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  • 1
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    Classification of High-Grade Serous Ovarian Cancer Using Tumor Morphologic Characteristics
    American Medical Association (AMA) ; 2022
    In:  JAMA Network Open Vol. 5, No. 10 ( 2022-10-14), p. e2236626-
    Details
    In: JAMA Network Open, American Medical Association (AMA), Vol. 5, No. 10 ( 2022-10-14), p. e2236626-
    Abstract: Despite similar histologic appearance among high-grade serous ovarian cancers (HGSOCs), clinical observations suggest vast differences in gross appearance. There is currently no systematic framework by which to classify HGSOCs according to their gross morphologic characteristics. Objective To develop and characterize a gross morphologic classification system for HGSOC. Design, Setting, and Participants This cohort study included patients with suspected advanced-stage ovarian cancer who presented between April 1, 2013, and August 5, 2016, to the University of Texas MD Anderson Cancer Center, a large referral center. Patients underwent laparoscopic assessment of disease burden before treatment and received a histopathologic diagnosis of HGSOC. Researchers assigning morphologic subtype and performing molecular analyses were blinded to clinical outcomes. Data analysis was performed between April 2020 and November 2021. Exposures Gross tumor morphologic characteristics. Main Outcomes and Measures Clinical outcomes and multiomic profiles of representative tumor samples of type I or type II morphologic subtypes were compared. Results Of 112 women (mean [SD] age 62.7 [9.7] years) included in the study, most patients (84% [94]) exhibited a predominant morphologic subtype and many (63% [71] ) had a uniform morphologic subtype at all involved sites. Compared with those with uniform type I morphologic subtype, patients with uniform type II morphologic subtype were more likely to have a favorable Fagotti score (83% [19 of 23] vs 46% [22 of 48] ; P  = .004) and thus to be triaged to primary tumor reductive surgery. Similarly, patients with uniform type II morphologic subtype also had significantly higher mean (SD) estimated blood loss (639 [559; 95% CI, 391-887] mL vs 415 [527; 95% CI, 253-577] mL; P  = .006) and longer mean (SD) operative time (408 [130; 95% CI, 350-466] minutes vs 333 [113; 95% CI, 298-367] minutes; P  = .03) during tumor reductive surgery. Type I tumors had enrichment of epithelial-mesenchymal transition (false discovery rate [FDR] q-value, 3.10 × 10 −24 ), hypoxia (FDR q-value, 1.52 × 10 −5 ), and angiogenesis pathways (FDR q-value, 2.11 × 10 −2 ), whereas type II tumors had enrichment of pathways related to MYC signaling (FDR q-value, 2.04 × 10 −9 ) and cell cycle progression (FDR q-value, 1.10 × 10 −5 ) by integrated proteomic and transcriptomic analysis. Abundances of metabolites and lipids also differed between the 2 morphologic subtypes. Conclusions and Relevance This study identified 2 novel, gross morphologic subtypes of HGSOC, each with unique clinical features and molecular signatures. The findings may have implications for triaging patients to surgery or chemotherapy, identifying outcomes, and developing tailored therapeutic strategies.
