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Advances in Genetics and Genomics of Ovarian Cancer
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Advances in Genetics and Genomics of Ovarian Cancer

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 December 2023) | Viewed by 18513

Special Issue Editor

Dr. Sohyun Hwang

E-Mail Website
Guest Editor
1. Department of Pathology, CHA Bundang Medical Center, CHA University, Sungnam-si, Gyeonggi-do, Republic of Korea
2. Department of Biomedical Science, Colledge of Life Science, CHA University, Sungnam-si, Gyeonggi-do, Republic of Korea
Interests: high-grade serous ovarian carcinoma; genome instability; DNA damage repair; cellular senescence; homologous recombination deficiency; 3D chromosomal organization

Special Issue Information

Dear Colleagues,

Ovarian cancer is a leading cause of death among patients with gynecological malignancies and the majority of ovarian cancer cases are high-grade serous carcinomas (HGSCs). Current estimates indicated that women with germline mutations in BRCA1 or BRCA2 have a 30% to 70% chance of developing ovarian cancer and TP53 mutation is clearly an early event in developing HGSCs. The Cancer Genome Atlas (TCGA) also reported that mutations in TP53 are present in more than 96% of HGSCs and homologous recombination (HR) deficiency (e.g. BRCA1 or BRCA2) is present in approximately 50% of the patients. This means that the other half of HGSCs have no apparent defect in HR. Moreover, HGSC is one of the most chromosamally variant malignancies (i.e., genome instability). CCNE1 amplification, RB1 loss and NF1 loss are frequently observed in HGSC.

In this era of targeted therapy, to reduce incidence and improve outcomes in HGSC, precise molecular characterization of HGSC from individual patients is very important. We need to understand the genetics and genomics of HGSC in a holistic way by considering several molecular pathways such as HR deficiency, P53 aberration, DNA damage repair, cellular senescence, immune evasion, DNA replication stress, genome instability and its epigenetic regulation. We also hope that 3D chromosome organization will provide new insights into the molecular mechanism of its chromosomal aberration and help in the identification of its new therapeutic targets.

 In this Special Issue of Genes on “Genetics and Genomics of Ovarian Cancer”, we welcome reviews, mini-reviews, new methods, and original research articles that advance our understanding of ovarian cancers. While the new insights driven by 3D chromosome organization on molecular mechanisms or pathways related to HGSC—such as P53 aberration, cellular senescence, immune evasion, and genome instability—will be of special interest, we will also be open to any topic that advances the understanding of ovarian cancers to develop a better therapeutic method.

Dr. Sohyun Hwang
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • high-grade serous ovarian carcinoma
  • genome instability
  • homologous recombination deficiency
  • P53 aberration
  • DNA damage repair
  • cellular senescence
  • PARP inhibitor
  • DNA replication stress
  • epigenetic regulation
  • 3D genome

Published Papers (7 papers)

