Germline mutations in RAD51C and RAD51D and hereditary predisposition to ovarian cancer

Soukupová, Jana; Lhotová, Klára; Janatová, Markéta; Kleiblová, Petra; Vočka, Michal; Foretová, Lenka; Zikán, Michal; Kleibl, Zdeněk

doi:10.48095/ccko202126

Cited by 3 publications

(4 citation statements)

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“…Using an isogenic glioma cell line, in which XRCC3 was downregulated by interference RNA, they demonstrated its importance as a possible target for therapeutic intervention [55]. Other studies have reported the association between single-nucleotide polymorphisms in the XRCC3 gene in hepatocellular carcinoma [56]. In the current research, we proved that PAC induces RAD51D only in MDA-MB-231 cells.…”

Section: Discussionsupporting

confidence: 61%

The Curcumin Analog PAC Is a Potential Solution for the Treatment of Triple-Negative Breast Cancer by Modulating the Gene Expression of DNA Repair Pathways

Almalki,

Al-Amri,

Alrashed

et al. 2023

IJMS

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Breast Cancer (BC) is one of the most common and challenging cancers among females worldwide. Conventional treatments for oral cancer rely on the use of radiology and surgery accompanied by chemotherapy. Chemotherapy presents many side effects, and the cells often develop resistance to this chemotherapy. It will be urgent to adopt alternative or complementary treatment strategies that are new and more effective without these negative effects to improve the well-being of patients. A substantial number of epidemiological and experimental studies reported that many compounds are derived from natural products such as curcumin and their analogs, which have a great deal of beneficial anti-BC activity by inducing apoptosis, inhibiting cell proliferation, migration, and metastasis, modulating cancer-related pathways, and sensitizing cells to radiotherapy and chemotherapy. In the present study, we investigated the effect of the curcumin-analog PAC on DNA repair pathways in MCF-7 and MDA-MB-231 human breast-cancer cell lines. These pathways are crucial for genome maintenance and cancer prevention. MCF-7 and MDA-MB-231 cells were exposed to PAC at 10 µM. MTT and LDH assays were conducted to evaluate the effects of PAC on cell proliferation and cytotoxicity. Apoptosis was assessed in breast cancer cell lines using flow cytometry with annexin/Pi assay. The expression of proapoptotic and antiapoptotic genes was determined by RT-PCR to see if PAC is active in programming cell death. Additionally, DNA repair signaling pathways were analyzed by PCR arrays focusing on genes being related and confirmed by quantitative PCR. PAC significantly inhibited breast-cancer cell proliferation in a time-dependent manner, more on MDA-MB-231 triple-negative breast cancer cells. The flow cytometry results showed an increase in apoptotic activity. These data have been established by the gene expression and indicate that PAC-induced apoptosis by an increased Bax and decreased Bcl-2 expression. Moreover, PAC affected multiple genes involved in the DNA repair pathways occurring in both cell lines (MCF-7 and MDA-MB231). In addition, our results suggest that PAC upregulated more than twice 16 genes (ERCC1, ERCC2, PNKP, POLL, MPG, NEIL2, NTHL1, SMUG1, RAD51D, RAD54L, RFC1, TOP3A, XRCC3, XRCC6BP1, FEN1, and TREX1) in MDA-MB-231, 6 genes (ERCC1, LIG1, PNKP, UNG, MPG, and RAD54L) in MCF-7, and 4 genes (ERCC1, PNKP, MPG, and RAD54L) in the two cell lines. In silico analysis of gene–gene interaction shows that there are common genes between MCF-7 and MDA-MB-321 having direct and indirect effects, among them via coexpression, genetic interactions, pathways, predicted and physical interactions, and shared protein domains with predicted associated genes indicating they are more likely to be functionally related. Our data show that PAC increases involvement of multiple genes in a DNA repair pathway, this certainly can open a new perspective in breast-cancer treatment.

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Section: Discussionsupporting

confidence: 61%

The Curcumin Analog PAC Is a Potential Solution for the Treatment of Triple-Negative Breast Cancer by Modulating the Gene Expression of DNA Repair Pathways

Almalki,

Al-Amri,

Alrashed

et al. 2023

IJMS

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“…The unintended mutations in RAD51D/MDM2/MAPK genes could have compromised the therapeutic effect of targeting BRCA1/TP53/RAS as they could activate RAD51D/ inactivate MDM2/activate MAPK, leading to the promotion of cancer growth [ 233 ]. The frequent findings of unintended mutations in undesirable site genes in these studies highlight the significant risk of non-selective site effects associated with CRISPR-Cas9 gene editing [ 234 ]. The research should analyze and compare the off-target effects observed when targeting different genes, which could provide insights into the gene-specific effects of CRISPR-Cas9 [ 235 , 236 ].…”