    Type of Medium: Online Resource
    ISSN: 2574-3805
    URL: Article
    DOI: 10.1001/jamanetworkopen.2022.36626
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2022
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  • 2
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    Abstract 2200: NF1 copy number alterations in clinically-defined subsets of high-grade serous ovarian cancers
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2200-2200
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2200-2200
    Abstract: Background: While high-grade serous ovarian cancers (HGSC) look alike at a histological level, there is marked variation in clinical outcomes; however, the underlying mechanisms are not well understood. We previously highlighted significant distinct molecular and cellular characteristics in highly clinically annotated HGSC tumor samples from patients who underwent complete gross resection (R0) or received neoadjuvant chemotherapy (NACT). Neurofibromatosis type 1 (NF1) is known to negatively regulate the Ras/MAPK signaling pathways and tumorigenesis. Here, we specifically validate the higher loss of NF1 copy number exhibited in the R0 compared to the NACT groups in patients with HGSC. Methods: Fresh-frozen tumor biopsies were collected from patients with HGSC treated under a systematic surgical algorithm: complete gross resection after primary surgery (R0, n=40); poor tumor response to NACT (NACT-PR, n=26); excellent tumor response to NACT with carboplatin and paclitaxel (NACT-ER, n=14). Primary or metastatic tumor sites for each patient were obtained pre-treatment and subjected to high-depth targeted DNA sequencing. Results: The average coverage of 568X for tumors and 291X for germline controls (matched blood samples) was obtained by targeted sequencing for each sample from the entire cohort. The median numbers of non-synonymous somatic mutations identified in the panel sequencing were 5 in R0, 3 in NACT-ER, and 5 in NACT-PR. Sixty-nine of the 80 samples (86.25%) had alterations in at least one of the ovarian cancer-related genes. The most frequently altered genes including somatic mutations and copy number variations were TP53 (68%), NF1 (65%) and ERBB2 (62%) in the R0 group whereas TP53 (50%), AKT1 (48%) and TERT (42%) in the NACT group. Gene alteration enrichment was evaluated by comparing between two groups. 17 genes were found to be enriched for alterations in the R0 group comparing to the NACT group; MLH3 (OR= 15.03, p & lt;0.001), CDK13 (OR=11.08, p & lt;0.001), GOPC (OR=9.96, p=0.0015), and NF1 (OR=4.25, p=0.0033). Importantly, among all the significantly enriched gene alterations, NF1 and CSMD3 were observed with consistent enrichment in the R0 versus the NACT group as we previously observed (Lee et al, Cell Reports, 2011). Conclusions: Our findings, using an independent validation cohort of patients, verified the higher loss of NF1 copy number in the R0 versus the NACT group. These findings could have major implications for clinical decision making and developing novel therapies for patients with HGSC. Citation Format: Sanghoon Lee, Li Zhao, Joseph Celestino, Richard A. Hajek, Margaret B. Morgan, Mark S. Kim, Shannon N. Westin, Amir A. Jazaeri, Nicole D. Fleming, Jinsong Liu, Jianhua Zhang, P Andrew Futreal, Anil K. Sood. NF1 copy number alterations in clinically-defined subsets of high-grade serous ovarian cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2200.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-2200
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 3
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    KMT2D/MLL2 inactivation is associated with recurrence in adult-type granulosa cell tumors of the ovary
    Springer Science and Business Media LLC ; 2018
    In:  Nature Communications Vol. 9, No. 1 ( 2018-06-27)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2018-06-27)
    Abstract: Adult-type granulosa cell tumors of the ovary (aGCTs) are rare gynecologic malignancies that exhibit a high frequency of somatic FOXL2 c.C402G (p.Cys134Trp) mutation. Treatment of relapsed aGCT remains a significant clinical challenge. Here we show, using whole-exome and cancer gene panel sequencing of 79 aGCTs from two independent cohorts, that truncating mutation of the histone lysine methyltransferase gene KMT2D (also known as MLL2 ) is a recurrent somatic event in aGCT. Mono-allelic KMT2D -truncating mutations are more frequent in recurrent (10/44, 23%) compared with primary (1/35, 3%) aGCTs ( p  = 0.02, two-sided Fisher’s exact test). IHC detects additional non- KMT2D -mutated aGCTs with loss of nuclear KMT2D expression, suggesting that non-genetic KMT2D inactivation may occur in this tumor type. These findings identify KMT2D inactivation as a novel driver event in aGCTs and suggest that mutation of this gene may increase the risk of disease recurrence.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-018-04950-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