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Research

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12 pages, 1501 KiB  
Article
T-Cell Receptor Repertoire Characteristics Associated with Prognostic Significance in High-Grade Serous Ovarian Carcinoma
by Ju-Won Kim, Sewha Kim, So-Yun Yang, Je-Gun Joung and Sohyun Hwang
Genes 2023, 14(4), 785; https://doi.org/10.3390/genes14040785 - 24 Mar 2023
Viewed by 1214
Abstract
High-grade serous ovarian carcinoma (HGSOC) is a fatal gynecological malignancy. Somatic recombination occurring during T-cell receptor (TCR) development results in TCR diversity, and the TCR repertoire, thus produced, is associated with immune response. This study analyzed the difference in the TCR repertoire and [...] Read more.
High-grade serous ovarian carcinoma (HGSOC) is a fatal gynecological malignancy. Somatic recombination occurring during T-cell receptor (TCR) development results in TCR diversity, and the TCR repertoire, thus produced, is associated with immune response. This study analyzed the difference in the TCR repertoire and their prognostic significance in 51 patients with HGSOC. The patient’s clinical characteristics, gene expression pattern, TCR clonotypes, and degree of tumor-infiltrating leukocytes (TILs) were analyzed, and the patients were divided into groups depending on their recurrence pattern, tumor-infiltrating leukocyte (TIL) score, and homologous recombinant repair pathway deficiency (HRD)-associated mutations. The TCR repertoire was low in patients with recurrence and showed the expansion of eight TCR segments. Interestingly, a few genes correlated with the TCRs also showed a difference in expression according to the prognosis. Among them, seven genes were related to immune responses and KIAA1199 was up-regulated in ovarian cancer. Our study shows that the differences in the TCR repertoire in patients with ovarian cancer and their associated immune pathways could affect the prognosis of HGSOC. Full article
(This article belongs to the Special Issue Advances in Genetics and Genomics of Ovarian Cancer)
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11 pages, 1853 KiB  
Communication
BRCA1/2 Mutations in Vietnamese Patients with Hereditary Breast and Ovarian Cancer Syndrome
by Trong-Nhan N. Le, Van-Khanh Tran, Thu-Thuy Nguyen, Nam S. Vo, Tham H. Hoang, Hoang-Long Vo, Thanh-Hai T. Nguyen, Phuoc-Dung Nguyen, Viet-Tien Nguyen, Thanh-Van Ta and Huy-Thinh Tran
Genes 2022, 13(2), 268; https://doi.org/10.3390/genes13020268 - 29 Jan 2022
Cited by 4 | Viewed by 3310
Abstract
(1) Background: Individuals with BRCA1/2 gene mutations are at increased risk of breast and ovarian cancer. The prevalence of BRCA1/2 mutations varies by race and ethnicity, and the prevalence and the risks associated with most BRCA1/2 mutations has not been unknown in the [...] Read more.
(1) Background: Individuals with BRCA1/2 gene mutations are at increased risk of breast and ovarian cancer. The prevalence of BRCA1/2 mutations varies by race and ethnicity, and the prevalence and the risks associated with most BRCA1/2 mutations has not been unknown in the Vietnamese population. We herein screen the entire BRCA1 and BRCA2 genes for breast and ovarian cancer patients with a family history of breast cancer and ovarian cancer, thereby, suggesting a risk score associated with carrier status and history for aiding personalized treatment; (2) Methods: Between December 2017 and December 2019, Vietnamese patients who had a pathological diagnosis of breast and epithelial ovarian cancer were followed up, prospectively, after treatment from two large institutions in Vietnam. Blood samples from 33 Vietnamese patients with hereditary breast and ovarian cancers (HBOC) syndrome were collected and analyzed using Next Generation Sequencing; (3) Results: Eleven types of mutations in both BRCA1 (in nine patients) and BRCA2 (in three patients) were detected, two of which (BRCA1:p.Tyr1666Ter and BRCA2:p.Ser1341Ter) have not been previously documented in the literature. Seven out of 19 patient’s relatives had BRCA1/2 gene mutations. All selected patients were counselled about the likelihood of cancer rising and prophylactic screening and procedures. The study established a risk score associated with the cohorts based on carrier status and family history; (4) Conclusions: Our findings suggested the implications for the planning of a screening programme for BRCA1 and BRCA2 genes testing in breast and ovarian cancer patients and genetic screening in their relatives. BRCA1/2 mutation carriers without cancer should have early and regular cancer screening, and prophylactic measures. This study could be beneficial for a diverse group in a large population-specific cohort, related to HBOC Syndrome. Full article
(This article belongs to the Special Issue Advances in Genetics and Genomics of Ovarian Cancer)
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16 pages, 5577 KiB  
Article
Classification of High-Grade Serous Ovarian Carcinoma by Epithelial-to-Mesenchymal Transition Signature and Homologous Recombination Repair Genes
by Min-Hwan Sohn, Se Ik Kim, Jong-Yeon Shin, Hee Seung Kim, Hyun Hoon Chung, Jae-Weon Kim, Maria Lee and Jeong-Sun Seo
Genes 2021, 12(7), 1103; https://doi.org/10.3390/genes12071103 - 20 Jul 2021
Cited by 9 | Viewed by 3386
Abstract
High-grade serous ovarian cancer (HGSOC) is one of the deadliest cancers that can occur in women. This study aimed to investigate the molecular characteristics of HGSOC through integrative analysis of multi-omics data. We used fresh-frozen, chemotherapy-naïve primary ovarian cancer tissues and matched blood [...] Read more.
High-grade serous ovarian cancer (HGSOC) is one of the deadliest cancers that can occur in women. This study aimed to investigate the molecular characteristics of HGSOC through integrative analysis of multi-omics data. We used fresh-frozen, chemotherapy-naïve primary ovarian cancer tissues and matched blood samples of HGSOC patients and conducted next-generation whole-exome sequencing (WES) and RNA sequencing (RNA-seq). Genomic and transcriptomic profiles were comprehensively compared between patients with germline BRCA1/2 mutations and others with wild-type BRCA1/2. HGSOC samples initially divided into two groups by the presence of germline BRCA1/2 mutations showed mutually exclusive somatic mutation patterns, yet the implementation of high-dimensional analysis of RNA-seq and application of epithelial-to-mesenchymal (EMT) index onto the HGSOC samples revealed that they can be divided into two subtypes; homologous recombination repair (HRR)-activated type and mesenchymal type. Patients with mesenchymal HGSOC, characterized by the activation of the EMT transcriptional program, low genomic alteration and diverse cell-type compositions, exhibited significantly worse overall survival than did those with HRR-activated HGSOC (p = 0.002). In validation with The Cancer Genome Atlas (TCGA) HGSOC data, patients with a high EMT index (≥the median) showed significantly worse overall survival than did those with a low EMT index (<the median) (p = 0.030). In conclusion, through a comprehensive multi-omics approach towards our HGSOC cohorts, two distinctive types of HGSOC (HRR-activated and mesenchymal) were identified. Our novel EMT index seems to be a potential prognostic biomarker for HGSOC. Full article
(This article belongs to the Special Issue Advances in Genetics and Genomics of Ovarian Cancer)
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15 pages, 1641 KiB  
Article
MET Expression and Cancer Stem Cell Networks Impact Outcome in High-Grade Serous Ovarian Cancer
by Maria Bååth, Jenny-Maria Jönsson, Sofia Westbom Fremer, Laura Martín de la Fuente, Lena Tran, Susanne Malander, Päivi Kannisto, Anna Måsbäck, Gabriella Honeth and Ingrid Hedenfalk
Genes 2021, 12(5), 742; https://doi.org/10.3390/genes12050742 - 14 May 2021
Cited by 5 | Viewed by 2536
Abstract
Overexpression of the receptor tyrosine kinase MET has been linked to poor survival in several cancer types, and MET has been suggested to interact with stem cell networks. In vitro studies have further suggested a possible benefit of a combined treatment using PARP [...] Read more.
Overexpression of the receptor tyrosine kinase MET has been linked to poor survival in several cancer types, and MET has been suggested to interact with stem cell networks. In vitro studies have further suggested a possible benefit of a combined treatment using PARP and MET inhibitors. We used a tissue microarray (TMA) with 130 samples of advanced-stage high-grade serous fallopian tube/ovarian cancer (HGSC) to investigate the prognostic value of MET protein expression alone and in combination with the stem cell factor SOX2. The possible synergistic effects of a PARP and MET inhibitor treatment were evaluated in two cell lines with BRCA1 or BRCA2 deficiency and in their BRCA1/2-proficient counterparts. Patients with tumors positive for MET had worse overall survival (log-rank test, p = 0.015) compared to patients with MET-negative tumors. The prognostic role of MET was even more prominent in the subgroup of patients with SOX2-negative tumors (p = 0.0081). No synergistic effects of the combined treatment with PARP and MET inhibitors were found in the cell lines examined. We conclude that MET expression could be used as a marker for OS in HGSC and that stemness should be taken into consideration when evaluating the mechanisms of this effect. Full article
(This article belongs to the Special Issue Advances in Genetics and Genomics of Ovarian Cancer)
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Review

