Skip to main content
main-content

01.12.2018 | Research article | Ausgabe 1/2018 Open Access

BMC Cancer 1/2018

Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer

Zeitschrift:
BMC Cancer > Ausgabe 1/2018
Autoren:
Timothy O’Donnell, Elizabeth L. Christie, Arun Ahuja, Jacqueline Buros, B. Arman Aksoy, David D. L. Bowtell, Alexandra Snyder, Jeff Hammerbacher
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:https://​doi.​org/​10.​1186/​s12885-017-3825-0) contains supplementary material, which is available to authorized users.

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.
Zusatzmaterial
Additional file 1 Samples. Sample identifiers, basic clinical and chemotherapy information, specimen purities, mutation and neoantigen burden, contributions of major mutational signatures to mutations and neoantigens, and CIBERSORT immune infiltrate estimates. (CSV 224 kb)
12885_2017_3825_MOESM1_ESM.csv
Additional file 2 Mutations. Somatic variants and their read counts, predicted effects, and resulting neoantigens. (CSV 105000 kb)
12885_2017_3825_MOESM2_ESM.csv
Additional file 3 HLA types. Patient HLA types. (CSV 5 kb)
12885_2017_3825_MOESM3_ESM.csv
Additional file 4 Supplemental figures. Figures S1–S11. (PDF 798 kb)
12885_2017_3825_MOESM4_ESM.pdf
Additional file 5 Mutational signatures. COSMIC signatures and extracted chemotherapy signatures. (CSV 5 kb)
12885_2017_3825_MOESM5_ESM.csv
Additional file 6 Signature deconvolutions. Results of mutational signature deconvolution, including a separate analysis of mutations unique to the treated paired samples. (CSV 42 kb)
12885_2017_3825_MOESM6_ESM.csv
Additional file 7 Shared neoantigens. Neoantigens predicted for multiple patients. (CSV 1 kb)
12885_2017_3825_MOESM7_ESM.csv
Additional file 8 Supplemental statistical notebook. Bayesian models to compare mutation, neoantigen, and expressed neoantigen burdens in treated and untreated samples. (PDF 980 kb)
12885_2017_3825_MOESM8_ESM.pdf
Literatur
Über diesen Artikel

Weitere Artikel der Ausgabe 1/2018

BMC Cancer 1/2018 Zur Ausgabe

Neu im Fachgebiet Onkologie


 

Mail Icon II Newsletter

Bestellen Sie unseren kostenlosen Newsletter Update Onkologie und bleiben Sie gut informiert – ganz bequem per eMail.

Bildnachweise