Neoadjuvant chemotherapy induces genomic and transcriptomic changes in ovarian cancer
<p>The growing use of neoadjuvant chemotherapy to treat advanced stage high-grade serous ovarian cancer (HGSOC) creates an opportunity to better understand chemotherapy-induced mutational and gene expression changes. Here we performed a cohort study including 34 patients with advanced stage II...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
American Association for Cancer Research
2021
|
| _version_ | 1797110765368377344 |
|---|---|
| author | Javellana, M Eckert, MA Heide, J Zawieracz, K Weigert, M Ashley, S Stock, E Chapel, D Huang, L Yamada, SD Ahmed, AA Lastra, RR Chen, M Lengyel, E |
| author_facet | Javellana, M Eckert, MA Heide, J Zawieracz, K Weigert, M Ashley, S Stock, E Chapel, D Huang, L Yamada, SD Ahmed, AA Lastra, RR Chen, M Lengyel, E |
| author_sort | Javellana, M |
| collection | OXFORD |
| description | <p>The growing use of neoadjuvant chemotherapy to treat advanced stage high-grade serous ovarian cancer (HGSOC) creates an opportunity to better understand chemotherapy-induced mutational and gene expression changes. Here we performed a cohort study including 34 patients with advanced stage IIIC or IV HGSOC to assess changes in the tumor genome and transcriptome in women receiving neoadjuvant chemotherapy. RNA sequencing and panel DNA sequencing of 596 cancer-related genes was performed on paired formalin-fixed paraffin-embedded specimens collected before and after chemotherapy, and differentially expressed genes (DEG) and copy-number variations (CNV) in pre- and post-chemotherapy samples were identified. Following tissue and sequencing quality control, the final patient cohort consisted of 32 paired DNA and 20 paired RNA samples. Genomic analysis of paired samples did not reveal any recurrent chemotherapy-induced mutations. Gene expression analyses found that most DEGs were upregulated by chemotherapy, primarily in the chemotherapy-resistant specimens. AP-1 transcription factor family genes (<em>FOS</em>, <em>FOSB</em>, <em>FRA-1</em>) were particularly upregulated in chemotherapy-resistant samples. CNV analysis identified recurrent 11q23.1 amplification, which encompasses <em>SIK2</em>. <em>In vitro</em>, combined treatment with AP-1 or SIK2 inhibitors with carboplatin or paclitaxel demonstrated synergistic effects. These data suggest that AP-1 activity and <em>SIK2</em> copy-number amplification are induced by chemotherapy and may represent mechanisms by which chemotherapy resistance evolves in HGSOC. AP-1 and SIK2 are druggable targets with available small molecule inhibitors and represent potential targets to circumvent chemotherapy resistance.</p> |
| first_indexed | 2024-03-07T07:59:27Z |
| format | Journal article |
| id | oxford-uuid:bcd2de81-84a0-47b9-bc92-55d42b9f04e1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:59:27Z |
| publishDate | 2021 |
| publisher | American Association for Cancer Research |
| record_format | dspace |
| spelling | oxford-uuid:bcd2de81-84a0-47b9-bc92-55d42b9f04e12023-09-12T10:54:16ZNeoadjuvant chemotherapy induces genomic and transcriptomic changes in ovarian cancerJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:bcd2de81-84a0-47b9-bc92-55d42b9f04e1EnglishSymplectic ElementsAmerican Association for Cancer Research2021Javellana, MEckert, MAHeide, JZawieracz, KWeigert, MAshley, SStock, EChapel, DHuang, LYamada, SDAhmed, AALastra, RRChen, MLengyel, E<p>The growing use of neoadjuvant chemotherapy to treat advanced stage high-grade serous ovarian cancer (HGSOC) creates an opportunity to better understand chemotherapy-induced mutational and gene expression changes. Here we performed