Journal Article

DKFZ-2022-01906

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Heterozygous BRCA1/2 and Mismatch Repair Gene Pathogenic Variants in Children and Adolescents with Cancer.

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

2022
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/jnci/djac151

Abstract: 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.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.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.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.

Note: 2022 Nov 14;114(11):1523-1532

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Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. DKTK HD zentral (HD01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2022

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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