Combined Targeted Resequencing of Cytosine DNA Methylation and Mutations of DNA Repair Genes with Potential Use for Poly(ADP-Ribose) Polymerase 1 Inhibitor Sensitivity Testing

Publication date: Available online 19 December 2018Source: The Journal of Molecular DiagnosticsAuthor(s): Christina Grimm, Axel Fischer, Angela M. Farrelly, Roshni Kalachand, Roberta Castiglione, Elena Wasserburger, Michelle Hussong, Anne M. Schultheis, Janine Altmüller, Holger Thiele, Hans C. Reinhardt, Kai Hauschulz, Bryan T. Hennessy, Ralf Herwig, Matthias Lienhard, Reinhard Buettner, Michal R. SchweigerCurrent molecular tumor diagnostics encompass panel sequencing to detect mutations, copy number alterations, and rearrangements. However, tumor suppressor genes can also be inactivated by methylation within their promoter region. These epigenetic alterations are so far rarely assessed in the clinical setting. Therefore, we established the AllCap protocol facilitating the combined detection of mutations and DNA methylation at the coding and promoter regions of 342 DNA repair genes in one experiment. We demonstrate the use of the protocol by applying it to ovarian cancer cell lines with different responsiveness to poly(ADP-ribose) polymerase inhibition. BRCA1, ATM, ATR, and EP300 mutations and methylation of the BRCA1 promoter were detected as potential predictors for therapy response. The required amount of input DNA was optimized, and the application to formalin-fixed, paraffin-embedded tissue samples was verified to improve the clinical applicability. Thus, by adding DNA methylation values to panel resequencings, the AllCap assay will add another important level of in...
Source: The Journal of Molecular Diagnostics - Category: Pathology Source Type: research

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Contributors : Dong-Joo Cheon ; Sandra Orsulic ; Vincent FunariSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensCollagen type XI alpha 1 (COL11A1) is identified as one of the most upregulated genes in cisplatin-resistant ovarian cancer and recurrent ovarian cancer. However, the exact functions of COL11A1 in cisplatin resistance are unknown. The goal of this study is to determine molecular mechanisms by which COL11A1 confers cisplatin resistance in ovarian cancer cells. We overexpressed COL11A1 in A2780 and OVCAR3 ovarian cancer cells, which express very low endogenous levels of COL11A1...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research
This study investigated the concordance in microsatellite instability (MSI) and mismatch repair (MMR) status between primary and corresponding metastatic colorectal cancer (CRC). METHODS: Consecutive patients with metastatic CRC who had both primary and metastatic tumors diagnosed at our institution in January 2008 through December 2016 were identified. Immunohistochemistry was used to test the MMR status of both primary and matched metastatic tumors, and PCR analysis was performed to test MSI in patients with deficient MMR (dMMR) status. RESULTS: A total of 369 patients were included. Of the 46 patients with MSI-h...
Source: Journal of the National Comprehensive Cancer Network : JNCCN - Category: Cancer & Oncology Tags: J Natl Compr Canc Netw Source Type: research
Abstract BACKGROUND: Women who carry a pathogenic mutation in either a BRCA1 DNA repair associated or BRCA2 DNA repair associated (BRCA1 or BRCA2) gene have a high lifetime risk of developing breast and tubo-ovarian cancer. To manage this risk women may choose to undergo risk-reducing surgery to remove breast tissue, ovaries, and fallopian tubes. Surgery should increase survival, but can impact women's lives adversely at the psychological and psychosexual levels. Interventions to facilitate psychological adjustment and improve quality of life post risk-reducing surgery are needed. OBJECTIVES: To examine psych...
Source: Cochrane Database of Systematic Reviews - Category: General Medicine Authors: Tags: Cochrane Database Syst Rev Source Type: research
It is by now widely recognized that ovarian cancer (OC) harbours a remarkable degree of genomic disarray and instability and presents with a wide range of mutations [1,2]. Indeed, around 50% of all high-grade serous ovarian tumours are estimated to have a deficiency in the homologous recombination (HR) DNA repair mechanism, with about 15% of carcinomas harbouring a germline and 6% a somatic Breast Related Cancer Antigens (BRCA) 1-2 mutation. These mutations confer to the cell a disability to repair DNA through the HR pathway, leading to a condition defined as homologous recombination deficiency (HRD) [1,3].
