Journal Article

DKFZ-2024-00034

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Molecular analysis of cancer genomes in children with Lynch syndrome: Exploring causal associations.

Weijers, D. D. ; Hirsch, S.DKFZ* ; Bakhuizen, J. J. ; van Engelen, N. ; Kester, L. A. ; Kranendonk, M. E. G. ; Hiemcke-Jiwa, L. S. ; de Vos-Kerkhof, E. ; Loeffen, J. L. C. ; Autry, R.DKFZ* ; Pajtler, K.DKFZ* ; Jäger, N.DKFZ* ; Jongmans, M. C. J. ; Kuiper, R. P.

2024
Wiley-Liss Bognor Regis

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Please use a persistent id in citations: doi:10.1002/ijc.34832

Abstract: Lynch syndrome (LS) predisposes to cancer in adulthood and is caused by heterozygous germline variants in a mismatch repair (MMR) gene. Recent studies show an increased prevalence of LS among children with cancer, suggesting a causal relationship. For LS-spectrum (LSS) cancers, including high-grade gliomas and colorectal cancer, causality has been supported by typical MMR-related tumor characteristics, but for non-LSS cancers, causality is unclear. We characterized 20 malignant tumors of 18 children with LS, including 16 non-LSS tumors. We investigated second hits, tumor mutational load, mutational signatures and MMR protein expression. In all LSS tumors and three non-LSS tumors, we detected MMR deficiency caused by second hit somatic alterations. Furthermore, these MMR-deficient tumors carried driver variants that likely originated as a consequence of MMR deficiency. However, in 13 non-LSS tumors (81%), a second hit and MMR deficiency were absent, thus a causal link between LS and cancer development in these children is lacking. These findings demonstrate that causality of LS in children with cancer, which can be determined by molecular tumor characterization, seems to be restricted to specific tumor types. Large molecular and epidemiological studies are needed to further refine the tumor spectrum in children with LS.

Keyword(s): Lynch syndrome ; cancer predisposition ; mismatch repair ; mutational signatures ; pediatric cancer

Note: 2024 Apr 15;154(8):1455-1463

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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 2024

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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