Germline mutation in either BRCA1 or BRCA2 is associated with an increased risk of ovarian cancer, particularly the most common invasive histotype - serous carcinoma. In addition, serous ovarian ...cancers have an unusually high frequency of other molecular events involving BRCA pathway dysfunction. Recent findings show a high frequency of TP53 mutation, chromosomal instability, distinct molecular subtypes and DNA copy number-driven changes in gene expression. These findings suggest a model in which homologous recombination repair deficiency initiates a cascade of molecular events that sculpt the evolution of high-grade serous ovarian cancer and dictate its response to therapy.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Cyclin E1 (
) amplification is associated with primary treatment resistance and poor outcome in high-grade serous ovarian cancer (HGSC). Here, we explore approaches to target
-amplified cancers and ...potential strategies to overcome resistance to targeted agents.
To examine dependency on
in
-amplified HGSC, we utilized siRNA and conditional shRNA gene suppression, and chemical inhibition using dinaciclib, a small-molecule CDK2 inhibitor. High-throughput compound screening was used to identify selective synergistic drug combinations, as well as combinations that may overcome drug resistance. An observed relationship between
and the AKT pathway was further explored in genomic data from primary tumors, and functional studies in fallopian tube secretory cells.
We validate
as a therapeutic target by demonstrating selective sensitivity to gene suppression. However, we found that dinaciclib did not trigger amplicon-dependent sensitivity in a panel of HGSC cell lines. A high-throughput compound screen identified synergistic combinations in
-amplified HGSC, including dinaciclib and AKT inhibitors. Analysis of genomic data from TCGA demonstrated coamplification of
and
Overexpression of Cyclin E1 and AKT isoforms, in addition to mutant
, imparted malignant characteristics in untransformed fallopian tube secretory cells, the dominant site of origin of HGSC.
These findings suggest a specific dependency of
-amplified tumors for AKT activity, and point to a novel combination of dinaciclib and AKT inhibitors that may selectively target patients with
-amplified HGSC.
.
The five-year survival rate of epithelial ovarian cancer (EOC) is approximately 35-40% despite maximal treatment efforts, highlighting a need for stratification biomarkers for personalized treatment. ...Here we extract 657 quantitative mathematical descriptors from the preoperative CT images of 364 EOC patients at their initial presentation. Using machine learning, we derive a non-invasive summary-statistic of the primary ovarian tumor based on 4 descriptors, which we name "Radiomic Prognostic Vector" (RPV). RPV reliably identifies the 5% of patients with median overall survival less than 2 years, significantly improves established prognostic methods, and is validated in two independent, multi-center cohorts. Furthermore, genetic, transcriptomic and proteomic analysis from two independent datasets elucidate that stromal phenotype and DNA damage response pathways are activated in RPV-stratified tumors. RPV and its associated analysis platform could be exploited to guide personalized therapy of EOC and is potentially transferrable to other cancer types.
ABCB1 encodes Multidrug Resistance protein (MDR1), an ATP-binding cassette member involved in the cellular efflux of chemotherapeutic drugs. Here we report that ovarian and breast samples from ...chemotherapy treated patients are positive for multiple transcriptional fusions involving ABCB1, placing it under the control of a strong promoter while leaving its open reading frame intact. We identified 15 different transcriptional fusion partners involving ABCB1, as well as patients with multiple distinct fusion events. The partner gene selected depended on its structure, promoter strength, and chromosomal proximity to ABCB1. Fusion positivity was strongly associated with the number of lines of MDR1-substrate chemotherapy given. MDR1 inhibition in a fusion positive ovarian cancer cell line increased sensitivity to paclitaxel more than 50-fold. Convergent evolution of ABCB1 fusion is therefore frequent in chemotherapy resistant recurrent ovarian cancer. As most currently approved PARP inhibitors (PARPi) are MDR1 substrates, prior chemotherapy may precondition resistance to PARPi.
Somatically acquired mutations, which contribute to tumorigenesis, are usually specific to tumor tissue. Sequencing of the whole transcriptome — the entire set of messenger RNAs — in ovarian ...granulosa-cell tumors implicated a somatic mutation in
FOXL2
in a large majority of the tumors that were analyzed.
Sequencing of the whole transcriptome — the entire set of messenger RNAs — in ovarian granulosa-cell tumors implicated a somatic mutation in
FOXL2
in a large majority of the tumors that were analyzed.
Granulosa-cell tumors (GCTs) occur at a frequency of 1 per 100,000 persons and account for less than 5% of all ovarian cancers.
1
For women with advanced-stage or recurrent disease, the effectiveness of traditional chemotherapy has been limited, indicating the need for more effective therapeutic approaches.
2
For stage I and II disease, reported 5-year survival rates vary widely, from 55% to 95%, perhaps indicating inconsistent diagnostic criteria for GCTs.
1
The histopathological features of these tumors (Figure 1) can be mimicked by a variety of other neoplasms.
3
The cause and molecular pathogenesis of GCTs are unknown.
4
–
7
GCTs have morphologic and molecular . . .
