Small-scale mutations are infrequent as mechanisms of resistance in post-PARP inhibitor tumour samples in high grade serous ovarian cancer
Abstract While the introduction of poly-(ADP)-ribose polymerase (PARP) inhibitors in homologous recombination DNA repair (HR) deficient high grade serous ovarian, fallopian tube and primary peritoneal cancers (HGSC) has improved patient survival, resistance to PARP inhibitors frequently occurs. Prec...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-12-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-48153-x |
| _version_ | 1827581684372996096 |
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| author | Nikki L. Burdett Madelynne O. Willis Ahwan Pandey Sian Fereday AOCS Study Group Anna DeFazio David D. L. Bowtell Elizabeth L. Christie |
| author_facet | Nikki L. Burdett Madelynne O. Willis Ahwan Pandey Sian Fereday AOCS Study Group Anna DeFazio David D. L. Bowtell Elizabeth L. Christie |
| author_sort | Nikki L. Burdett |
| collection | DOAJ |
| description | Abstract While the introduction of poly-(ADP)-ribose polymerase (PARP) inhibitors in homologous recombination DNA repair (HR) deficient high grade serous ovarian, fallopian tube and primary peritoneal cancers (HGSC) has improved patient survival, resistance to PARP inhibitors frequently occurs. Preclinical and translational studies have identified multiple mechanisms of resistance; here we examined tumour samples collected from 26 women following treatment with PARP inhibitors as part of standard of care or their enrolment in clinical trials. Twenty-one had a germline or somatic BRCA1/2 mutation. We performed targeted sequencing of 63 genes involved in DNA repair processes or implicated in ovarian cancer resistance. We found that just three individuals had a small-scale mutation as a definitive resistance mechanism detected, having reversion mutations, while six had potential mechanisms of resistance detected, with alterations related to BRCA1 function and mutations in SHLD2. This study indicates that mutations in genes related to DNA repair are detected in a minority of HGSC patients as genetic mechanisms of resistance. Future research into resistance in HGSC should focus on copy number, transcriptional and epigenetic aberrations, and the contribution of the tumour microenvironment. |
| first_indexed | 2024-03-08T22:39:56Z |
| format | Article |
| id | doaj.art-f4358b16fa324c52a3bfdc6037f121f8 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-08T22:39:56Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-f4358b16fa324c52a3bfdc6037f121f82023-12-17T12:17:07ZengNature PortfolioScientific Reports2045-23222023-12-0113111010.1038/s41598-023-48153-xSmall-scale mutations are infrequent as mechanisms of resistance in post-PARP inhibitor tumour samples in high grade serous ovarian cancerNikki L. Burdett0Madelynne O. Willis1Ahwan Pandey2Sian Fereday3AOCS Study GroupAnna DeFazio4David D. L. Bowtell5Elizabeth L. Christie6Peter MacCallum Cancer CentrePeter MacCallum Cancer CentrePeter MacCallum Cancer CentrePeter MacCallum Cancer CentreCentre for Cancer Research, The Westmead Institute for Medical ResearchPeter MacCallum Cancer CentrePeter MacCallum Cancer CentreAbstract While the introduction of poly-(ADP)-ribose polymerase (PARP) inhibitors in homologous recombination DNA repair (HR) deficient high grade serous ovarian, fallopian tube and primary peritoneal cancers (HGSC) has improved patient survival, resistance to PARP inhibitors frequently occurs. Preclinical and translational studies have identified multiple mechanisms of resistance; here we examined tumour samples collected from 26 women following treatment with PARP inhibitors as part of standard of care or their enrolment in clinical trials. Twenty-one had a germline or somatic BRCA1/2 mutation. We performed targeted sequencing of 63 genes involved in DNA repair processes or implicated in ovarian cancer resistance. We found that just three individuals had a small-scale mutation as a definitive resistance mechanism detected, having reversion mutations, while six had potential mechanisms of resistance detected, with alterations related to BRCA1 function and mutations in SHLD2. This study indicates that mutations in genes related to DNA repair are detected in a minority of HGSC patients as genetic mechanisms of resistance. Future research into resistance in HGSC should focus on copy number, transcriptional and epigenetic aberrations, and the contribution of the tumour microenvironment.https://doi.org/10.1038/s41598-023-48153-x |
| spellingShingle | Nikki L. Burdett Madelynne O. Willis Ahwan Pandey Sian Fereday AOCS Study Group Anna DeFazio David D. L. Bowtell Elizabeth L. Christie Small-scale mutations are infrequent as mechanisms of resistance in post-PARP inhibitor tumour samples in high grade serous ovarian cancer Scientific Reports |
| title | Small-scale mutations are infrequent as mechanisms of resistance in post-PARP inhibitor tumour samples in high grade serous ovarian cancer |
| title_full | Small-scale mutations are infrequent as mechanisms of resistance in post-PARP inhibitor tumour samples in high grade serous ovarian cancer |
| title_fullStr | Small-scale mutations are infrequent as mechanisms of resistance in post-PARP inhibitor tumour samples in high grade serous ovarian cancer |
| title_full_unstemmed | Small-scale mutations are infrequent as mechanisms of resistance in post-PARP inhibitor tumour samples in high grade serous ovarian cancer |
| title_short | Small-scale mutations are infrequent as mechanisms of resistance in post-PARP inhibitor tumour samples in high grade serous ovarian cancer |
| title_sort | small scale mutations are infrequent as mechanisms of resistance in post parp inhibitor tumour samples in high grade serous ovarian cancer |
| url | https://doi.org/10.1038/s41598-023-48153-x |
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