A Retrospective Cross-Sectional Cohort Trial Assessing the Prevalence of MTHFR Polymorphisms and the Influence of Diet on Platinum Resistance in Ovarian Cancer Patients

Ovarian cancer has the lowest survival rate in gynaecologic malignancies with a 5-year survival rate of 43%. Platinum resistance is one of the main drivers of ovarian cancer mortality, of which aberrant methylation has been cited as a significant contributor. Understanding the essential role of the methylenetetrahydrofolate reductase enzyme (MTHFR) on DNA synthesis and repair, and how nutrient status can vastly affect its performance, led to the investigation of MTHFR status and dietary influence on platinum response in epithelial ovarian cancer (EOC) patients. Twenty-five adult female patients who completed first-line platinum-based chemotherapy for primary ovarian cancer were selected from Icon Cancer Centres in Australia. Participants were grouped based on platinum response. A full medical and family history, food frequency questionnaire and single blood test were completed, testing for MTHFR polymorphisms, serum folate, serum and active B12 and homocysteine levels. Nineteen of twenty-five participants had an MTHFR polymorphism. Of those, 20% were compound heterozygous, 12% were heterozygous C677T (CT), 4% homozygous C677T, 12% homozygous A1298C and 28% were heterozygous A1298C (AC). Statistically significant associations were found between dietary zinc (p = 0.0086; 0.0030; 0.0189) and B12 intakes in CT genotypes (p = 0.0157; 0.0030; 0.0068) indicating that zinc or vitamin B12 intakes below RDI were associated with this genotype. There were strong associations of vitamin B6 intakes in AC genotypes (p = 0.0597; 0.0547; 0.0610), and dietary folate in compound heterozygotes with sensitive and partially sensitive disease (p = 0.0627; 0.0510). There were also significant associations between serum folate (p = 0.0478) and dietary B12 (p = 0.0350) intakes above RDI and platinum sensitivity in wild-types as well as strong associations with homocysteine levels (p = 0.0886) and zinc intake (p = 0.0514). Associations with dietary B12 (p = 0.0514) and zinc intakes (p = 0.0731) were also strong in resistant wild types. Results indicate that dietary zinc, B12 and B6 intakes may be associated with platinum sensitivity dependent on MTHFR genotype. These results require further research to clarify the dosages necessary to elicit a response; however, they provide a novel foundation for acknowledging the role of diet on treatment response in EOC.

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CHD4 regulates platinum sensitivity through MDR1 expression in ovarian cancer: A potential role of CHD4 inhibition as a combination therapy with platinum agents

PLoS ONE ◽

10.1371/journal.pone.0251079 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0251079

Author(s):

Yoshiko Oyama ◽

Shogo Shigeta ◽

Hideki Tokunaga ◽

Keita Tsuji ◽

Masumi Ishibashi ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

The Cancer Genome Atlas ◽

Ovarian Cancer Cells ◽

Platinum Resistance ◽

Nucleosome Remodeling ◽

Platinum Sensitivity ◽

Mdr1 Expression ◽

Platinum Agents

Platinum sensitivity is an important prognostic factor in patients with ovarian cancer. Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a core member of the nucleosome remodeling and deacetylase complex, which functions as a chromatin remodeler. Emerging evidence indicates that CHD4 could be a potential therapeutic target for cancer therapy. The purpose of this study was to clarify the role of CHD4 in ovarian cancer and investigate its therapeutic potential focusing on platinum sensitivity. In an analysis of the Cancer Genome Atlas ovarian cancer dataset, CHD4 gene amplification was associated with worse overall survival. CHD4 mRNA expression was significantly higher in platinum-resistant samples in a subsequent clinical sample analysis, suggesting that CHD4 overexpression conferred platinum resistance to ovarian cancer cells, resulting in poor patient survival. In concordance with these findings, CHD4 knockdown enhanced the induction of apoptosis mediated by cisplatin in ovarian cancer cells TOV21G and increased cisplatin sensitivity in multiple ovarian cancer cells derived from different subtypes. However, CHD4 knockdown did not affect the expression of RAD51 or p21, the known targets of CHD4 in other cancer types that can modulate platinum sensitivity. Knockdown and overexpression assays revealed that CHD4 positively regulated the expression of multi-drug transporter MDR1 and its coding protein p-glycoprotein. In addition, a first-in-class CHD4/SMARCA5 inhibitor ED2-AD101 showed synergistic interactions with cisplatin. Our findings suggest that CHD4 mediates platinum sensitivity by modulating MDR1 expression in ovarian cancer. Further, CHD4 suppression has a potential to be a novel therapeutic strategy in combination with platinum agents.

