ABSTRACT
The majority of patients with ovarian cancer ultimately develop recurrent chemotherapy-resistant disease. Treatment stratification is mainly based on histological subtype and stage, prior response to platinum-based chemotherapy, and time to recurrent disease. Here, we integrated clinical treatment, treatment response, and survival data with whole-genome sequencing profiles of 132 solid tumor biopsies of metastatic epithelial ovarian cancer to explore genome-informed stratification opportunities. Samples from primary and recurrent disease harbored comparable numbers of single nucleotide variants and structural variants. Mutational signatures represented platinum exposure, homologous recombination deficiency, and aging. Unsupervised hierarchical clustering based on genomic input data identified specific ovarian cancer subgroups, characterized by homologous recombination deficiency, genome stability, and duplications. The clusters exhibited distinct response rates and survival probabilities which could thus potentially be used for genome-informed therapy stratification for more personalized ovarian cancer treatment.
ABSTRACT
Here, we describe a novel approach for rapid discovery of a set of tumor-specific genomic structural variants (SVs), based on a combination of low coverage cancer genome sequencing using Oxford Nanopore with an SV calling and filtering pipeline. We applied the method to tumor samples of high-grade ovarian and prostate cancer patients and validated on average ten somatic SVs per patient with breakpoint-spanning PCR mini-amplicons. These SVs could be quantified in ctDNA samples of patients with metastatic prostate cancer using a digital PCR assay. The results suggest that SV dynamics correlate with and may improve existing treatment-response biomarkers such as PSA. https://github.com/UMCUGenetics/SHARC .
Subject(s)
Biomarkers, Tumor , Circulating Tumor DNA , Genomic Structural Variation , Molecular Diagnostic Techniques , Nanopore Sequencing , Neoplasms/diagnosis , Neoplasms/genetics , Computational Biology/methods , Female , Humans , Liquid Biopsy/methods , Male , Molecular Diagnostic Techniques/methods , Molecular Diagnostic Techniques/standards , Organ Specificity/genetics , Real-Time Polymerase Chain Reaction , Reproducibility of Results , Sensitivity and Specificity , Sequence Analysis, DNAABSTRACT
Ovarian cancer (OC) is a heterogeneous disease usually diagnosed at a late stage. Experimental in vitro models that faithfully capture the hallmarks and tumor heterogeneity of OC are limited and hard to establish. We present a protocol that enables efficient derivation and long-term expansion of OC organoids. Utilizing this protocol, we have established 56 organoid lines from 32 patients, representing all main subtypes of OC. OC organoids recapitulate histological and genomic features of the pertinent lesion from which they were derived, illustrating intra- and interpatient heterogeneity, and can be genetically modified. We show that OC organoids can be used for drug-screening assays and capture different tumor subtype responses to the gold standard platinum-based chemotherapy, including acquisition of chemoresistance in recurrent disease. Finally, OC organoids can be xenografted, enabling in vivo drug-sensitivity assays. Taken together, this demonstrates their potential application for research and personalized medicine.
Subject(s)
Organoids/pathology , Ovarian Neoplasms/pathology , Adult , Aged , Animals , Cell Line, Tumor , Drug Screening Assays, Antitumor , Female , Genomics , Heterografts , Humans , Mice, SCID , Middle Aged , Mutation , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Precision MedicineABSTRACT
BACKGROUND: Pelvic floor disorders are a major public health issue. For female genital prolapse, sacrocolpopexy is the gold standard. Laparoscopic ventral mesh rectopexy is a relatively new and promising technique correcting rectal prolapse. There is no literature combining the 2 robotically assisted techniques. OBJECTIVE: This study was designed to evaluate the safety, quality of life, and functional and sexual outcomes of robot-assisted sacrocolporectopexy for multicompartment prolapse of the pelvic floor. DESIGN: This was a prospective, observational cohort study. SETTINGS: The study was conducted in a tertiary care setting. PATIENTS: All sexually active patients undergoing robot-assisted sacrocolporectopexy at our institution between 2012 and 2014 were included. INTERVENTION: Robot-assisted sacrocolporectopexy was the study intervention. MAIN OUTCOME MEASURES: Preoperative and postoperative (12 months) questionnaires using the Urinary Distress Inventory, Pescatori Incontinence Scale, Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire, and Pelvic Floor Impact Questionnaire were completed. In addition Wexner and Vaizey incontinence scores and the Wexner constipation score were recorded postoperatively. RESULTS: Fifty-one patients underwent robot-assisted sacrocolporectopexy (median follow-up, 12.5 months). The simplified Pelvic Organ Prolapse Quantification improved significantly (p < 0.0005) for all 4 of the anatomic landmarks. Both median fecal (preoperative and postoperative Pescatori 4 vs 3, p = 0.002) and urinary incontinence scores (Urinary Distress Inventory, 27.8 vs 22.2; p < 0.0005) improved significantly at 12 months. Postoperatively median Wexner (3) and Vaizey incontinence (6) and Wexner Constipation (7) scores were noted. A positive effect on sexual function (Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire score 31.8 vs 35.9; p = 0.002) and quality of life for each compartment (p < 0.0005) was observed. One patient (2%) developed mesh erosion. No multicompartment recurrences were detected. LIMITATIONS: This was a observational study with a limited follow-up, no control group, and no preoperatively validated constipation score. CONCLUSIONS: Robot-assisted sacrocolporectopexy is a safe and effective technique for multicompartment prolapse in terms of functional outcome, quality of life, and sexual function.