EPV007/#582 DNA damage repair is altered by inhibition of discoidin domain receptor 2 (DDR2) through metabolic rewiring in homologous-recombination proficient ovarian cancer models

Abstract Regulation of homologous recombination (HR) is central for cancer prevention. However, too little HR can increase cancer incidence, whereas too much HR can drive cancer resistance to therapy. Importantly, therapeutics targeting HR deficiency have demonstrated a profound efficacy in the clinic improving patient outcomes, particularly for breast and ovarian cancer. RAD51 is central to DNA damage repair in the HR pathway. As such, understanding the function and regulation of RAD51 is essential for cancer biology. This review will focus on the role of RAD51 in cancer and beyond and how modulation of its function can be exploited as a cancer therapeutic.

Download Full-text

Genomic characterization of brain metastases (BM) in high-grade serous ovarian cancer (HGSOC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e13580 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e13580-e13580

Author(s):

Renata Duchnowska ◽

Anna Maria Supernat ◽

Rafał Pęksa ◽

Marta Łukasiewicz ◽

Tomasz Stokowy ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Damage ◽

Somatic Mutations ◽

Dna Damage Repair ◽

Genetic Alterations ◽

High Grade ◽

Serous Ovarian Cancer ◽

Primary Tumors ◽

Tp53 Mutations ◽

Damage Repair

e13580 Background: BM are a rare occurrence in ovarian cancer (OC) and their molecular characteristics is virtually unknown. DNA damage repair (DDR) deficiency is prevalent in OC, and co-mutated TP53 and any DDR denotes high tumor mutation burden (TMB). We genetically characterized a unique series of high-grade serous ovarian cancer (HGSOC) patients who developed BM to identify alterations of potential clinical relevance. Methods: Whole-exome sequencing (2x150bp, SureSelectXT Library Prep Kit, Illumina’s NovaSeq platform) was performed in matched BM, primary tumors (PT) and normal tissue. DNA was extracted from FFPE samples using QIAamp DNA FFPE Tissue Kit (Qiagen, Germany). All mutations were checked with Catalogue of Somatic Mutations in Cancer (COSMIC) and Integrative Genomics Viewer (IGV). Results: Study group included 10 HGSOC patients (International Federation of Gynecology and Obstetrics classification (FIGO) II-IV, mean age at diagnosis 48 years, range 35-59). Median time from primary HGSOC diagnosis to BM was 38 months (range, 18 to 149). TP53 somatic mutations were found in both primary tumor (PT) and BM in 8 patients. The other 2 cases harbored TP53 mutations not reported in COSMIC catalogue: p.S60L and intronic TP53 mutation preceding p.I322 (IGV). In 9 cases TP53 mutations coexisted with germline or somatic DNA damage repair deficiency. Four cases contained BRCA1 mutations (all germline), and none harbored germline BRCA2 mutation. Other mutated genes included MLH1 (2 somatic, 2 germline), ATR (4 germline, 1 somatic), AMT (1 somatic), RAD50 (1 somatic), ERCC4 (1 somatic), FANCD2 (1 somatic) and RPA1 (1 germline). Three mutation signatures defined in the COSMIC database were indentified in BM: 6, 20 and 30. In 6 cases these mutations were shared in PT, and in another 4 their presence in PT could not be determined due to technical reasons. Median survival from BM was 31 months (range, 5 to 184). Conclusions: Genomic analysis of BM provides an opportunity to identify potentially clinically informative alterations. Mutational profiles in PT are generally reflected in BM. Detected genetic alterations suggest their potential sensitivity to PARP inhibitors and immunotherapy.

Download Full-text

Wilms’ tumor gene WT1 promotes homologous recombination‐mediated DNA damage repair

Molecular Carcinogenesis ◽

10.1002/mc.22248 ◽

2014 ◽

Vol 54 (12) ◽

pp. 1758-1771 ◽

Cited By ~ 9

Author(s):

Yusuke Oji ◽

Naoya Tatsumi ◽

Junya Kobayashi ◽

Mari Fukuda ◽

Tazu Ueda ◽

...