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c-MYC and Epithelial Ovarian Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.601512 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jeyshka M. Reyes-González ◽

Pablo E. Vivas-Mejía

Keyword(s):

Patient Outcome ◽

Ovarian Cancer ◽

Standard Of Care ◽

Initial Response ◽

Platinum Resistance ◽

Therapy Regimen ◽

Clinical Challenge ◽

Tumor Types ◽

Improve Patient

Ovarian cancer is the deadliest of gynecological malignancies with approximately 49% of women surviving 5 years after initial diagnosis. The standard of care for ovarian cancer consists of cytoreductive surgery followed by platinum-based combination chemotherapy. Unfortunately, despite initial response, platinum resistance remains a major clinical challenge. Therefore, the identification of effective biomarkers and therapeutic targets is crucial to guide therapy regimen, maximize clinical benefit, and improve patient outcome. Given the pivotal role of c-MYC deregulation in most tumor types, including ovarian cancer, assessment of c-MYC biological and clinical relevance is essential. Here, we briefly describe the frequency of c-MYC deregulation in ovarian cancer and the consequences of its targeting.

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The role of single nucleotide polymorphisms of the ERCC1 and MMS19 genes in predicting platinum-sensitivity, progression-free and overall survival in advanced epithelial ovarian cancer

Gynecologic Oncology ◽

10.1016/j.ygyno.2013.04.054 ◽

2013 ◽

Vol 130 (2) ◽

pp. 377-382 ◽

Cited By ~ 12

Author(s):

K.M. Moxley ◽

D.M. Benbrook ◽

L. Queimado ◽

R.E. Zuna ◽

D. Thompson ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Single Nucleotide Polymorphisms ◽

Epithelial Ovarian Cancer ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Platinum Sensitivity ◽

Advanced Epithelial Ovarian Cancer

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Critical role of Wnt/β-catenin signaling in driving epithelial ovarian cancer platinum resistance

Oncotarget ◽

10.18632/oncotarget.4690 ◽

2015 ◽

Vol 6 (27) ◽

pp. 23720-23734 ◽

Cited By ~ 105

Author(s):

Anil Belur Nagaraj ◽

Peronne Joseph ◽

Olga Kovalenko ◽

Sareena Singh ◽

Amy Armstrong ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Critical Role ◽

Platinum Resistance

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Frequently deleted genes in ovarian cancer as indicators of platinum response.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.5583 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 5583-5583

Author(s):

Scooter Willis ◽

Victor Manuel Villalobos ◽

Brandon Michael Young ◽

Branimir I. Sikic ◽

Brian Leyland-Jones

Keyword(s):