Section: Safety and Delivery Challengesmentioning

confidence: 99%

“…The frequent findings of unintended mutations in undesirable site genes in these studies highlight the significant risk of non-selective site effects associated with CRISPR-Cas9 gene editing [234]. The research should analyze and compare the off-target effects observed when targeting different genes, which could provide insights into the gene-specific effects of CRISPR-Cas9 [235,236].…”

Section: Delivery Challenges and Safety Measures In Crispr-based Gene...mentioning

confidence: 99%

Comprehensive review of CRISPR-based gene editing: mechanisms, challenges, and applications in cancer therapy

Chehelgerdi,

Khorramian-Ghahfarokhi

et al. 2024

Mol Cancer

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The CRISPR system is a revolutionary genome editing tool that has the potential to revolutionize the field of cancer research and therapy. The ability to precisely target and edit specific genetic mutations that drive the growth and spread of tumors has opened up new possibilities for the development of more effective and personalized cancer treatments. In this review, we will discuss the different CRISPR-based strategies that have been proposed for cancer therapy, including inactivating genes that drive tumor growth, enhancing the immune response to cancer cells, repairing genetic mutations that cause cancer, and delivering cancer-killing molecules directly to tumor cells. We will also summarize the current state of preclinical studies and clinical trials of CRISPR-based cancer therapy, highlighting the most promising results and the challenges that still need to be overcome. Safety and delivery are also important challenges for CRISPR-based cancer therapy to become a viable clinical option. We will discuss the challenges and limitations that need to be overcome, such as off-target effects, safety, and delivery to the tumor site. Finally, we will provide an overview of the current challenges and opportunities in the field of CRISPR-based cancer therapy and discuss future directions for research and development. The CRISPR system has the potential to change the landscape of cancer research, and this review aims to provide an overview of the current state of the field and the challenges that need to be overcome to realize this potential.

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“…The importance of genes other than BRCA1 and BRCA2 was highlighted in several studies (Guo et al, 2019 ) including one from the Czech Republic that suggested to add both RAD51C and RAD51D to the list of genes tested (Soukupová et al, 2021 ). In another review that summarized published studies, Pietragalla et al showed that genes like TP53 in Li‐Fraumeni syndrome, STK11 in Peutz‐Jeghers syndrome, the mismatch repair genes in Lynch syndrome, CHEK2, RAD51, BRIP1 , and PALB2 are frequent enough to be added to the panel of tested genes (Pietragalla et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Prevalence and clinical implications of germline mutations among Jordanian patients with ovarian cancer. The Jordanian exploratory cancer genetics (Jo‐ECAG) ovarian study

Abdel‐Razeq

Al-Azzam

Elemian

et al. 2022

Molec Gen & Gen Med

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Background Ovarian cancer is one of the most common gynecological malignancies. Due to the absence of effective screening methods, ovarian cancer is usually diagnosed at late stages. Patients with pathogenic and likely‐pathogenic germline variants (PGVs) in BRCA1 or BRCA2 harbor elevated risk of developing both ovarian and breast cancers. Identifying PGVs may help in both cancer prevention and active disease treatment. Worldwide prevalence of PGVs varies and the matter is poorly addressed among Arab patients. Methods Patients with epithelial ovarian, fallopian tube or primary peritoneal cancers were offered the universal 20 or 84‐multi‐gene panel testing as per standard guidelines. Cascade family screening was also offered to all first and second‐degree relatives of PGV positive patients. Genetic testing was done at a referral lab using a next generation sequencing (NGS)‐based platform. Results During the study period, 152 patients, median age (range): 50 (18–79) years old, were tested. The majority ( n = 100, 65.8%) had high‐grade serous carcinoma, and 106 patients (69.7%) had metastatic disease at presentation. In total, 38 (25.0%) had PGVs, while 47 (30.9%) others had variants of uncertain significance (VUS). PGVs were mostly in BRCA1 ( n = 21, 13.8%) and in BRCA2 ( n = 12, 7.9%), while 6 (3.9%) others had PGVs in non‐ BRCA1/2 genes . PGV rates were significantly higher among 15 patients with a positive family history of ovarian cancer (60.0%, p = .022) and among 52 patients with a positive family history of breast cancer (40.4%, p = .017). Conclusions PGVs are common among Jordanian women with ovarian cancer, and mostly occur in BRCA1/2 . Given its clinical impact on disease prevention and precision therapy, universal testing should be routinely offered.

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Germline mutations in RAD51C and RAD51D and hereditary predisposition to ovarian cancer

Cited by 3 publications

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The Curcumin Analog PAC Is a Potential Solution for the Treatment of Triple-Negative Breast Cancer by Modulating the Gene Expression of DNA Repair Pathways

The Curcumin Analog PAC Is a Potential Solution for the Treatment of Triple-Negative Breast Cancer by Modulating the Gene Expression of DNA Repair Pathways

Comprehensive review of CRISPR-based gene editing: mechanisms, challenges, and applications in cancer therapy

Prevalence and clinical implications of germline mutations among Jordanian patients with ovarian cancer. The Jordanian exploratory cancer genetics (Jo‐ECAG) ovarian study

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