Tumor genomic, transcriptomic, and immune profiling characterizes differential response to first‐line platinum chemotherapy in high grade serous ovarian cancer

Weberpals, Johanne I.; Pugh, Trevor J.; Marco-Casanova, Paola; Goss, Glenwood D.; Wright, Natalie Andrews; Rath, Pramod C.; Torchia, Jonathon; Fortuna, Alexander; Jones, Gemma N.; Roudier, Martine P.; Bernard, Laurence; Lo, Bryan; Torti, Dax; Leόn, Alberto J.; Marsh, Kayla; Hodgson, Darren; Duciaume, Marc M.; Howat, William J.; Lukashchuk, Natalia; Lazic, Stanley E.; Whelan, Doreen; Sekhon, Harmanjatinder S.

doi:10.1002/cam4.3831

Cited by 14 publications

(10 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, a study comparing TP53 isoforms in 31 HGSC patients identified significantly lower levels of total TP53 transcript in TP53 wild‐type tumors than in mutated ones 43 . Nevertheless, a recent study using RNA‐sequencing of 39 HGSC patients did not observe a significant difference in the TP53 transcript expression between good and poor HGSC responders on the basis of progression‐free interval to platinum‐based therapy 44 . Comparison of ovarian cancer cell lines, p53‐null (SKOV‐3), TP53 wild‐type (A2780), and mutant TP53 R248 (OVCAR‐3), showed the highest p53 protein expression for TP53 R248 cells in vitro 45 .…”

Section: Discussionmentioning

confidence: 97%

“…43 Nevertheless, a recent study using RNA-sequencing of 39 HGSC patients did not observe a significant difference in the TP53 transcript expression between good and poor HGSC responders on the basis of progression-free interval to platinum-based therapy. 44 Comparison of ovarian cancer cell lines, p53-null (SKOV-3), TP53 wild-type (A2780), and mutant TP53 R248 (OVCAR-3), showed the highest p53 protein expression for TP53 R248 cells in vitro. 45 Furthermore, cisplatinresistant A2780 cells with wild-type TP53 have reduced p53 and downstream signaling and avoid apoptosis compared to p53 mutated cells.…”

Section: Tp53 Gene Expression and Its Association With Clinical Data ...mentioning

confidence: 99%

See 1 more Smart Citation

Targeted DNA sequencing of high‐grade serous ovarian carcinoma reveals association of TP53 mutations with platinum resistance when combined with gene expression

Holý,

Hlaváč,

Šeborová

et al. 2024

Intl Journal of Cancer

View full text Add to dashboard Cite

High‐grade serous ovarian carcinoma (HGSC) is the most common subtype of ovarian cancer and is among the most fatal gynecological malignancies worldwide, due to late diagnosis at advanced stages and frequent therapy resistance. In 47 HGSC patients, we assessed somatic and germline genetic variability of a custom panel of 144 known or suspected HGSC‐related genes by high‐coverage targeted DNA sequencing to identify the genetic determinants associated with resistance to platinum‐based therapy. In the germline, the most mutated genes were DNAH14 (17%), RAD51B (17%), CFTR (13%), BRCA1 (11%), and RAD51 (11%). Somatically, the most mutated gene was TP53 (98%), followed by CSMD1/2/3 (19/19/36%), and CFTR (23%). Results were compared with those from whole exome sequencing of a similar set of 35 HGSC patients. Somatic variants in TP53 were also validated using GENIE data of 1287 HGSC samples. Our approach showed increased prevalence of high impact somatic and germline mutations, especially those affecting splice sites of TP53, compared to validation datasets. Furthermore, nonsense TP53 somatic mutations were negatively associated with patient survival. Elevated TP53 transcript levels were associated with platinum resistance and presence of TP53 missense mutations, while decreased TP53 levels were found in tumors carrying mutations with predicted high impact, which was confirmed in The Cancer Genome Atlas data (n = 260). Targeted DNA sequencing of TP53 combined with transcript quantification may contribute to the concept of precision oncology of HGSC. Future studies should explore targeting the p53 pathway based on specific mutation types and co‐analyze the expression and mutational profiles of other key cancer genes.