Ovarian Cancer ◽

Gene Signature ◽

Replication Study ◽

Rank Test ◽

Outcome Analysis ◽

Platinum Resistance ◽

P Value ◽

Full Cohort ◽

Gene Signatures ◽

Platinum Sensitivity

5583 Background: Integrating chromosomal deletions/amplifications with sequencing alterations is increasingly important in the determination of key drivers of outcome in cancer (Leary 2008, Curtis 2012). We introduce a novel computational approach, Gene Set Outcome Analysis, to determine gene signatures constrained to regions with frequent deletion or amplification events in ovarian cancer identified by TCGA. Differential expressions of mRNA from these genes are used as a proxy for loss of function from deletions or amplifications. Methods: Gene signatures from each region were evaluated using log-rank test comparing high and low gene expression groups split by cohort mean. In total, 30,119,708 signatures constrained to 47 deleted and 36 amplified regions were tested for PFS for first line platinum treatment in a random 2/3 split of TCGA ovarian cohort (n=262) resulting in 26,271 gene signatures with p < .001. The remaining 1/3 cohort (n=135) and full cohort (n=397) were used as a replication study where 111 signatures have a p < .01 located in 2 deletion and 1 amplification region. The signature with the lowest p-value from each region that validated in the replication study, were evaluated in GSE9891 (n=179) (Tothill 2008) for PFS when treated with platinum and taxol resulting in gene signatures from 2 deletion regions with p<.05. Results: Greater than mean expression in this gene signature [OXTR, SATB1, WNT7A, SH3BP5, CRBN, ATG7, CRELD1, TMEM43] located at 3p23-p26.2 predicts poor response to platinum chemotherapy in TCGA full ovarian cohort (17.9 vs 14 months p = 1.4E-7) and validates in GSE9891 (19.6 vs 13.3 months p = .014). Using a separate, compact gene signature [CAAP1, LRRC19, IFNA8] located at 9p21.2, samples with lower than mean expression demonstrate increased platinum sensitivity in TCGA full ovarian cohort (12.2 vs 18.2 months p = 1.0E-6) and in GSE9891 (15.5 vs 18.6 p = .055). Conclusions: Response to platinum therapy is an important predictor of survival in high-risk ovarian cancer patients. These signatures arising from common deletion and amplification events in ovarian cancer can anticipate platinum sensitivity and merits further study for use in choosing optimal therapies studying platinum resistance mechanisms.

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Role of FOXO protein's abnormal activation through PI3K / AKT pathway in platinum resistance of ovarian cancer

Journal of Obstetrics and Gynaecology Research ◽

10.1111/jog.14753 ◽

2021 ◽

Author(s):

Yun‐Yue Shi ◽

Xiang‐Tian Meng ◽

Ya‐Nan Xu ◽

Xiu‐Juan Tian

Keyword(s):

Ovarian Cancer ◽

Akt Pathway ◽

Platinum Resistance

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RUNX3 Transcript Variants Have Distinct Roles in Ovarian Carcinoma and Differently Influence Platinum Sensitivity and Angiogenesis

Cancers ◽

10.3390/cancers13030476 ◽

2021 ◽

Vol 13 (3) ◽

pp. 476

Author(s):

Karolin Heinze ◽

Martin Hölzer ◽

Martin Ungelenk ◽

Melanie Gerth ◽

Jürgen Thomale ◽

...

Keyword(s):

Ovarian Cancer ◽

Transcript Variant ◽

Platinum Resistance ◽

Chemotherapy Response ◽

Proteomic Profiling ◽

Platinum Sensitivity ◽

Γh2ax Foci ◽

Angiogenesis Assay ◽

Transcript Variants ◽

Skov3 Cells

The prognosis of late-stage epithelial ovarian cancer (EOC) patients is affected by chemotherapy response and the malignant potential of the tumor cells. In earlier work, we identified hypermethylation of the runt-related transcription factor 3 gene (RUNX3) as a prognostic biomarker and contrary functions of transcript variants (TV1 and TV2) in A2780 and SKOV3 cells. The aim of the study was to further validate these results and to increase the knowledge about RUNX3 function in EOC. New RUNX3 overexpression models of high-grade serous ovarian cancer (HGSOC) were established and analyzed for phenotypic (IC50 determination, migration, proliferation and angiogenesis assay, DNA damage analysis) and transcriptomic consequences (NGS) of RUNX3 TV1 and TV2 overexpression. Platinum sensitivity was affected by a specific transcript variant depending on BRCA background. RUNX3 TV2 induced an increased sensitivity in BRCA1wt cells (OVCAR3), whereas TV1 increased the sensitivity and induced a G2/M arrest under treatment in BRCA1mut cells (A13-2-12). These different phenotypes relate to differences in DNA repair: homologous recombination deficient A13-2-12 cells show less γH2AX foci despite higher levels of Pt-DNA adducts. RNA-Seq analyses prove transcript variant and cell-line-specific RUNX3 effects. Pathway analyses revealed another clinically important function of RUNX3—regulation of angiogenesis. This was confirmed by thrombospondin1 analyses, HUVEC spheroid sprouting assays and proteomic profiling. Importantly, conditioned media (CM) from RUNX3 TV1 overexpressing A13-2-12 cells induced an increased HUVEC sprouting. Altogether, the presented data support the hypothesis of different functions of RUNX3 transcript variants related to the clinically relevant processes—platinum resistance and angiogenesis.

