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Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer

View ORCID ProfileTimothy O’Donnell, View ORCID ProfileElizabeth L. Christie, View ORCID ProfileArun Ahuja, View ORCID ProfileJacqueline Buros, View ORCID ProfileB. Arman Aksoy, View ORCID ProfileDavid D. L. Bowtell, View ORCID ProfileAlexandra Snyder, View ORCID ProfileJeff Hammerbacher
doi: https://doi.org/10.1101/090134
Timothy O’Donnell
1Mount Sinai School of Medicine, New York, USA
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Elizabeth L. Christie
2Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia
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Arun Ahuja
1Mount Sinai School of Medicine, New York, USA
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Jacqueline Buros
1Mount Sinai School of Medicine, New York, USA
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B. Arman Aksoy
1Mount Sinai School of Medicine, New York, USA
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David D. L. Bowtell
2Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia
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Alexandra Snyder
3Deptartment of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, USA
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  • For correspondence: snyderca@mskcc.org
Jeff Hammerbacher
1Mount Sinai School of Medicine, New York, USA
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  • For correspondence: hammer@hammerlab.org
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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 12 high grade serous ovarian carcinoma (HGSC) patients with pre- and post-chemotherapy samples collected in the Australian Ovarian Cancer Study. We additionally analyzed 16 patients from the cohort with post-treatment samples only, including five primary surgical samples exposed to neoadjuvant chemotherapy. Our approach integrates tumor whole genome and RNA sequencing with class I MHC binding prediction and mutational signatures of chemotherapy exposure extracted from two preclinical studies.

Results The mutational signatures for cisplatin and cyclophosphamide identified in a preclinical model had significant but inexact associations with the relevant exposure in the clinical samples. In an analysis stratified by tissue type (solid tumor or ascites), relapse samples collected after chemotherapy harbored a median of 90% more expressed neoantigens than untreated primary samples, a figure that combines the effects of chemotherapy and other mutagenic processes operative during relapse. Neoadjuvant-treated primary samples showed no detectable increase over untreated samples. 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 HGSC tumors harbor nearly double the predicted expressed neoantigen burden of primary samples, but mutations associated with chemotherapy signatures account for only a small part of this increase. The mutagenic processes responsible for most neoantigens are similar between primary and relapse samples. Our analyses are based on mutations detectable from whole genome sequencing of bulk samples and do not account for neoantigens present in small populations of cells.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted December 01, 2016.
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Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer
Timothy O’Donnell, Elizabeth L. Christie, Arun Ahuja, Jacqueline Buros, B. Arman Aksoy, David D. L. Bowtell, Alexandra Snyder, Jeff Hammerbacher
bioRxiv 090134; doi: https://doi.org/10.1101/090134
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Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer
Timothy O’Donnell, Elizabeth L. Christie, Arun Ahuja, Jacqueline Buros, B. Arman Aksoy, David D. L. Bowtell, Alexandra Snyder, Jeff Hammerbacher
bioRxiv 090134; doi: https://doi.org/10.1101/090134

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