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  • 4
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    Molecular Analysis of Clinically Defined Subsets of High-Grade Serous Ovarian Cancer
    Elsevier BV ; 2020
    In:  Cell Reports Vol. 31, No. 2 ( 2020-04), p. 107502-
    Details
    In: Cell Reports, Elsevier BV, Vol. 31, No. 2 ( 2020-04), p. 107502-
    Type of Medium: Online Resource
    ISSN: 2211-1247
    URL: Article
    DOI: 10.1016/j.celrep.2020.03.066
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
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  • 5
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    Abstract 5473: Genomic profiling of chemotherapy-related clonal hematopoiesis in patients with high-grade serous ovarian cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5473-5473
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5473-5473
    Abstract: Background: Clonal hematopoiesis (CH) is identified as the presence of clonal populations of hematopoietic stem cells (HSC). Hematopoietic lineage differentiation is subjected to genetic mutations that, due to fitness advantages, might give rise to clonally expanded populations. Clonal hematopoiesis of indeterminate potential (CHIP) is defined as the outgrowth of a single clone driven by acquired somatic mutation(s) in HSCs, in the absence of hematological abnormalities. Previous studies have been shown the association of CH with aging and a higher risk of developing secondary hematologic malignancies in cancer patients treated with chemotherapy agents. It is therefore of great interest to study CH incidence prior to and post chemotherapy exposure and its association with the evolution of hematologic malignancies. We aimed to characterize CHIP variants of a highly selected group of patients with high-grade serous ovarian cancer (HGSC) who underwent neoadjuvant chemotherapy; moreover, while previous CHIP studies are largely knowledge based and are limited to known hematologic genes or target gene panels, our study discovers novel CHIP mutations. Methods: Comprehensive ultra-high-depth whole exome sequencing using unique molecular barcode technologies was performed using plasma-derived cell-free DNA and matched white blood cells DNA and tumor DNA from pre-NACT (n=12) and post-NACT (n=12) samples of patients with HGSC who have excellent or poor response to NACT. Using spike-in mutated DNAs as positive controls, we detected variant alleles at 1% variant allele frequency. Results: We identified on average about 3,000 candidate CHIP variants in one patient. Among these, 1,977 variants affecting 1,375 genes were recurrently found in more than one patient. These CHIP genes include not only previous reported CHIP genes (e.g. DNMT3A, JAK2, TET2, and KMT2D) but also many novel CHIP candidates (such as RPTN, MTCH2, FAM186A, CACNA1A, FCGBP, and MUC3A). A number of CHIP mutations were uniquely found enriched in post-chemotherapy samples (e.g. ARID1A T290P, TP53 G245D, SMARCA4 G495D, and CIC T2456P). Interestingly, there is a strong enrichment of COSMIC cancer census genes in CHIP genes identified in every patient. Conclusions: Our findings corroborate the notion that CHIP mutations are present in nonmalignant blood cells of patients with HGSC, and some are enriched after chemotherapy. Moreover, our innovative sequencing approach allowed discovery of novel candidate CHIP genes. The systematic identification of CHIP in patients with HGSC might be an important new clinical consideration when establishing chemotherapy protocols. Citation Format: Sara Corvigno, Jun Yao, Li Zhao, Amma Asare, Joseph Celestino, Richard Hajek, Ency Arboleda Goette, Elaine Stur, Emine Bayraktar, Mark S Kim, Ping Song, Qingxiu Zhang, Xingzhi Song, Mohammad Mohammad, Kenna Shaw, Jianhua Zhang, Karen Lu, Amir Jazaeri, Shannon Westin, Anil Sood, Sanghoon Lee. Genomic profiling of chemotherapy-related clonal hematopoiesis in patients with high-grade serous ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5473.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-5473
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 6
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    Abstract 2941: Functional proteomic aberrations post-chemotherapy with paclitaxel and carboplatin in patients with advanced ovarian cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2941-2941
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2941-2941