High-grade serous ovarian cancers (HGSCs) are characterized by a high frequency of TP53 mutations, BRCA1/2 inactivation, homologous recombination dysfunction, and widespread copy number changes. ...Cyclin E1 (CCNE1) gene amplification has been reported to occur independently of BRCA1/2 mutation, and it is associated with primary treatment failure and reduced patient survival. Insensitivity of CCNE1 -amplified tumors to platinum cross-linking agents may be partly because of an intact BRCA1/2 pathway. Both BRCA1/2 dysfunction and CCNE1 amplification are known to promote genomic instability and tumor progression. These events may be mutually exclusive, because either change provides a path to tumor development, with no selective advantage to having both mutations. Using data from a genome-wide shRNA synthetic lethal screen, we show that BRCA1 and members of the ubiquitin pathway are selectively required in cancers that harbor CCNE1 amplification. Furthermore, we show specific sensitivity of CCNE1 -amplified tumor cells to the proteasome inhibitor bortezomib. These findings provide an explanation for the observed mutual exclusivity of CCNE1 amplification and BRCA1/2 loss in HGSC and suggest a unique therapeutic approach for treatment-resistant CCNE1 -amplified tumors.
CCNE1 Amplification as a Therapeutic Target Au-Yeung, George; Mileshkin, Linda; Bowtell, David D L
Journal of clinical oncology,
03/2023, Letnik:
41, Številka:
9
Journal Article
High-grade serous cancer (HGSC) is the most common cancer of the ovary and is characterized by chromosomal instability. Defects in homologous recombination repair (HRR) are associated with genomic ...instability in HGSC, and are exploited by therapy targeting DNA repair. Defective HRR causes uniparental deletions and loss of heterozygosity (LOH). Our purpose is to profile LOH in HGSC and correlate our findings to clinical outcome, and compare HGSC and high-grade breast cancers.
We examined LOH and copy number changes using single nucleotide polymorphism array data from three HGSC cohorts and compared results to a cohort of high-grade breast cancers. The LOH profiles in HGSC were matched to chemotherapy resistance and progression-free survival (PFS).
LOH-based clustering divided HGSC into two clusters. The major group displayed extensive LOH and was further divided into two subgroups. The second group contained remarkably less LOH. BRCA1 promoter methylation was associated with the major group. LOH clusters were reproducible when validated in two independent HGSC datasets. LOH burden in the major cluster of HGSC was similar to triple-negative, and distinct from other high-grade breast cancers. Our analysis revealed an LOH cluster with lower treatment resistance and a significant correlation between LOH burden and PFS.
Separating HGSC by LOH-based clustering produces remarkably stable subgroups in three different cohorts. Patients in the various LOH clusters differed with respect to chemotherapy resistance, and the extent of LOH correlated with PFS. LOH burden may indicate vulnerability to treatment targeting DNA repair, such as PARP1 inhibitors.
Purpose Germline BRCA1 or BRCA2 mutations in patients with high-grade serous ovarian cancer (HGSC) are associated with favorable responses to chemotherapy. However, secondary intragenic (reversion) ...mutations that restore protein function lead to clinically significant rates of acquired resistance. The goal of this study was to determine whether reversion mutations could be found in an unbiased manner in circulating cell-free DNA (cfDNA) to predict treatment response in HGSC. Patients and Methods Plasma and tumor samples were obtained from 30 patients with HGSC with either BRCA1 or BRCA2 germline mutation. Two cohorts were ascertained: patients with a malignancy before undergoing primary HGSC debulking surgery (n = 14) or patients at disease recurrence (n = 16). Paired tumor and plasma samples were available for most patients (24 of 30). Targeted amplicon, next-generation sequencing was performed using primers that flanked germline mutations, whose design did not rely on prior knowledge of reversion sequences. Results Five patients were identified with intragenic mutations predicted to restore BRCA1/2 open reading frames, including two patients with multiple independent reversion alleles. Reversion mutations were only detected in tumor samples from patients with recurrent disease (five of 16) and only in cfDNA from patients with a tumor-detected reversion (three of five). Findings from a rapid autopsy of a patient with multiple independent reversions indicated that reversion-allele frequency in metastatic sites is an important determinant of assay sensitivity. Abundance of tumor-derived DNA in total cell-free DNA, as measured by TP53 mutant allele frequency, also affected assay sensitivity. All patients with reversions detected in tumor-derived DNA were resistant to platin- or poly ADP ribose polymerase inhibitor-based chemotherapy. Conclusion Reversion mutations can be detected in an unbiased analysis of cfDNA, suggesting clinical utility for predicting chemotherapy response in recurrent HGSC.
Myc transcriptional activity is frequently deregulated in human cancers, but a Myc-driven gene signature with prognostic ability across multiple tumor types remains lacking. Here, we selected 18 ...Myc-regulated genes from published studies of Myc family targets in epithelial ovarian cancer (EOC) and neuroblastoma. A Myc family activity score derived from the 18 genes was correlated to
/
/
expression in a panel of 35 cancer cell lines. The prognostic ability of this signature was evaluated in neuroblastoma, medulloblastoma, diffuse large B-cell lymphoma (DLBCL), and EOC microarray gene expression datasets using Kaplan-Meier and multivariate Cox regression analyses and was further validated in 42 primary neuroblastomas using qPCR. Cell lines with high
, and/or
gene expression exhibited elevated expression of the signature genes. Survival analysis showed that the signature was associated with poor outcome independently of well-defined prognostic factors in neuroblastoma, breast cancer, DLBCL, and medulloblastoma. In EOC, the 18-gene Myc activity signature was capable of identifying a group of patients with poor prognosis in a "high-
" molecular subtype but not in the overall cohort. The predictive ability of this signature was reproduced using qPCR analysis of an independent cohort of neuroblastomas, including a subset of tumors without
amplification. These data reveal an 18-gene Myc activity signature that is highly predictive of poor prognosis in diverse Myc-associated malignancies and suggest its potential clinical application in the identification of Myc-driven tumors that might respond to Myc-targeted therapies.
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