A5084420374- PARP inhibition in cancer therapy
- Ovarian cancer diagnosis and treatment
- BRCA gene mutations in cancer
- Cancer Genomics and Diagnostics
- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- Genetic factors in colorectal cancer
- RNA Research and Splicing
- Protein Degradation and Inhibitors
- Chromatin Remodeling and Cancer
- Cancer-related molecular mechanisms research
- Advanced Breast Cancer Therapies
- Endometrial and Cervical Cancer Treatments
- Reproductive Biology and Fertility
- Epigenetics and DNA Methylation
- Cancer-related Molecular Pathways
- Molecular Biology Techniques and Applications
- Renal cell carcinoma treatment
- RNA modifications and cancer
- Pancreatic and Hepatic Oncology Research
- Nutrition, Genetics, and Disease
- Toxin Mechanisms and Immunotoxins
- Cancer Immunotherapy and Biomarkers
- Lung Cancer Research Studies
- Ethics in Clinical Research
University of Washington
2016-2025
Seattle University
2006-2024
Fred Hutch Cancer Center
2009-2024
Stanford University
2024
Woman's Cancer Foundation
2009-2023
University of Washington Medical Center
2014-2023
Brotman Baty Institute
2022-2023
Seattle Pacific University
2020-2023
Mayo Clinic in Florida
2015-2022
The Ohio State University
2014-2022
Abstract Purpose: Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact somatic BRCA1/2 mutations in other homologous recombination DNA repair genes is uncertain. Experimental Design: Using targeted capture massively parallel genomic sequencing, we assessed 390 for loss-of-function 30 genes, including BRCA1, BRCA2, 11 the pathway. Results: Thirty-one percent had a deleterious (24%) and/or (9%) mutation one or more...
Inherited loss-of-function mutations in BRCA1 and BRCA2 other tumor suppressor genes predispose to ovarian carcinomas, but the overall burden of disease due inherited is not known. Using targeted capture massively parallel genomic sequencing, we screened for germ-line 21 DNA from women with primary ovarian, peritoneal, or fallopian tube carcinoma. Subjects were consecutively enrolled at diagnosis selected age family history. All classes mutations, including point large deletions insertions,...
Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance initial treatment patients high-grade serous ovarian carcinoma. In an international, phase 3, placebo-controlled trial, we assessed efficacy veliparib added to first-line induction carboplatin and paclitaxel continued monotherapy previously untreated stage III or IV Patients were randomly assigned a 1:1:1 ratio...
Germline mutations in BRCA1 and BRCA2 are relatively common women with ovarian, fallopian tube, peritoneal carcinoma (OC) causing a greatly increased lifetime risk of these cancers, but the frequency relevance inherited other genes is less well characterized.To determine importance germline cancer-associated OC.A study population 1915 woman OC available DNA were identified from University Washington (UW) gynecologic tissue bank (n = 570) Gynecologic Oncology Group (GOG) phase III clinical...
Genetic testing for inherited mutations in BRCA1 and BRCA2 has become integral to the care of women with a severe family history breast or ovarian cancer, but an unknown number patients receive negative (ie, wild-type) results when they actually carry pathogenic mutation. Furthermore, other cancer genes generally are not evaluated.To determine frequency types undetected cancer-predisposing BRCA1, BRCA2, CHEK2, TP53, PTEN among from high-risk families (wild-type) genetic test BRCA2.Between...
The NCCN Clinical Practice Guidelines in Oncology for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide recommendations genetic testing counseling hereditary cancer syndromes risk management patients who are diagnosed with a syndrome. focus on associated an increased of breast and/or ovarian cancer. panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data publications abstracts, reevaluate update recommendations....
All cancers develop as a result of mutations in certain genes, such those involved the regulation cell growth and/or DNA repair, 1,2 but not all these are inherited from parent.For example, sporadic can occur somatic/ tumor cells only, and de novo for first time germ (i.e., egg or sperm) fertilized itself during early embryogen-
Secondary somatic BRCA1/2 mutations may restore protein in hereditary ovarian carcinomas. In cell lines, BRCA2 restoration mediates resistance to platinum chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors. We assessed primary recurrent BRCA1/2-mutated carcinomas define the frequency of secondary correlate these changes with clinical outcomes.Neoplastic cells were isolated laser capture microdissection, DNA was sequenced at site known germline mutation. When found that restored...
