The impact of rare germline variants on human somatic mutation processes
Abstract Somatic mutations are an inevitable component of ageing and the most important cause of cancer. The rates and types of somatic mutation vary across individuals, but relatively few inherited influences on mutation processes are known. We perform a gene-based rare variant association study wi...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-022-31483-1 |
| _version_ | 1797689102844297216 |
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| author | Mischan Vali-Pour Solip Park Jose Espinosa-Carrasco Daniel Ortiz-Martínez Ben Lehner Fran Supek |
| author_facet | Mischan Vali-Pour Solip Park Jose Espinosa-Carrasco Daniel Ortiz-Martínez Ben Lehner Fran Supek |
| author_sort | Mischan Vali-Pour |
| collection | DOAJ |
| description | Abstract Somatic mutations are an inevitable component of ageing and the most important cause of cancer. The rates and types of somatic mutation vary across individuals, but relatively few inherited influences on mutation processes are known. We perform a gene-based rare variant association study with diverse mutational processes, using human cancer genomes from over 11,000 individuals of European ancestry. By combining burden and variance tests, we identify 207 associations involving 15 somatic mutational phenotypes and 42 genes that replicated in an independent data set at a false discovery rate of 1%. We associate rare inherited deleterious variants in genes such as MSH3, EXO1, SETD2, and MTOR with two phenotypically different forms of DNA mismatch repair deficiency, and variants in genes such as EXO1, PAXIP1, RIF1, and WRN with deficiency in homologous recombination repair. In addition, we identify associations with other mutational processes, such as APEX1 with APOBEC-signature mutagenesis. Many of the genes interact with each other and with known mutator genes within cellular sub-networks. Considered collectively, damaging variants in the identified genes are prevalent in the population. We suggest that rare germline variation in diverse genes commonly impacts mutational processes in somatic cells. |
| first_indexed | 2024-03-12T01:41:12Z |
| format | Article |
| id | doaj.art-22847fd38e7c4b5e9fbc949293592c93 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-12T01:41:12Z |
| publishDate | 2022-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-22847fd38e7c4b5e9fbc949293592c932023-09-10T11:17:20ZengNature PortfolioNature Communications2041-17232022-06-0113112110.1038/s41467-022-31483-1The impact of rare germline variants on human somatic mutation processesMischan Vali-Pour0Solip Park1Jose Espinosa-Carrasco2Daniel Ortiz-Martínez3Ben Lehner4Fran Supek5Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST)Centro Nacional de Investigaciones Oncológicas (CNIO)Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST)Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST)Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST)Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST)Abstract Somatic mutations are an inevitable component of ageing and the most important cause of cancer. The rates and types of somatic mutation vary across individuals, but relatively few inherited influences on mutation processes are known. We perform a gene-based rare variant association study with diverse mutational processes, using human cancer genomes from over 11,000 individuals of European ancestry. By combining burden and variance tests, we identify 207 associations involving 15 somatic mutational phenotypes and 42 genes that replicated in an independent data set at a false discovery rate of 1%. We associate rare inherited deleterious variants in genes such as MSH3, EXO1, SETD2, and MTOR with two phenotypically different forms of DNA mismatch repair deficiency, and variants in genes such as EXO1, PAXIP1, RIF1, and WRN with deficiency in homologous recombination repair. In addition, we identify associations with other mutational processes, such as APEX1 with APOBEC-signature mutagenesis. Many of the genes interact with each other and with known mutator genes within cellular sub-networks. Considered collectively, damaging variants in the identified genes are prevalent in the population. We suggest that rare germline variation in diverse genes commonly impacts mutational processes in somatic cells.https://doi.org/10.1038/s41467-022-31483-1 |
| spellingShingle | Mischan Vali-Pour Solip Park Jose Espinosa-Carrasco Daniel Ortiz-Martínez Ben Lehner Fran Supek The impact of rare germline variants on human somatic mutation processes Nature Communications |
| title | The impact of rare germline variants on human somatic mutation processes |
| title_full | The impact of rare germline variants on human somatic mutation processes |
| title_fullStr | The impact of rare germline variants on human somatic mutation processes |
| title_full_unstemmed | The impact of rare germline variants on human somatic mutation processes |
| title_short | The impact of rare germline variants on human somatic mutation processes |
| title_sort | impact of rare germline variants on human somatic mutation processes |
| url | https://doi.org/10.1038/s41467-022-31483-1 |
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