Source: Cancer Treatment Reviews - Category: Cancer & Oncology Authors: Tags: Systematic or Meta-analysis Studies Source Type: research
Contributors : Lesley Conrad ; Ken Lin ; Tulip Nandu ; Bryan Gibson ; Ali Gazdar ; Jayanthi Lea ; W L KrausSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensInhibitors of nuclear poly(ADP-ribose) polymerase (PARP) enzymes (e.g., PARP-1) have improved clinical outcomes in ovarian cancer, especially in patients with BRCA1/2 gene mutations or additional homologous recombination (HR) DNA repair pathway deficiencies. These defects serve as biomarkers for response to PARP inhibitors (PARPi). We sought to identify an additional biomarker that could predict responses to both conventional chemot...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research
ConclusionsTinostamustine was generally well tolerated in patients with advanced solid tumours and limited treatment options. The phase II portion of this study will further investigate the efficacy of the RP2D of 80  mg/m2 tinostamustine IV over 60  minutes in SCLC, triple-negative breast cancer, soft tissue sarcoma, ovarian cancer, and endometrial cancer. Funding: Mundipharma EDO GmbH.Clinical trial identificationNCT03345485.Editorial acknowledgementEditorial support (in the form of writing assistance, collating author comments, grammatical editing and referencing) was provided by Sarah Birch, PhD, at Makar...
Source: Annals of Oncology - Category: Cancer & Oncology Source Type: research
AbstractBackgroundPoly(ADP-ribose) polymerases (PARPs) play a key role in DNA damage repair (DDR). DDR defects due to HRRm (eg BRCA mutation [BRCAm]) or resulting in HRD (eg global loss of heterozygosity) may sensitize tumors to PARP inhibitors, eg olaparib. Olaparib monotherapy has activity in BRCAm ovarian, breast, pancreatic, and prostate cancer, and in prostate cancer with DDR defects beyond BRCAm (TOPARP). Olaparib improved efficacy outcomes vs placebo/chemotherapy as treatment in  ≤ 3rd-line (3L) HER2-negative BRCAm breast cancer (OlympiAD) and ≥2L BRCAm ovarian cancer (SOLO3), and maintenance the...
Source: Annals of Oncology - Category: Cancer & Oncology Source Type: research
o Francesco Salvatore BRCA1 and BRCA2 are the genes most frequently associated with hereditary breast and ovarian cancer (HBOC). They are crucial for the maintenance of genome stability, particularly in the homologous recombination-mediated repair pathway of DNA double-strand breaks (HR-DSBR). Widespread BRCA1/2 next-generation sequencing (NGS) screening has revealed numerous variants of uncertain significance. Assessing the clinical significance of these variants is challenging, particularly regarding the clinical management of patients. Here, we report the functional characterization of the unclassified BRCA2 c.829...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
Publication date: Available online 25 September 2019Source: Seminars in Cancer BiologyAuthor(s): Derek B. Oien, Christopher L. Pathoulas, Upasana Ray, Prabhu Thirusangu, Eleftheria Kalogera, Viji ShridharAbstractQuinacrine, also known as mepacrine, has originally been used as an antimalarial drug for close to a century, but was recently rediscovered as an anticancer agent. The mechanisms of anticancer effects of quinacrine are not well understood. The anticancer potential of quinacrine was discovered in a screen for small molecule activators of p53, and was specifically shown to inhibit NFκB suppression of p53. Howev...
Source: Seminars in Cancer Biology - Category: Cancer & Oncology Source Type: research
This study aims to summarize the indications and toxicity of PARP inhibitors, the mechanism of action, targeted treatment of drug resistance, and potential methods to manage drug-resistant diseases. We used the term "ovarian cancer" and the names of each PARP inhibitor as keywords to search articles published in the Medical Subject Headings (MeSH) on Pubmed, along with the keywords "clinicaltrials.gov" and "google.com/patents" as well as "uspto.gov." The FDA has approved olaparib, niraparib, and rucaparib for treatment of recurrent epithelial ovarian cancer (EOC). Talazoparib and vel...
Source: Current Drug Targets - Category: Drugs & Pharmacology Authors: Tags: Curr Drug Targets Source Type: research
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