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Kratz, C.P.* ; Smirnov, D. ; Autry, R.* ; Jäger, N.* ; Waszak, S.M.* ; Großhennig, A.* ; Berutti, R. ; Wendorff, M.* ; Hainaut, P.* ; Pfister, S.M.* ; Prokisch, H. ; Ripperger, T.* ; Malkin, D.*

Heterozygous BRCA1 and BRCA2 and mismatch repair gene pathogenic variants in children and adolescents with cancer.

J. Natl. Cancer Inst. 114, 1523-1532 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
BACKGROUND: Genetic predisposition is a significant cause of cancer, yet little is known about the role of "adult cancer predisposition syndromes" in childhood cancer. We examined the extent to which heterozygous pathogenic germline variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, MSH2, MSH6, MLH1, and PMS2 contribute to cancer risk in children and adolescents. METHODS: We conducted a meta-analysis of 11 studies that incorporated comprehensive germline testing for children and adolescents with cancer. ClinVar pathogenic/likely pathogenic variants (PVs) in genes of interest were compared to two control groups. Results were validated in a cohort of mainly European cases and controls. We employed the Proxy External Controls Association Test to account for different pipelines. RESULTS: Among 3,975 children/adolescents with cancer, significant associations with cancer risk were observed for PVs in BRCA1/2 (26 PVs vs 63 PVs among 27,501 controls, OR 2.78, 95%-CI 1.69-4.45, p<.001) and mismatch repair (MMR) genes (19 PVs vs 14 PVs among 27,501 controls, OR 7.33, 95%-CI 3.64-14.82, p<.001). Associations were seen in brain and other solid tumors, yet not in hematologic neoplasms. We confirmed similar findings in 1,664 pediatric cancer patients primarily of European descent. CONCLUSION: These data suggest that heterozygous PVs in BRCA1/2 and MMR genes contribute with reduced penetrance to cancer risk in children/adolescents. No changes to predictive genetic testing and surveillance recommendations are required.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 0027-8874
e-ISSN 1460-2105
Journal Journal of the National Cancer Institute
Quellenangaben Volume: 114, Issue: 11, Pages: 1523-1532 Article Number: , Supplement: ,
Publisher Oxford University Press
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)