Genomic profiling for copy number changes in plasma of ovarian cancer patients – a new era for cancer diagnostics?

Breast phyllodes tumour (PT) is a rare fibroepithelial tumour. The genetic alterations contributing to its tumorigenesis are largely unknown. To identify genomic regions involved in pathogenesis and progression of PTs we obtained genome-wide copy number profiles by array comparative genomic hybridization (CGH).DNA was isolated from fresh-frozen tissue samples. 11 PTs and 3 fibroadenomas, a frequently occurring fibroepithelial breast tumour, were analyzed. Arrays composed of 2464 genomic clones were used, providing a resolution of ~1.4 Mb across the genome. Each clone contains at least one STS for linkage to the human genome sequence.No copy number changes were detected in fibroadenomas. On the other hand, 10 of 11 PT (91%) showed DNA copy number alterations. The mean number of chromosomal events in PT was 5.5 (range 0–16) per case. A mean of 2.0 gains (range 0–10) and 3.0 losses (range 0–9) was seen per case of PT. Three cases showed amplifications. DNA copy number change was not related to PT grade. We observed recurrent loss on chromosome 1q, 4p, 10, 13q, 15q, 16, 17p, 19 and X. Recurrent copy number gain was seen on 1q, 2p, 3q, 7p, 8q, 16q, 20.In this study we used array CGH for genomic profiling of fibroepithelial breast tumours. Whereas most PT showed chromosomal instability, fibroadenomas lacked copy number changes. Some copy number aberrations had not previously been associated with PT. Several well-known cancer related genes, such as TP53 and members of the Cadherin, reside within the recurrent regions of copy number alteration. Since copy number change was found in all benign PT, genomic instability may be an early event in PT genesis.

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Next-generation sequencing-based genomic profiling analysis reveals novel mutations for clinical diagnosis in Chinese primary epithelial ovarian cancer patients

Journal of Ovarian Research ◽

10.1186/s13048-019-0494-4 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 4

Author(s):

Lei Zhang ◽

Min Luo ◽

Hongying Yang ◽

Shaoyan Zhu ◽

Xianliang Cheng ◽

...

Keyword(s):

Ovarian Cancer ◽

Next Generation Sequencing ◽

Epithelial Ovarian Cancer ◽

Cancer Patients ◽

Clinical Diagnosis ◽

Genomic Profiling ◽

Novel Mutations ◽

Primary Epithelial Ovarian Cancer ◽

Profiling Analysis ◽

Generation Sequencing

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Clinical and analytical validation of FoundationOne Liquid CDx, a novel 324-gene blood-based comprehensive genomic profiling assay.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e13685 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e13685-e13685 ◽

Cited By ~ 1

Author(s):

Ryan Woodhouse ◽

Lucas Dennis ◽

Meijuan Li ◽

Christine Burns ◽

Pei Ma ◽

...

Keyword(s):