show abstract

Section: Discussionmentioning

confidence: 97%

Section: Tp53 Gene Expression and Its Association With Clinical Data ...mentioning

confidence: 99%

Targeted DNA sequencing of high‐grade serous ovarian carcinoma reveals association of TP53 mutations with platinum resistance when combined with gene expression

Holý,

Hlaváč,

Šeborová

et al. 2024

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…SOC is a main histological subtype of OC with a poor prognosis. Debulking surgery combined with platinum-based chemotherapy is the primary therapy of SOC [ 25 ]. Although platinum-based therapy continued to be the first-line option of advanced-stage SOC, platinum is not the best approach for partial patients with limited platinum sensitivity (a platinum-treatment free interval of 6–12 months) [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptome-based stemness indices analysis reveals platinum-based chemo-theraputic response indicators in advanced-stage serous ovarian cancer

et al. 2021

View full text Add to dashboard Cite

show abstract

“…IHC analysis was performed by two independent pathology investigators at 400× magnification in five randomly selected representative fields separately. A quantitative scoring system was applied to the assessment [22]. e staining intensity criteria were as follows: no positive coloring count 0 points, light yellow (weak positive) count 1 points, brown yellow (positive) count 2 points, and brown Journal of Oncology (strong positive) count 3 points.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Upregulated Expression of CYBRD1 Predicts Poor Prognosis of Patients with Ovarian Cancer

Chen

Cao

Jiang

et al. 2021

Journal of Oncology

View full text Add to dashboard Cite

Cytochrome b reductase 1 (CYBRD1) promotes the development of ovarian serous cystadenocarcinoma (OV). We assessed the function of CYBRD1 in OV underlying The Cancer Genome Atlas (TCGA) database. The correlation between clinicopathological characteristics and CYBRD1 expression was estimated. The Cox proportional hazards regression model and the Kaplan–Meier method were applied to identify clinical features related to overall survival and disease-specific survival. Gene set enrichment analysis (GSEA) was applied to identify the relationship between CYBRD1 expression and immune infiltration. CYBRD1 expression in OV was significantly associated with poor outcomes of primary therapy and FIGO stage. Patients with high levels of CYBRD1 expression were prone to the development of a poorly differentiated tumor and experience of an unfavorable outcome. CYBRD1 expression had significant association with shorter OS and acts as an independent predictor of poor outcome. Moreover, enhanced CYBRD1 expression was positively associated with Tem, NK cells, and mast cells but negatively associated with CD56 bright NK cells and Th2 cells. CYBRD1 expression may serve as a diagnostic and prognostic indicator of OV patients. The mechanisms of poor prognosis of CYBRD1-mediated OV may include increased iron uptake, regulation of immune microenvironment, ferroptosis related pathway, and ERK signaling pathway, among which ferroptosis and ERK signaling pathway may be important pathways of CYBRD1-mediated OV. Furthermore, we verified that CYBRD1 was upregulated in OV and significant correlated with lymph nodes metastasis, advanced stage, poor-differentiated tumor, and poor clinical prognosis in East Hospital cohort. The results of this study may provide guidance for the development of optimal treatment strategies for OV.

show abstract

Tumor genomic, transcriptomic, and immune profiling characterizes differential response to first‐line platinum chemotherapy in high grade serous ovarian cancer

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 14 publications

References 56 publications

Targeted DNA sequencing of high‐grade serous ovarian carcinoma reveals association of TP53 mutations with platinum resistance when combined with gene expression

Targeted DNA sequencing of high‐grade serous ovarian carcinoma reveals association of TP53 mutations with platinum resistance when combined with gene expression

Transcriptome-based stemness indices analysis reveals platinum-based chemo-theraputic response indicators in advanced-stage serous ovarian cancer

Upregulated Expression of CYBRD1 Predicts Poor Prognosis of Patients with Ovarian Cancer

Contact Info

Product

Resources

About