    Abstract: Background: High-grade serous ovarian cancer (HGSOC) remains the leading cause of death from gynecologic malignancies. Here, we examined tumoral proteome changes following neoadjuvant chemotherapy (NACT) to identify potential predictive and prognostic biomarkers of response to primary chemotherapy. Methods: A total of 65 tissue specimens from 10 patients with advanced-stage HGSOC were collected from matched pre- and post-NACT (3 cycles of dose-dense paclitaxel and carboplatin). Protein expression was assessed using reverse-phase protein arrays (RPPA). All relative protein levels using 297 antibodies were normalized by the expression level of pre-treatment samples, and then protein expression alterations and functional analyses were performed by Reactome pathway analysis followed by statistical analysis. Results: The protein expression patterns of samples tended to cluster according to the time point (pre- and post-treatment) by a non-supervised clustering analysis using all the proteins assessed in the RPPA panel. Five differentially expressed proteins among 239 proteins (adj. p & lt;0.1, log2FC≥1) were identified by RPPA. We identified XBP1, MYH11, and S100A4 as being upregulated and CCNB1 and TFRC were down-regulated post-treatment compared to pre-treatment. We also observed significant enrichment of specific functional and signaling pathways by pathway analysis; these included PI3K/AKT signaling, necrosis and programmed cell death (upregulated, p & lt;0.05, FDR & lt;1), and cell cycle and homology-directed repair (HDR) through homologous recombination repair and G2/M checkpoints (down-regulated, p & lt;0.02, FDR & lt;0.5) in post-treatment compared to pre-treatment. Interestingly, cell cycle, DNA damage, and G2 checkpoint pathways at post-treatment exhibited significantly lower pathway scores than pre-treatment. Conclusion: Our findings identified significant proteomic alterations following NACT, and could provide insights into interval proteomic alterations following induction chemotherapy in advanced-stage ovarian cancer patients. These data present information to optimize future clinical trial designs for patients with ovarian cancer. Citation Format: Sanghoon Lee, Li Zhao, Joseph Celestino, Kelly M. Rangel, Richard A. Hajek, Mark S. Kim, Sara E. Sharafi, Jinsong Liu, Nicole D. Fleming, Karen H. Lu, Jianhua Zhang, P. Andrew Futreal, Gordon B. Mills, Shannon N. Westin, Anil K. Sood, Amir A. Jazaeri, Robert L. Coleman. Functional proteomic aberrations post-chemotherapy with paclitaxel and carboplatin in patients with advanced ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2941.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-2941
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 7
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    Molecular Profiles of Serum-Derived Extracellular Vesicles in High-Grade Serous Ovarian Cancer
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 15 ( 2022-07-23), p. 3589-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 15 ( 2022-07-23), p. 3589-
    Abstract: Patients with high-grade serous ovarian cancer (HGSC) who have no visible residual disease (R0) after primary surgery have the best clinical outcomes, followed by patients who undergo neoadjuvant chemotherapy (NACT) and have a response enabling interval cytoreductive surgery. Clinically useful biomarkers for predicting these outcomes are still lacking. Extracellular vesicles (EVs) have been recognized as liquid biopsy-based biomarkers for early cancer detection and disease surveillance in other disease settings. In this study, we performed extensive molecular characterization of serum-derived EVs and correlated the findings with therapeutic outcomes in patients with HGSC. Using EV-DNA whole-genome sequencing and EV-RNA sequencing, we identified distinct somatic EV-DNA alterations in cancer-hallmark genes and in ovarian cancer genes, as well as significantly altered oncogenic pathways between the R0 group and NACT groups. We also found significantly altered EV-RNA transcriptomic variations and enriched pathways between the groups. Taken together, our data suggest that the molecular characteristics of EVs could enable prediction of patients with HGSC who could undergo R0 surgery or respond to chemotherapy.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14153589
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
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  • 8
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    Integrated multi-omic analysis of low-grade ovarian serous carcinoma collected from short and long-term survivors
    Springer Science and Business Media LLC ; 2022
    In:  Journal of Translational Medicine Vol. 20, No. 1 ( 2022-12-17)
    Details
    In: Journal of Translational Medicine, Springer Science and Business Media LLC, Vol. 20, No. 1 ( 2022-12-17)
