Therapeutic implications for ovarian cancer emerging from the Tumor Cancer Genome Atlas (original) (raw)

Genetic alterations and their therapeutic implications in epithelial ovarian cancer

BMC Cancer, 2021

Background Genetic alterations for epithelial ovarian cancer are insufficiently characterized. Previous studies are limited regarding included histologies, gene numbers, copy number variant (CNV) detection, and interpretation of pathway alteration patterns of individual patients. Methods We sequenced 410 genes to analyze mutations and CNV of 82 ovarian carcinomas, including high-grade serous (n = 37), endometrioid (n = 22) and clear cell (n = 23) histologies. Eligibility for targeted therapy was determined for each patient by a pathway-based approach. The analysis covered DNA repair, receptor tyrosine kinase, PI3K/AKT/MTOR, RAS/MAPK, cell cycle, and hedgehog pathways, and included 14 drug targets. Results Postulated PARP, MTOR, and CDK4/6 inhibition sensitivity were most common. BRCA1/2 alterations, PTEN loss, and gain of PIK3CA and CCND1 were characteristic for high-grade serous carcinomas. Mutations of ARID1A, PIK3CA, and KRAS, and ERBB2 gain were enriched in the other histologies...

PIK3R1W624R Is an Actionable Mutation in High Grade Serous Ovarian Carcinoma

Cells

Identifying cancer drivers and actionable mutations is critical for precision oncology. In epithelial ovarian cancer (EOC) the majority of mutations lack biological or clinical validation. We fully characterized 43 lines of Patient-Derived Xenografts (PDXs) and performed copy number analysis and whole exome sequencing of 12 lines derived from naïve, high grade EOCs. Pyrosequencing allowed quantifying mutations in the source tumours. Drug response was assayed on PDX Derived Tumour Cells (PDTCs) and in vivo on PDXs. We identified a PIK3R1W624R variant in PDXs from a high grade serous EOC. Allele frequencies of PIK3R1W624R in all the passaged PDXs and in samples of the source tumour suggested that it was truncal and thus possibly a driver mutation. After inconclusive results in silico analyses, PDTCs and PDXs allowed the showing actionability of PIK3R1W624R and addiction of PIK3R1W624R carrying cells to inhibitors of the PI3K/AKT/mTOR pathway. It is noteworthy that PIK3R1 encodes the p...

Somatic mutations favorable to patient survival are predominant in ovarian carcinomas

PloS one, 2014

Somatic mutation accumulation is a major cause of abnormal cell growth. However, some mutations in cancer cells may be deleterious to the survival and proliferation of the cancer cells, thus offering a protective effect to the patients. We investigated this hypothesis via a unique analysis of the clinical and somatic mutation datasets of ovarian carcinomas published by the Cancer Genome Atlas. We defined and screened 562 macro mutation signatures (MMSs) for their associations with the overall survival of 320 ovarian cancer patients. Each MMS measures the number of mutations present on the member genes (except for TP53) covered by a specific Gene Ontology (GO) term in each tumor. We found that somatic mutations favorable to the patient survival are predominant in ovarian carcinomas compared to those indicating poor clinical outcomes. Specially, we identified 19 (3) predictive MMSs that are, usually by a nonlinear dose-dependent effect, associated with good (poor) patient survival. Th...

A Succinct Molecular Profile of High-grade Ovarian Cancer

IntechOpen, 2022

Abstract Several studies have been carried out to determine the complexity of ovarian cancer as a disease with multiple distinct types that presents with symptoms similar to those in other gynaecological, gastrointestinal and genitourinary diseases. The malignant variants of common epithelial and germ cell tumours constitute the bulk of ovarian tumours and are classified histologically based on the presumed tissue of ori- gin. Molecular diagnosis is now aiding in the early detection and treatment of ovarian cancer even before metastasis sets in. Thus studying the molecular profiles of each type is key to understanding the origin and pathogenesis as well as genetic aberrations and mutations involved in the development of the disease. Ovarian cancers originate either from the ovary or fallopian tube and are found majorly to harbour mutations in PTEN, KRAS, BRAF, BRCA1, BRCA2 and TP53, with TP53 mutations being the most frequent. Genetic testing for ovarian cancers involves testing for the aforementioned genes, and in the nearest future, an advanced method that would detect these genes in blood and uterine lavage is expected. There is an urgent need for further studies on the detailed mechanisms underlying the roles of mutant TP53 in ovarian cancer development and its potential role in therapeutic interventions. Keywords: molecular profile, epithelial ovarian carcinoma, high-grade serous ovarian carcinoma, recurrent clear cell carcinoma, TP53 mutations

New Hypothesis on Pathogenesis of Ovarian Cancer Lead to Future Tailored Approaches

BioMed Research International, 2013

In the last decades, management of epithelial ovarian cancer (EOC) has been based on the staging system of the International Federation of Gynecology and Obstetrics (FIGO), and different classifications have been proposed for EOC that take account of grade of differentiation, histological subtype, and clinical features. However, despite taxonomic efforts, EOC appears to be not a unique disease; its subtypes differ for epidemiological and genetic risk factors, precursor lesions, patterns of spread, response to chemotherapy, and prognosis. Nevertheless, carboplatin plus paclitaxel combination represents the only standard treatment in adjuvant and advanced settings. This paper summarizes theories about the classification and origin of EOC and classical and new prognostic factors. It presents data about standard treatment and novel agents. We speculate about the possibility to create tailored therapy based on specific mutations in ovarian cancer and to personalize prevention.