Inherited loss-of-function mutations in the tumor suppressor genes BRCA1 , BRCA2 and multiple other predispose to high risks of breast and/or ovarian cancer. Cancer-associated inherited these are collectively quite common, but individually rare or even private. Genetic testing for has become an integral part clinical practice, is generally limited two women with severe family histories To determine whether massively parallel, “next-generation” sequencing would enable accurate, thorough,...
Patients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited.To evaluate the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor niraparib combined pembrolizumab in patients carcinoma.The TOPACIO/KEYNOTE-162 (Niraparib Combination With Pembrolizumab Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women advanced metastatic...
Abstract Although ovarian carcinomas with mutated BRCA1 or BRCA2 are sensitive to platinum compounds, such eventually develop resistance. Previously, we showed that acquired resistance cisplatin in BRCA2-mutated tumors can be mediated by secondary intragenic mutations restore the wild-type reading frame. Here, show of also occur BRCA1-mutated cancer We evaluated nine recurrent cancers previously treated including five resistance, one primary and three sensitivity. Four six platinum-resistant...
Although PARP inhibitors (PARPi) target homologous recombination defective tumours, drug resistance frequently emerges, often via poorly understood mechanisms. Here, using genome-wide and high-density CRISPR-Cas9 "tag-mutate-enrich" mutagenesis screens, we identify close to full-length mutant forms of PARP1 that cause in vitro vivo PARPi resistance. Mutations both within outside the DNA-binding zinc-finger domains alter trapping, as does a mutation found clinical case This reinforces...
Abstract Based on genomic analysis, 50% of high-grade serous ovarian cancers (HGSC) are predicted to have DNA repair defects. Whether this substantial subset HGSCs actually functional defects remains unknown. Here, we devise a platform for profiling in short-term patient-derived HGSC organoids. We tested 33 organoid cultures derived from 22 patients with homologous recombination (HR) and replication fork protection. Regardless gene mutational status, defect HR the organoids correlated PARP...
PURPOSE We report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial bevacizumab women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma. METHODS A total 1,873 incompletely resected stage III to IV disease were randomly assigned 1:1:1 six 21-day cycles intravenous carboplatin (area under concentration v time curve 6) and paclitaxel (175 mg/m 2 ) versus chemotherapy plus concurrent (15 mg/kg, maintenance...
Abstract High-grade epithelial ovarian carcinomas containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and PARP inhibitors (PARPi), while restoration of HR function due secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core pathway 12 pairs pretreatment postprogression tumor biopsy samples collected from patients ARIEL2 Part 1, a phase II study the PARPi rucaparib...
A key resistance mechanism to platinum-based chemotherapies and PARP inhibitors in BRCA-mutant cancers is the acquisition of BRCA reversion mutations that restore protein function. To estimate prevalence high-grade ovarian carcinoma (HGOC), we performed targeted next-generation sequencing circulating cell-free DNA (cfDNA) extracted from pretreatment postprogression plasma patients with deleterious germline or somatic treated inhibitor rucaparib. were identified cfDNA 18% (2/11)...
Abstract Acquired platinum resistance is a serious problem in the treatment of ovarian carcinomas. However, mechanism drug has not been elucidated. Here, we show functional significance restoration BRCA2 protein by secondary mutations acquired BRCA2-mutated carcinoma. Three cancer cell lines (PEO1, PEO4, and PEO6) were derived from mutation [5193C>G (Y1655X)] carrier with carcinoma cisplatin [5193C>T (Y1655Y)] that canceled inherited mutation. PEO1 was deficient sensitive to...
The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide recommendations genetic testing counseling risk assessment management hereditary cancer syndromes. focus on syndromes associated with an increased of breast and/or ovarian are intended to assist clinical shared decision-making. These Insights summarize major discussion points the 2015 panel meeting. Major topics this year included multigene testing, less common mutations, salpingectomy reduction. also...
An integrated analysis was undertaken to characterize the antitumor activity and safety profile of oral poly(ADP-ribose) polymerase inhibitor rucaparib in patients with relapsed high-grade ovarian carcinoma (HGOC).