    Abstract: Low-grade serous ovarian cancer (LGSOC) is a rare disease that occurs more frequently in younger women than those with high-grade disease. The current treatment is suboptimal and a better understanding of the molecular pathogenesis of this disease is required. In this study, we compared the proteogenomic analyses of LGSOCs from short- and long-term survivors (defined as  〈  40 and  〉  60 months, respectively). Our goal was to identify novel mutations, proteins, and mRNA transcripts that are dysregulated in LGSOC, particularly in short-term survivors. Methods Initially, targeted sequencing of 409 cancer-related genes was performed on 22 LGSOC and 6 serous borderline ovarian tumor samples. Subsequently, whole-genome sequencing analysis was performed on 14 LGSOC samples (7 long-term survivors and 7 short-term survivors) with matched normal tissue samples. RNA sequencing (RNA-seq), quantitative proteomics, and phosphoproteomic analyses were also performed. Results We identified single-nucleotide variants (SNVs) (range: 5688–14,833 per sample), insertion and deletion variants (indels) (range: 880–1065), and regions with copy number variants (CNVs) (range: 62–335) among the 14 LGSOC samples. Among all SNVs and indels, 2637 mutation sites were found in the exonic regions. The allele frequencies of the detected variants were low (median12%). The identified recurrent nonsynonymous missense mutations included KRAS , NRAS , EIF1AX , UBR5 , and DNM3 mutations . Mutations in DNM3 and UBR5 have not previously been reported in LGSOC. For the two samples, somatic DNM3 nonsynonymous missense mutations in the exonic region were validated using Sanger sequencing. The third sample contained two missense mutations in the intronic region of DNM3 , leading to a frameshift mutation detected in RNA transcripts in the RNA-seq data. Among the 14 LGSOC samples, 7754 proteins and 9733 phosphosites were detected by global proteomic analysis. Some of these proteins and signaling pathways, such as BST1, TBXAS1, MPEG1, HBA1, and phosphorylated ASAP1, are potential therapeutic targets. Conclusions This is the first study to use whole-genome sequencing to detect somatic mutations in LGSOCs with matched normal tissues. We detected and validated novel mutations in DNM3 , which were present in 3 of the 14 samples analyzed. Additionally, we identified novel indels, regions with CNVs, dysregulated mRNA, dysregulated proteins, and phosphosites that are more prevalent in short-term survivors. This integrated proteogenomic analysis can guide research into the pathogenesis and treatment of LGSOC.
    Type of Medium: Online Resource
    ISSN: 1479-5876
    URL: Article
    DOI: 10.1186/s12967-022-03820-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 9
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    Abstract 5106: Distinct molecular profiles of serum-derived extracellular vesicles in high-grade serous ovarian cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5106-5106
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5106-5106
    Abstract: Background: Patients with high-grade serous ovarian cancer (HGSC) who have no visible residual disease (CGR) after primary surgery have the best clinical outcomes, followed by patients who undergo neoadjuvant chemotherapy (NACT) and have response enabling interval cytoreductive surgery. Through comprehensive omics analyses, we previously characterized molecular and cellular profiles of highly clinically defined HGSC from patients who had CGR versus those triaged to NACT. However, clinically useful predictive biomarkers for such distinctions are still lacking. Extracellular vesicles (EVs) have been recognized as liquid biopsy-based biomarkers for early cancer detection and disease surveillance in other disease settings. Here, we performed extensive molecular characterization of serum-derived EVs and correlated them with therapeutic outcomes in patients with HGSC. Methods: Serum-derived medium/large size EVs from patients with HGSC treated under a systematic surgical algorithm were isolated following standard methods of the International Society for Extracellular Vesicles. Patients had either complete gross resection after primary surgery (R0, n=3); poor response to NACT (NACT-PR, n=4), or excellent response to NACT with carboplatin and paclitaxel (NACT-ER, n=3); tissue and matched germline blood samples have already been comprehensively analyzed (Lee et al, Cell Reports, 2020). The isolated EV-DNA and EV-RNA were subjected to whole-genome sequencing and RNA sequencing, respectively. Results: We identified somatic EV-DNA alterations in cancer hallmark genes, including FAT1 and KMT2D as the most frequent mutated genes. Interestingly, we found alterations in ovarian cancer-related genes, including BRCA2 and RAD51 in R0; BRCA2 in NACT-ER; TP53, CDK13, CDK12, BRAF, AKT2, and ARID1A in NACT-PR patients. We also identified 26,338 genes expressed in the EV-RNA transcriptomic profiles. The analysis of the enrichment of cancer hallmark pathways showed that the R0 group was more enriched in the interferon α/γ, PI3K/AKT/mTOR signaling, and DNA repair pathways. Interestingly, we also identified 6,757 differentially expressed genes (DEGs) in the CGR