DiffInvex identifies evolutionary shifts in driver gene repertoires during tumorigenesis and chemotherapy
Abstract Somatic cells can transform into tumors due to mutations, and the tumors further evolve towards increased aggressiveness and therapy resistance. We develop DiffInvex, a framework for identifying changes in selection acting on individual genes in somatic genomes, drawing on an empirical muta...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59397-8 |
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| _version_ | 1849326885704564736 |
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| author | Ahmed Khalil Fran Supek |
| author_facet | Ahmed Khalil Fran Supek |
| author_sort | Ahmed Khalil |
| collection | DOAJ |
| description | Abstract Somatic cells can transform into tumors due to mutations, and the tumors further evolve towards increased aggressiveness and therapy resistance. We develop DiffInvex, a framework for identifying changes in selection acting on individual genes in somatic genomes, drawing on an empirical mutation rate baseline derived from non-coding DNA that accounts for shifts in neutral mutagenesis during cancer evolution. We apply DiffInvex to >11,000 somatic whole-genome sequences from ~30 cancer types or healthy tissues, identifying genes where point mutations are under conditional positive or negative selection during exposure to specific chemotherapeutics, suggesting drug resistance mechanisms occurring via point mutation. DiffInvex identifies 11 genes exhibiting treatment-associated selection for different classes of chemotherapies, linking selected mutations in PIK3CA, APC, MAP2K4, SMAD4, STK11 and MAP3K1 with drug exposure. Various gene-chemotherapy associations are further supported by differential functional impact of mutations pre- versus post-therapy, and are also replicated in independent studies. In addition to nominating drug resistance genes, we contrast the genomes of healthy versus cancerous cells of matched human tissues. We identify noncancerous expansion-specific drivers, including NOTCH1 and ARID1A. DiffInvex can also be applied to diverse analyses in cancer evolution to identify changes in driver gene repertoires across time or space. |
| format | Article |
| id | doaj-art-dac0aac4c2b748fcab3a30bef0b871d4 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-dac0aac4c2b748fcab3a30bef0b871d42025-08-20T03:48:02ZengNature PortfolioNature Communications2041-17232025-05-0116112010.1038/s41467-025-59397-8DiffInvex identifies evolutionary shifts in driver gene repertoires during tumorigenesis and chemotherapyAhmed Khalil0Fran Supek1Institute for Research in Biomedicine (IRB Barcelona)Institute for Research in Biomedicine (IRB Barcelona)Abstract Somatic cells can transform into tumors due to mutations, and the tumors further evolve towards increased aggressiveness and therapy resistance. We develop DiffInvex, a framework for identifying changes in selection acting on individual genes in somatic genomes, drawing on an empirical mutation rate baseline derived from non-coding DNA that accounts for shifts in neutral mutagenesis during cancer evolution. We apply DiffInvex to >11,000 somatic whole-genome sequences from ~30 cancer types or healthy tissues, identifying genes where point mutations are under conditional positive or negative selection during exposure to specific chemotherapeutics, suggesting drug resistance mechanisms occurring via point mutation. DiffInvex identifies 11 genes exhibiting treatment-associated selection for different classes of chemotherapies, linking selected mutations in PIK3CA, APC, MAP2K4, SMAD4, STK11 and MAP3K1 with drug exposure. Various gene-chemotherapy associations are further supported by differential functional impact of mutations pre- versus post-therapy, and are also replicated in independent studies. In addition to nominating drug resistance genes, we contrast the genomes of healthy versus cancerous cells of matched human tissues. We identify noncancerous expansion-specific drivers, including NOTCH1 and ARID1A. DiffInvex can also be applied to diverse analyses in cancer evolution to identify changes in driver gene repertoires across time or space.https://doi.org/10.1038/s41467-025-59397-8 |
| spellingShingle | Ahmed Khalil Fran Supek DiffInvex identifies evolutionary shifts in driver gene repertoires during tumorigenesis and chemotherapy Nature Communications |
| title | DiffInvex identifies evolutionary shifts in driver gene repertoires during tumorigenesis and chemotherapy |
| title_full | DiffInvex identifies evolutionary shifts in driver gene repertoires during tumorigenesis and chemotherapy |
| title_fullStr | DiffInvex identifies evolutionary shifts in driver gene repertoires during tumorigenesis and chemotherapy |
| title_full_unstemmed | DiffInvex identifies evolutionary shifts in driver gene repertoires during tumorigenesis and chemotherapy |
| title_short | DiffInvex identifies evolutionary shifts in driver gene repertoires during tumorigenesis and chemotherapy |
| title_sort | diffinvex identifies evolutionary shifts in driver gene repertoires during tumorigenesis and chemotherapy |
| url | https://doi.org/10.1038/s41467-025-59397-8 |
| work_keys_str_mv | AT ahmedkhalil diffinvexidentifiesevolutionaryshiftsindrivergenerepertoiresduringtumorigenesisandchemotherapy AT fransupek diffinvexidentifiesevolutionaryshiftsindrivergenerepertoiresduringtumorigenesisandchemotherapy |