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Platinum-Induced Ubiquitination of Phosphorylated H2AX by RING1A is Mediated by Replication Protein A in Ovarian Cancer

10.1101/2020.04.30.070185 ◽

2020 ◽

Author(s):

Shruthi Sriramkumar ◽

Timothy D. Matthews ◽

Ahmed H. Ghobashi ◽

Samuel A. Miller ◽

Pamela S. VanderVere-Carozza ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Damage ◽

Excision Repair ◽

Protein A ◽

Replication Protein A ◽

Replication Protein ◽

Platinum Resistance ◽

Platinum Agents ◽

Chromatin Modifiers

AbstractPlatinum resistance is a common occurrence in high grade serous ovarian cancer (HGSOC) and a major cause of OC deaths. Platinum agents form DNA crosslinks, which activate nucleotide excision repair (NER), fanconi anemia (FA) and homologous recombination repair (HRR) pathways. Chromatin modifications occur in the vicinity of DNA damage and play an integral role in the DNA damage response (DDR). Chromatin modifiers, including polycomb repressive complex 1 (PRC1) members, and chromatin structure are frequently dysregulated in OC and can potentially contribute to platinum resistance. However, the role of chromatin modifiers in the repair of platinum DNA damage in OC is not well understood. We demonstrate that the PRC1 complex member RING1A mediates monoubiquitination of lysine 119 of phosphorylated H2AX (γH2AXub1) at sites of platinum DNA damage in OC cells. After platinum treatment, our results reveal that NER and HRR both contribute to RING1A localization and γH2AX monoubiquitination. Importantly, replication protein A (RPA), involved in both NER and HRR, mediates RING1A localization to sites of damage. Furthermore, RING1A deficiency impaired the activation of the G2/M DNA damage checkpoint and reduced the ability of OC cells to repair platinum DNA damage. Elucidating the role of RING1A in the DDR to platinum agents will allow for the identification of therapeutic targets to improve the response of OC to standard chemotherapy regimens.

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The Role of Induction Chemotherapy in Inoperable Ovarian Cancer

Tumori Journal ◽

10.1177/030089168907500620 ◽

1989 ◽

Vol 75 (6) ◽

pp. 609-614 ◽

Cited By ~ 10

Author(s):

Michela Donadio ◽

Gianmaria Bonardi ◽

Valter Iberti ◽

Oscar Bertetto ◽

Flavio Carnino ◽

...

Keyword(s):

Ovarian Cancer ◽

Survival Rate ◽

Induction Chemotherapy ◽

Advanced Ovarian Cancer ◽

Progression Free Survival ◽

Residual Tumor ◽

Free Survival ◽

Median Progression Free Survival ◽

Optimal Debulking

Thirty patients with bulky advanced ovarian cancer surgically not resectable, received combination chemotherapy (median of 4.1 cycles; range, 3-7) including cisplatin or carboplatin, followed by a second surgical effort. Clinical CR+PR was observed in 24/30 (80 %) patients after chemotherapy. Our study deals only with these 24 patients, and the 6 patients who did not respond to chemotherapy are not part of this report. At debulking, 7/24 (29.1 %) patients had a complete macroscopic resection; 9/24 (37.5 %) patients had a partial resection (residual tumor <2 cm). These data suggest that debulking is feasible and successful after chemotherapy containing cisplatin or its derivative. Overall median survival from diagnosis was 18.9 months; the 3-year survival rate was 28 %. Median progression-free survival from diagnosis was 13.5 months. The results observed in our study indicate that the use of induction chemotherapy can play an important role in increasing the chances of optimal debulking in patients presenting with unresectable ovarian cancer.

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