versus the NACT groups (absolute log2-fold change ≥2 and adjusted p-value & lt;0.05). Among the DEGs, we identified 67 genes that were cancer hallmark genes, and 21 of them were overexpressed in the NACT group and 46 were overexpressed in the R0 group. Noticeably, 11 DEGs were directly related to ovarian cancer: TP53, PTEN, CCND1, BARD1, PMS2, and MLH3 were significantly overexpressed in the NACT group, while BRCA2, CSMD3, and GABRA6 were overexpressed in the R0 group. Conclusions: Taken together, our preliminary data suggest that molecular characteristics of EVs could provide an accurate prediction of patients with HGSC who can undergo CGR with surgery and respond to chemotherapy. Citation Format: Li Zhao, Shaolin Ma, Nicole D. Fleming, Joseph Celestino, Mark S. Kim, Richard A. Hajek, Nicholas B. Jennings, Erika J. Thompson, Hongli Tang, Shannon N. Westin, Amir A. Jazaeri, Jianhua Zhang, P Andrew Futreal, Anil K. Sood, Sanghoon Lee. Distinct molecular profiles of serum-derived extracellular vesicles in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5106.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-5106
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    Abstract 5738: Transcriptomic profiles of response to neoadjuvant chemotherapy in patients with high-grade serous ovarian cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5738-5738
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5738-5738
    Abstract: Background: High-grade serous ovarian cancer (HGSC) is the most aggressive epithelial ovarian cancer, exhibiting tumor heterogeneity, molecular abnormality, and variable clinical outcomes. The heterogeneity and apparent adaptability of the HGSC genome under selective pressure by chemotherapy likely explain the high rates of drug resistance in HGSC. However, the underlying mechanisms of drug resistance are not well understood. Following our previous findings of significant distinct molecular and cellular characteristics in pre-treatment tumor samples from highly clinically annotated HGSC patients who received neoadjuvant chemotherapy (NACT), we examined post-treatment transcriptomic changes associated with excellent or poor responders to NACT in HGSC patients. Methods: Thirty tumor tissues (pre- and post-treatment) after 3 to 4 cycles of NACT were collected from HGSC patients at interval cytoreductive debulking surgery from the following groups: excellent response to NACT with carboplatin/paclitaxel (post-ER, n=8); poor response to NACT (post-PR, n=8). Primary or metastatic sites for each patient were obtained (n=13, post-ER; n=17, post-PR) and subjected to RNA sequencing. The downstream bioinformatics analysis was then performed and compared with the data from the matched pre-NACT samples from the same patients (Lee et al., Cell Reports, 2020). Results: We identified a total of 9,764 upregulated and 2,762 downregulated differentially expressed genes (DEGs, absolute log2FC & gt;=2, adj-p & lt;0.05) in the post-NACT samples vs the pre-NACT samples in the ER group. In contrast, 11,246 upregulated and 1,320 downregulated DEGs were found in the NACT-PR group. Ovarian cancer-related genes, including KRAS, NRAS, BRCA1/2, RB1, NF1, MLH1, PIK3CA, MSH2, AKT1, and NOTCH3 were differentially expressed in post-NACT vs pre-NACT in both ER and PR groups. TP53 was exclusively upregulated in post-ER vs pre-ER, and GABRA6 was exclusively upregulated in post-PR vs pre-PR. In signaling pathway analysis, apoptosis and DNA repair-related pathways were exclusively downregulated in post-ER vs pre-ER. Interestingly, the percentage of immune cells − CD8 and macrophages M0 were significantly elevated in post-ER (p & lt;0.05), while γδ T cells and activated dendritic cells were significantly decreased in the post-ER (p & lt;0.05), not in the PR. Neutrophil cells were significantly lower in post-PR vs pre-PR, but not in ER group. We also found that the level of ESR1 decreased significantly in post-ER vs post-PR (p & lt;0.05). The level of PAX8 significantly increased in post-PR vs post-ER (p & lt;0.05). Conclusions: Our transcriptomic analysis revealed distinct transcripts changes in post-NACT vs pre-NACT tumor tissues from HGSC patients with excellent or poor response to the NACT. These findings could enhance treatment decision-making and rationale for developing alternative therapies for patients with HGSC. Citation Format: Sanghoon Lee, Li Zhao, Nicole D. Fleming, Joseph Celestino, Richard A. Hajek, Margaret B. Morgan, Yan Liu, Shannon N. Westin, Amir A. Jazaeri, Jinsong Liu, Jianhua Zhang, P Andrew Futreal, Anil K. Sood. Transcriptomic profiles of response to neoadjuvant chemotherapy in patients with high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5738.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-5738
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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