Unraveling mutagenic processes influencing the tumor mutational patterns of individuals with constitutional mismatch repair deficiency

Dilys D. Weijers, Snežana Hinić, Emma Kroeze, Mark AJ Gorris, Gerty Schreibelt, Sjors Middelkamp, Arjen R. Mensenkamp, Reno Bladergroen, Kiek Verrijp, Nicoline Hoogerbrugge, Pieter Wesseling, Rachel S. Post, Jan LC Loeffen, Corrie EM Gidding, Mariëtte CA Kouwen, I. Jolanda M. Vries, Ruben Boxtel, Richarda M. Voer, Marjolijn CJ Jongmans and Roland P. Kuiper ()
Additional contact information
Dilys D. Weijers: Princess Máxima Center for Pediatric Oncology
Snežana Hinić: Radboud university medical center
Emma Kroeze: Princess Máxima Center for Pediatric Oncology
Mark AJ Gorris: Radboud university medical center
Gerty Schreibelt: Radboud university medical center
Sjors Middelkamp: Princess Máxima Center for Pediatric Oncology
Arjen R. Mensenkamp: Radboud university medical center
Reno Bladergroen: Princess Máxima Center for Pediatric Oncology
Kiek Verrijp: Radboud university medical center
Nicoline Hoogerbrugge: Radboud university medical center
Pieter Wesseling: Princess Máxima Center for Pediatric Oncology
Rachel S. Post: Radboud university medical center
Jan LC Loeffen: Princess Máxima Center for Pediatric Oncology
Corrie EM Gidding: Princess Máxima Center for Pediatric Oncology
Mariëtte CA Kouwen: Radboud university medical center
I. Jolanda M. Vries: Radboud university medical center
Ruben Boxtel: Princess Máxima Center for Pediatric Oncology
Richarda M. Voer: Radboud university medical center
Marjolijn CJ Jongmans: Princess Máxima Center for Pediatric Oncology
Roland P. Kuiper: Princess Máxima Center for Pediatric Oncology

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Constitutional mismatch repair deficiency (CMMRD), caused by bi-allelic germline variants in mismatch repair (MMR) genes, is associated with high cancer incidence early in life. A better understanding of mutational processes driving sequential CMMRD tumors can advance optimal treatment. Here, we describe a genomic characterization on a representative collection of CMMRD-associated tumors consisting of 41 tumors from 17 individuals. Mutational patterns in these tumors appear to be influenced by multiple factors, including the affected MMR gene and tumor type. Somatic polymerase proofreading mutations, commonly present in brain tumors, are also found in a T-cell lymphoblastic lymphoma displaying associated mutational patterns. We show prominent mutational patterns in two second primary hematological malignancies after temozolomide treatment. Furthermore, an indel signature, characterized by one-base pair cytosine insertions in cytosine homopolymers, is found in 54% of tumors. In conclusion, analysis of sequential CMMRD tumors reveals diverse mutational patterns influenced by the affected MMR gene, tumor type and treatment history.

Date: 2025
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DOI: 10.1038/s41467-025-59775-2

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