Keyword(s):

Dna Damage ◽

Homologous Recombination ◽

Wilms Tumor ◽

Dna Damage Repair ◽

Wilms Tumor Gene ◽

Damage Repair ◽

Tumor Gene

Download Full-text

Molecular and Clinical Significance of Stanniocalcin-1 Expression in Breast Cancer Through Promotion of Homologous Recombination-Mediated DNA Damage Repair

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.731086 ◽

2021 ◽

Vol 9 ◽

Author(s):

Jing Hou ◽

Jigan Cheng ◽

ZeHua Dai ◽

Na Wei ◽

Huan Chen ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Homologous Recombination ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Dna Damage Repair ◽

Breast Cancer Cell Lines ◽

Enzyme Linked Immunosorbent Assay ◽

Glycoprotein Hormone ◽

Damage Repair

Stanniocalcin-1 (STC1) is a glycoprotein hormone whose abnormal expression has been reported to be associated with a variety of tumors, but its function in breast cancer is not well understood. Through modulation of STC1 expression in different breast cancer cell lines, our study found that STC1 could promote the proliferation and growth of breast cancer cells and promote metastasis. Furthermore, STC1 reduced apoptosis induction by irradiation. We also found that STC1 could promote a homologous recombination-mediated DNA damage repair by recruiting BRCA1 to sites of damage. Moreover, STC1 silencing sensitized breast cancer cells to treatment with irradiation (IR), olaparib, or cisplatin in vitro. In clinical settings, the serum concentration of STC1 was higher in breast cancer patients than in healthy women, as detected by enzyme-linked immunosorbent assay (ELISA). In addition, immunohistochemical staining of breast cancer specimens showed that a high expression of STC1 was negatively correlated with recurrence-free survival in breast cancer, indicating that STC1 expression could be used as a predictive marker for a poor prognosis in breast cancer. All these findings indicate that STC1 promotes breast cancer tumorigenesis and that breast cancers with a high level of STC1 are more resistant to treatment, probably through homologous recombination (HR) promotion. Furthermore, combining STC1 inhibition and DNA damage-inducing drugs may be a novel approach to improve the survival of patients with STC1-expressing breast cancer.

Download Full-text

The tumor suppressor BRCA1/BARD1 complex localizes to the synaptonemal complex and regulates recombination under meiotic dysfunction in Caenorhabditis elegans

10.1101/280909 ◽

2018 ◽

Author(s):

Qianyan Li ◽

Takamune T. Saito ◽

Alison J. Deshong ◽

Marina Martinez Garcia ◽

Saravanapriah Nadarajan ◽

...

Keyword(s):

Dna Damage ◽

Caenorhabditis Elegans ◽

Tumor Suppressor ◽

Homologous Recombination ◽

Synaptonemal Complex ◽

Meiotic Recombination ◽

Dna Damage Repair ◽

Chromosome Synapsis ◽

Brca1 Mutations ◽

Damage Repair

AbstractBreast cancer susceptibility gene 1(BRCA1) and binding partner BRCA1-associated RING domain protein 1 (BARD1) form an essential E3 ubiquitin ligase important for DNA damage repair and homologous recombination. In Caenorhabditis elegans BRCA1/BRC-1 and BARD1/BRD-1 orthologs are not essential, but function in DNA damage repair and homologous recombination, as well as in meiosis. In proliferating germ cells and in early meiotic prophase, BRC-1 and BRD-1 are nucleoplasmic, with enrichment at foci that partially overlap with the recombinase RAD-51. In mid-pachytene, BRC-1 and BRD-1 are observed on tracks, before concentrating to the short arms of bivalents, co-localizing with a central region component of the synaptonemal complex. We found that BRD-1 is essential for BRC-1 to associate with chromatin and the synaptonemal complex, but BRC-1 is not required for BRD-1 localization; the complex fails to properly localize in the absence of either meiotic recombination or chromosome synapsis. Inactivation of BRC-1/BRD-1 enhances the embryonic lethality of mutants that perturb chromosome synapsis and crossover recombination, suggesting that BRC-1/BRD-1 plays an important role in monitoring recombination in the context of the synaptonemal complex. We discovered that BRC-1/BRD-1 stabilizes the RAD51 filament when the formation of a crossover-intermediate is disrupted. Further, in the absence of BRC-1/BRD-1 crossover distribution is altered, and under meiotic dysfunction, crossover numbers are perturbed. Together, our studies indicate that BRC-1/BRD-1 localizes to the synaptonemal complex where it serves a checkpoint function to monitor and modulate meiotic recombination.Project SummaryOur genomes are passed down from one generation to the next through the specialized cell division program of meiosis. Meiosis is highly regulated to coordinate both the large scale chromosomal and fine scale DNA events to ensure fidelity. We analyzed the role of the tumor suppressor BRCA1/BARD1 complex in meiosis in the worm, Caenorhabditis elegans. We find that BRCA1/BARD1 localizes dynamically to the proteinaeous structure that aligns maternal and paternal chromosomes, where it regulates crossover recombination. Although BRCA1/BARD1 mutants have only subtle meiotic defects, we show that this complex plays a critical role in meiotic recombination when meiosis is perturbed. These results highlight the complexity of ensuring accurate transmission of the genome and uncover the requirement for this conserved complex in meiosis. As women carrying BRCA1 mutations with no indication of cancer have fertility defects, our results provide insight into why BRCA1 mutations impact reproductive success.

Download Full-text