a cohort study including 34 patients with advanced stage IIIC or IV HGSOC to assess changes in the tumor genome and transcriptome in women receiving neoadjuvant chemotherapy. RNA sequencing and panel DNA sequencing of 596 cancer-related genes was performed on paired formalin-fixed paraffin-embedded specimens collected before and after chemotherapy, and differentially expressed genes (DEG) and copy-number variations (CNV) in pre- and post-chemotherapy samples were identified. Following tissue and sequencing quality control, the final patient cohort consisted of 32 paired DNA and 20 paired RNA samples. Genomic analysis of paired samples did not reveal any recurrent chemotherapy-induced mutations. Gene expression analyses found that most DEGs were upregulated by chemotherapy, primarily in the chemotherapy-resistant specimens. AP-1 transcription factor family genes (<em>FOS</em>, <em>FOSB</em>, <em>FRA-1</em>) were particularly upregulated in chemotherapy-resistant samples. CNV analysis identified recurrent 11q23.1 amplification, which encompasses <em>SIK2</em>. <em>In vitro</em>, combined treatment with AP-1 or SIK2 inhibitors with carboplatin or paclitaxel demonstrated synergistic effects. These data suggest that AP-1 activity and <em>SIK2</em> copy-number amplification are induced by chemotherapy and may represent mechanisms by which chemotherapy resistance evolves in HGSOC. AP-1 and SIK2 are druggable targets with available small molecule inhibitors and represent potential targets to circumvent chemotherapy resistance.</p> |
| spellingShingle | Javellana, M Eckert, MA Heide, J Zawieracz, K Weigert, M Ashley, S Stock, E Chapel, D Huang, L Yamada, SD Ahmed, AA Lastra, RR Chen, M Lengyel, E Neoadjuvant chemotherapy induces genomic and transcriptomic changes in ovarian cancer |
| title | Neoadjuvant chemotherapy induces genomic and transcriptomic changes in ovarian cancer |
| title_full | Neoadjuvant chemotherapy induces genomic and transcriptomic changes in ovarian cancer |
| title_fullStr | Neoadjuvant chemotherapy induces genomic and transcriptomic changes in ovarian cancer |
| title_full_unstemmed | Neoadjuvant chemotherapy induces genomic and transcriptomic changes in ovarian cancer |
| title_short | Neoadjuvant chemotherapy induces genomic and transcriptomic changes in ovarian cancer |
| title_sort | neoadjuvant chemotherapy induces genomic and transcriptomic changes in ovarian cancer |
| work_keys_str_mv | AT javellanam neoadjuvantchemotherapyinducesgenomicandtranscriptomicchangesinovariancancer AT eckertma neoadjuvantchemotherapyinducesgenomicandtranscriptomicchangesinovariancancer AT heidej neoadjuvantchemotherapyinducesgenomicandtranscriptomicchangesinovariancancer AT zawieraczk neoadjuvantchemotherapyinducesgenomicandtranscriptomicchangesinovariancancer AT weigertm neoadjuvantchemotherapyinducesgenomicandtranscriptomicchangesinovariancancer AT ashleys neoadjuvantchemotherapyinducesgenomicandtranscriptomicchangesinovariancancer AT stocke neoadjuvantchemotherapyinducesgenomicandtranscriptomicchangesinovariancancer AT chapeld neoadjuvantchemotherapyinducesgenomicandtranscriptomicchangesinovariancancer AT huangl neoadjuvantchemotherapyinducesgenomicandtranscriptomicchangesinovariancancer AT yamadasd neoadjuvantchemotherapyinducesgenomicandtranscriptomicchangesinovariancancer AT ahmedaa neoadjuvantchemotherapyinducesgenomicandtranscriptomicchangesinovariancancer AT lastrarr neoadjuvantchemotherapyinducesgenomicandtranscriptomicchangesinovariancancer AT chenm neoadjuvantchemotherapyinducesgenomicandtranscriptomicchangesinovariancancer AT lengyele neoadjuvantchemotherapyinducesgenomicandtranscriptomicchangesinovariancancer |