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16 pages, 1038 KiB  
Review
Cellular Functions of Deubiquitinating Enzymes in Ovarian Adenocarcinoma
by Yosuk Min, Hong-Beom Park, Kwang-Hyun Baek and Sohyun Hwang
Genes 2023, 14(4), 886; https://doi.org/10.3390/genes14040886 - 09 Apr 2023
Cited by 2 | Viewed by 1723
Abstract
In ovarian cancer patients, the 5-year survival rate is 90% for stages I and II, but only 30% for stages III and IV. Unfortunately, as 75% of the patients are diagnosed at stages III and IV, many experience a recurrence. To ameliorate this, [...] Read more.
In ovarian cancer patients, the 5-year survival rate is 90% for stages I and II, but only 30% for stages III and IV. Unfortunately, as 75% of the patients are diagnosed at stages III and IV, many experience a recurrence. To ameliorate this, it is necessary to develop new biomarkers for early diagnosis and treatment. The ubiquitin–proteasome system is a post-translational modification that plays an important role in regulating protein stability through ubiquitination. In particular, deubiquitinating enzymes (DUBs) regulate protein stability through deubiquitinating substrate proteins. In this review, DUBs and substrates regulated by these enzymes are summarized based on their functions in ovarian cancer cells. This would be useful for the discovery of biomarkers for ovarian cancer and developing new therapeutic candidates. Full article
(This article belongs to the Special Issue Advances in Genetics and Genomics of Ovarian Cancer)
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22 pages, 1489 KiB  
Review
G-Quadruplex Matters in Tissue-Specific Tumorigenesis by BRCA1 Deficiency
by Sanghyun Kim and Sohyun Hwang
Genes 2022, 13(3), 391; https://doi.org/10.3390/genes13030391 - 22 Feb 2022
Cited by 6 | Viewed by 2873
Abstract
How and why distinct genetic alterations, such as BRCA1 mutation, promote tumorigenesis in certain tissues, but not others, remain an important issue in cancer research. The underlying mechanisms may reveal tissue-specific therapeutic vulnerabilities. Although the roles of BRCA1, such as DNA damage repair [...] Read more.
How and why distinct genetic alterations, such as BRCA1 mutation, promote tumorigenesis in certain tissues, but not others, remain an important issue in cancer research. The underlying mechanisms may reveal tissue-specific therapeutic vulnerabilities. Although the roles of BRCA1, such as DNA damage repair and stalled fork stabilization, obviously contribute to tumor suppression, these ubiquitously important functions cannot explain tissue-specific tumorigenesis by BRCA1 mutations. Recent advances in our understanding of the cancer genome and fundamental cellular processes on DNA, such as transcription and DNA replication, have provided new insights regarding BRCA1-associated tumorigenesis, suggesting that G-quadruplex (G4) plays a critical role. In this review, we summarize the importance of G4 structures in mutagenesis of the cancer genome and cell type-specific gene regulation, and discuss a recently revealed molecular mechanism of G4/base excision repair (BER)-mediated transcriptional activation. The latter adequately explains the correlation between the accumulation of unresolved transcriptional regulatory G4s and multi-level genomic alterations observed in BRCA1-associated tumors. In summary, tissue-specific tumorigenesis by BRCA1 deficiency can be explained by cell type-specific levels of transcriptional regulatory G4s and the role of BRCA1 in resolving it. This mechanism would provide an integrated understanding of the initiation and development of BRCA1-associated tumors. Full article
(This article belongs to the Special Issue Advances in Genetics and Genomics of Ovarian Cancer)
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Other

