Unraveling mutagenic processes influencing the tumor mutational patterns of individuals with constitutional mismatch repair deficiency
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. Her...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-05-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59775-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849725155179233280 |
|---|---|
| author | 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. van der Post Jan LC Loeffen Corrie EM Gidding Mariëtte CA van Kouwen I. Jolanda M. de Vries Ruben van Boxtel Richarda M. de Voer Marjolijn CJ Jongmans Roland P. Kuiper |
| author_facet | 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. van der Post Jan LC Loeffen Corrie EM Gidding Mariëtte CA van Kouwen I. Jolanda M. de Vries Ruben van Boxtel Richarda M. de Voer Marjolijn CJ Jongmans Roland P. Kuiper |
| author_sort | Dilys D. Weijers |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d89bcb0c120e4af1b29aad4234166c64 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d89bcb0c120e4af1b29aad4234166c642025-08-20T03:10:32ZengNature PortfolioNature Communications2041-17232025-05-0116111310.1038/s41467-025-59775-2Unraveling mutagenic processes influencing the tumor mutational patterns of individuals with constitutional mismatch repair deficiencyDilys D. Weijers0Snežana Hinić1Emma Kroeze2Mark AJ Gorris3Gerty Schreibelt4Sjors Middelkamp5Arjen R. Mensenkamp6Reno Bladergroen7Kiek Verrijp8Nicoline Hoogerbrugge9Pieter Wesseling10Rachel S. van der Post11Jan LC Loeffen12Corrie EM Gidding13Mariëtte CA van Kouwen14I. Jolanda M. de Vries15Ruben van Boxtel16Richarda M. de Voer17Marjolijn CJ Jongmans18Roland P. Kuiper19Princess Máxima Center for Pediatric OncologyDepartment of Human Genetics, Radboud university medical centerPrincess Máxima Center for Pediatric OncologyDepartment of Medical BioSciences, Radboud university medical centerDepartment of Medical BioSciences, Radboud university medical centerPrincess Máxima Center for Pediatric OncologyDepartment of Human Genetics, Radboud university medical centerPrincess Máxima Center for Pediatric OncologyDepartment of Medical BioSciences, Radboud university medical centerDepartment of Human Genetics, Radboud university medical centerPrincess Máxima Center for Pediatric OncologyDepartment of Pathology, Radboud university medical centerPrincess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyDepartment of Gastroenterology and Hepatology, Radboud university medical centerDepartment of Medical BioSciences, Radboud university medical centerPrincess Máxima Center for Pediatric OncologyDepartment of Human Genetics, Radboud university medical centerPrincess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyAbstract 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.https://doi.org/10.1038/s41467-025-59775-2 |
| spellingShingle | 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. van der Post Jan LC Loeffen Corrie EM Gidding Mariëtte CA van Kouwen I. Jolanda M. de Vries Ruben van Boxtel Richarda M. de Voer Marjolijn CJ Jongmans Roland P. Kuiper Unraveling mutagenic processes influencing the tumor mutational patterns of individuals with constitutional mismatch repair deficiency Nature Communications |
| title | Unraveling mutagenic processes influencing the tumor mutational patterns of individuals with constitutional mismatch repair deficiency |
| title_full | Unraveling mutagenic processes influencing the tumor mutational patterns of individuals with constitutional mismatch repair deficiency |
| title_fullStr | Unraveling mutagenic processes influencing the tumor mutational patterns of individuals with constitutional mismatch repair deficiency |
| title_full_unstemmed | Unraveling mutagenic processes influencing the tumor mutational patterns of individuals with constitutional mismatch repair deficiency |
| title_short | Unraveling mutagenic processes influencing the tumor mutational patterns of individuals with constitutional mismatch repair deficiency |
| title_sort | unraveling mutagenic processes influencing the tumor mutational patterns of individuals with constitutional mismatch repair deficiency |
| url | https://doi.org/10.1038/s41467-025-59775-2 |
| work_keys_str_mv | AT dilysdweijers unravelingmutagenicprocessesinfluencingthetumormutationalpatternsofindividualswithconstitutionalmismatchrepairdeficiency AT snezanahinic unravelingmutagenicprocessesinfluencingthetumormutationalpatternsofindividualswithconstitutionalmismatchrepairdeficiency AT emmakroeze unravelingmutagenicprocessesinfluencingthetumormutationalpatternsofindividualswithconstitutionalmismatchrepairdeficiency AT markajgorris unravelingmutagenicprocessesinfluencingthetumormutationalpatternsofindividualswithconstitutionalmismatchrepairdeficiency AT gertyschreibelt unravelingmutagenicprocessesinfluencingthetumormutationalpatternsofindividualswithconstitutionalmismatchrepairdeficiency AT sjorsmiddelkamp unravelingmutagenicprocessesinfluencingthetumormutationalpatternsofindividualswithconstitutionalmismatchrepairdeficiency AT arjenrmensenkamp unravelingmutagenicprocessesinfluencingthetumormutationalpatternsofindividualswithconstitutionalmismatchrepairdeficiency AT renobladergroen unravelingmutagenicprocessesinfluencingthetumormutationalpatternsofindividualswithconstitutionalmismatchrepairdeficiency AT kiekverrijp unravelingmutagenicprocessesinfluencingthetumormutationalpatternsofindividualswithconstitutionalmismatchrepairdeficiency AT nicolinehoogerbrugge unravelingmutagenicprocessesinfluencingthetumormutationalpatternsofindividualswithconstitutionalmismatchrepairdeficiency AT pieterwesseling unravelingmutagenicprocessesinfluencingthetumormutationalpatternsofindividualswithconstitutionalmismatchrepairdeficiency AT rachelsvanderpost unravelingmutagenicprocessesinfluencingthetumormutationalpatternsofindividualswithconstitutionalmismatchrepairdeficiency AT janlcloeffen unravelingmutagenicprocessesinfluencingthetumormutationalpatternsofindividualswithconstitutionalmismatchrepairdeficiency AT corrieemgidding unravelingmutagenicprocessesinfluencingthetumormutationalpatternsofindividualswithconstitutionalmismatchrepairdeficiency AT mariettecavankouwen unravelingmutagenicprocessesinfluencingthetumormutationalpatternsofindividualswithconstitutionalmismatchrepairdeficiency AT ijolandamdevries unravelingmutagenicprocessesinfluencingthetumormutationalpatternsofindividualswithconstitutionalmismatchrepairdeficiency AT rubenvanboxtel unravelingmutagenicprocessesinfluencingthetumormutationalpatternsofindividualswithconstitutionalmismatchrepairdeficiency AT richardamdevoer unravelingmutagenicprocessesinfluencingthetumormutationalpatternsofindividualswithconstitutionalmismatchrepairdeficiency AT marjolijncjjongmans unravelingmutagenicprocessesinfluencingthetumormutationalpatternsofindividualswithconstitutionalmismatchrepairdeficiency AT rolandpkuiper unravelingmutagenicprocessesinfluencingthetumormutationalpatternsofindividualswithconstitutionalmismatchrepairdeficiency |