TY - JOUR
T1 - Molecular analysis of cancer genomes in children with Lynch syndrome
T2 - Exploring causal associations
AU - Weijers, Dilys D
AU - Hirsch, Steffen
AU - Bakhuizen, Jette J
AU - van Engelen, Nienke
AU - Kester, Lennart A
AU - Kranendonk, Mariëtte E G
AU - Hiemcke-Jiwa, Laura S
AU - de Vos-Kerkhof, Evelien
AU - Loeffen, Jan L C
AU - Autry, Robert J
AU - Pajtler, Kristian W
AU - Jäger, Natalie
AU - Jongmans, Marjolijn C J
AU - Kuiper, Roland P
N1 - © 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
PY - 2024/4/15
Y1 - 2024/4/15
N2 - 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.
AB - 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.
KW - Child
KW - Humans
KW - Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
KW - Colorectal Neoplasms/pathology
KW - Neoplastic Syndromes, Hereditary
KW - Brain Neoplasms/genetics
KW - Germ-Line Mutation
KW - DNA Mismatch Repair/genetics
KW - Microsatellite Instability
KW - MutL Protein Homolog 1/genetics
KW - Lynch syndrome
KW - cancer predisposition
KW - mismatch repair
KW - mutational signatures
KW - pediatric cancer
UR - https://www.mendeley.com/catalogue/f33c24d6-b4b2-3c36-b710-8ea38724611e/
U2 - 10.1002/ijc.34832
DO - 10.1002/ijc.34832
M3 - Article
C2 - 38175816
SN - 0020-7136
VL - 154
SP - 1455
EP - 1463
JO - International journal of cancer
JF - International journal of cancer
IS - 8
ER -