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7 pages, 664 KiB  
Opinion
Genetic Risk Scores and Missing Heritability in Ovarian Cancer
by Yasaman Fatapour and James P. Brody
Genes 2023, 14(3), 762; https://doi.org/10.3390/genes14030762 - 21 Mar 2023
Cited by 1 | Viewed by 1567
Abstract
Ovarian cancers are curable by surgical resection when discovered early. Unfortunately, most ovarian cancers are diagnosed in the later stages. One strategy to identify early ovarian tumors is to screen women who have the highest risk. This opinion article summarizes the accuracy of [...] Read more.
Ovarian cancers are curable by surgical resection when discovered early. Unfortunately, most ovarian cancers are diagnosed in the later stages. One strategy to identify early ovarian tumors is to screen women who have the highest risk. This opinion article summarizes the accuracy of different methods used to assess the risk of developing ovarian cancer, including family history, BRCA genetic tests, and polygenic risk scores. The accuracy of these is compared to the maximum theoretical accuracy, revealing a substantial gap. We suggest that this gap, or missing heritability, could be caused by epistatic interactions between genes. An alternative approach to computing genetic risk scores, using chromosomal-scale length variation should incorporate epistatic interactions. Future research in this area should focus on this and other alternative methods of characterizing genomes. Full article
(This article belongs to the Special Issue Advances in Genetics and Genomics of Ovarian Cancer)
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