Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer
Abstract Background Patients with highly mutated tumors, such as melanoma or smoking-related lung cancer, have higher rates of response to immune checkpoint blockade therapy, perhaps due to increased neoantigen expression. Many chemotherapies including platinum compounds are known to be mutagenic, b...
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| Format: | Article |
| Language: | English |
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BMC
2018-01-01
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| Series: | BMC Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12885-017-3825-0 |
| _version_ | 1818289342435557376 |
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| author | Timothy O’Donnell Elizabeth L. Christie Arun Ahuja Jacqueline Buros B. Arman Aksoy David D. L. Bowtell Alexandra Snyder Jeff Hammerbacher |
| author_facet | Timothy O’Donnell Elizabeth L. Christie Arun Ahuja Jacqueline Buros B. Arman Aksoy David D. L. Bowtell Alexandra Snyder Jeff Hammerbacher |
| author_sort | Timothy O’Donnell |
| collection | DOAJ |
| description | Abstract Background Patients with highly mutated tumors, such as melanoma or smoking-related lung cancer, have higher rates of response to immune checkpoint blockade therapy, perhaps due to increased neoantigen expression. Many chemotherapies including platinum compounds are known to be mutagenic, but the impact of standard treatment protocols on mutational burden and resulting neoantigen expression in most human cancers is unknown. Methods We sought to quantify the effect of chemotherapy treatment on computationally predicted neoantigen expression for high grade serous ovarian carcinoma patients enrolled in the Australian Ovarian Cancer Study. In this series, 35 of 114 samples were collected after exposure to chemotherapy; 14 are matched with an untreated sample from the same patient. Our approach integrates whole genome and RNA sequencing of bulk tumor samples with class I MHC binding prediction and mutational signatures extracted from studies of chemotherapy-exposed Caenorhabditis elegans and Gallus gallus cells. We additionally investigated the relationship between neoantigens, tumor infiltrating immune cells estimated from RNA-seq with CIBERSORT, and patient survival. Results Greater neoantigen burden and CD8+ T cell infiltration in primary, pre-treatment samples were independently associated with improved survival. Relapse samples collected after chemotherapy harbored a median of 78% more expressed neoantigens than untreated primary samples, a figure that combines the effects of chemotherapy and other processes operative during relapse. The contribution from chemotherapy-associated signatures was small, accounting for a mean of 5% (range 0–16) of the expressed neoantigen burden in relapse samples. In both treated and untreated samples, most neoantigens were attributed to COSMIC Signature (3), associated with BRCA disruption, Signature (1), associated with a slow mutagenic process active in healthy tissue, and Signature (8), of unknown etiology. Conclusion Relapsed ovarian cancers harbor more predicted neoantigens than primary tumors, but the increase is due to pre-existing mutational processes, not mutagenesis from chemotherapy. |
| first_indexed | 2024-12-13T02:10:45Z |
| format | Article |
| id | doaj.art-b4240ed0d9144fbb998383ffee8930e9 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-13T02:10:45Z |
| publishDate | 2018-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-b4240ed0d9144fbb998383ffee8930e92022-12-22T00:03:02ZengBMCBMC Cancer1471-24072018-01-0118111110.1186/s12885-017-3825-0Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancerTimothy O’Donnell0Elizabeth L. Christie1Arun Ahuja2Jacqueline Buros3B. Arman Aksoy4David D. L. Bowtell5Alexandra Snyder6Jeff Hammerbacher7Icahn School of Medicine at Mount SinaiPeter MacCallum Cancer CentreIcahn School of Medicine at Mount SinaiIcahn School of Medicine at Mount SinaiIcahn School of Medicine at Mount SinaiPeter MacCallum Cancer CentreDepartment of Medicine, Memorial Sloan-Kettering Cancer CenterIcahn School of Medicine at Mount SinaiAbstract Background Patients with highly mutated tumors, such as melanoma or smoking-related lung cancer, have higher rates of response to immune checkpoint blockade therapy, perhaps due to increased neoantigen expression. Many chemotherapies including platinum compounds are known to be mutagenic, but the impact of standard treatment protocols on mutational burden and resulting neoantigen expression in most human cancers is unknown. Methods We sought to quantify the effect of chemotherapy treatment on computationally predicted neoantigen expression for high grade serous ovarian carcinoma patients enrolled in the Australian Ovarian Cancer Study. In this series, 35 of 114 samples were collected after exposure to chemotherapy; 14 are matched with an untreated sample from the same patient. Our approach integrates whole genome and RNA sequencing of bulk tumor samples with class I MHC binding prediction and mutational signatures extracted from studies of chemotherapy-exposed Caenorhabditis elegans and Gallus gallus cells. We additionally investigated the relationship between neoantigens, tumor infiltrating immune cells estimated from RNA-seq with CIBERSORT, and patient survival. Results Greater neoantigen burden and CD8+ T cell infiltration in primary, pre-treatment samples were independently associated with improved survival. Relapse samples collected after chemotherapy harbored a median of 78% more expressed neoantigens than untreated primary samples, a figure that combines the effects of chemotherapy and other processes operative during relapse. The contribution from chemotherapy-associated signatures was small, accounting for a mean of 5% (range 0–16) of the expressed neoantigen burden in relapse samples. In both treated and untreated samples, most neoantigens were attributed to COSMIC Signature (3), associated with BRCA disruption, Signature (1), associated with a slow mutagenic process active in healthy tissue, and Signature (8), of unknown etiology. Conclusion Relapsed ovarian cancers harbor more predicted neoantigens than primary tumors, but the increase is due to pre-existing mutational processes, not mutagenesis from chemotherapy.http://link.springer.com/article/10.1186/s12885-017-3825-0NeoantigenMutational signatureChemotherapy |
| spellingShingle | Timothy O’Donnell Elizabeth L. Christie Arun Ahuja Jacqueline Buros B. Arman Aksoy David D. L. Bowtell Alexandra Snyder Jeff Hammerbacher Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer BMC Cancer Neoantigen Mutational signature Chemotherapy |
| title | Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer |
| title_full | Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer |
| title_fullStr | Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer |
| title_full_unstemmed | Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer |
| title_short | Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer |
| title_sort | chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer |
| topic | Neoantigen Mutational signature Chemotherapy |
| url | http://link.springer.com/article/10.1186/s12885-017-3825-0 |
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