 and BRCA2, as well as other adult-onset cancer predisposition genes, represent (low penetrance) cancer risk alleles in children and adolescents (3-10). Recent results from integrative somatic-germline mutational signature (SBS3/BRCAness) analyses (3) as well as functional analyses (7) support this notion.

Despite several limitations, our findings that require confirmation employing a more sophisticated design agree with other studies providing growing evidence that suggests that variants in BRCA2 and other adult-onset cancer predisposition genes represent low-penetrance cancer risk alleles in children and adolescents.

Data availability

No new data were generated or analyzed for this response.

Author contributions

Christian Kratz, MD (Conceptualization; Writing – original draft); Dmitrii Smirnov, MS (Writing – review & editing); Robert Autry, PhD (Writing – review & editing); Natalie Jäger, PhD (Writing – review & editing); Sebastian M. Waszak, PhD (Writing – review & editing); Anika Großhennig, PhD (Writing – review & editing); Riccardo Berutti, PhD (Writing – review & editing); Mareike Wendorff, PhD (Writing – review & editing); Pierre Hainaut, PhD (Writing – review & editing); Stefan M. Pfister, MD (Writing – review & editing); Holger Prokisch, PhD (Writing – review & editing); Tim Ripperger, MD, PhD (Writing – review & editing); David Malkin, MD (Writing – review & editing)

Funding

CPK and SMP have been supported by the Deutsche Kinderkrebsstiftung (DKS2019.13) and Bundesministerium für Bildung und Forschung (BMBF) ADDRess (01GM1909A and 01GM1909E). RA is supported by the Everest Centre for Low-Grade Paediatric Brain Tumours (the Brain Tumour Charity, UK; GN-000382). SMW is supported by the Research Council of Norway (187615), the South-Eastern Norway Regional Health Authority, and the University of Oslo. TR has been supported by BMBF MyPred (01GM1911B). DM is supported by grants from the Canadian Institutes for Health Research (FDN-143234) and the Terry Fox Research Institute (TFRI #1081). DS and HP have been supported by BMBF (01GM1906B).

Conflicts of interest

None exist.

Acknowledgements

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.