Cancer Patients ◽

Copy Number ◽

Limit Of Detection ◽

Variant Calling ◽

Genomic Profiling ◽

Validity Data ◽

Multiple Tumor ◽

Additional Tool ◽

Therapeutic Decisions ◽

Comprehensive Genomic Profiling

e13685 Background: As the availability of precision therapies expand, a well-validated blood-based comprehensive genomic profiling (CGP) assay has the potential to provide considerable value as a complement to tissue-based testing to ensure that potentially life-extending therapies are administered to the patients most likely to benefit. Comprehensive clinical and analytical validity data for blood-based assays are crucial to enabling physicians to understand the true performance of available testing options. Methods: The FoundationOne Liquid CDx assay is a blood-based CGP assay that has been validated for a Premarket Approval (PMA) submission to the Food and Drug Administration (FDA). Validation studies included > 9,000 tests and > 30,000 unique variants across > 300 genes and > 50 cancer types, allowing for a comprehensive assessment of performance. Results: The results of these extensive studies demonstrate a 95% limit of detection (LoD) of 0.40% variant allele fraction (VAF) for select short variants (subs and indels), 0.37% VAF for select rearrangements, 21.7% tumor fraction (TF) for select copy number amplifications, and 30.4% TF for copy number losses. LoD for complex biomarkers such as microsatellite instability (MSI) and blood tumor mutational burden (bTMB) were also determined. The limit of blank (LoB) was shown to be the ideal value of zero. Reproducibility of variant calling was determined to be 99.59% with two-sided exact CI of (99.58%, 99.60%). In comparison with an orthogonal method, an overall PPA (95% CI) of 96.3% (94.8, 97.4%) and NPA (95% CI) of > 99.9% (99.9%, 100.0%) was observed. Critically, clinical validity and concordance with tissue-based CGP results across multiple tumor types were also evaluated. Conclusions: The results of these studies demonstrate that FoundationOne Liquid CDx accurately and reproducibly detects the major types of genomic alterations (short variants, rearrangements, and copy number alterations), as well as complex biomarkers, such as MSI, bTMB, and tumor fraction. These data demonstrate that the assay can identify genomic variants that may inform therapeutic decisions for cancer patients with any solid tumor using a single blood sample. Additionally, clinical validation results establish FoundationOne Liquid CDx as an additional tool for physicians in the therapeutic management of cancer patients.

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Identification of DNA copy number changes in microdissected serous ovarian cancer tissue using a cDNA microarray platform

Cancer Genetics and Cytogenetics ◽

10.1016/j.cancergencyto.2004.03.002 ◽

2004 ◽

Vol 155 (2) ◽

pp. 97-107 ◽

Cited By ~ 21

Author(s):

Hiroshi Tsuda ◽

Michael J. Birrer ◽

Yoichi M. Ito ◽

Yasuo Ohashi ◽

Ming Lin ◽

...

Keyword(s):

Ovarian Cancer ◽

Cdna Microarray ◽

Copy Number ◽

Microarray Platform ◽

Cancer Tissue ◽

Serous Ovarian Cancer ◽

Dna Copy Number ◽

Ovarian Cancer Tissue ◽

Copy Number Changes

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Lack of independent prognostic and predictive value of centromere 17 copy number changes in breast cancer patients with known HER2 and TOP2A status

Molecular Oncology ◽

10.1016/j.molonc.2011.11.006 ◽

2011 ◽

Vol 6 (1) ◽

pp. 88-97 ◽

Cited By ~ 13

Author(s):

Kirsten Vang Nielsen ◽

Bent Ejlertsen ◽

Susanne Møller ◽

Maj-Britt Jensen ◽

Eva Balslev ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Predictive Value ◽

Copy Number ◽

Breast Cancer Patients ◽

Copy Number Changes

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The prognostic role of aberrant copy number of DDB1, PRPF19, CDKN1B, and с-Myc genes in ovarian cancer patients

Almanac of Clinical Medicine ◽

10.18786/2072-0505-2021-49-020 ◽

2020 ◽

Vol 49 ◽

Author(s):

E. V. Verenikina ◽

N. A. Petrusenko ◽

M. M. Kecheryukova

Keyword(s):

Ovarian Cancer ◽

Cancer Patients ◽

Tumor Cells ◽

Copy Number ◽

Genetic Locus ◽

Adverse Outcomes ◽

Research Centre ◽

Genetic Loci ◽

Relative Copy Number ◽

Frequent Relapses

Rationale: Ovarian cancer is the leading death cause in gynecological malignancies. More than 70% of the patients are diagnosed with progressing disease extending to outside the true pelvis. The 5-year survival of ovarian cancer patients remains low (about 47%) due to frequent relapses and drug resistance. Identification of markers for early diagnosis and relapse prediction could improve the outcomes of the disease.Aim: To assess relative copy number of cancer-associated genetic loci c-Myc, CDK12, CDKN1B, PRPF19, ERBB2, DDB1, GAB2, COL6A3 in the tumor cells of ovarian cancer, in order to identify potential prognostic oncomarkers in ovarian cancer patients.Materials and methods: The study included 50 women aged 27 to 70 years with ovarian cancer T1-3сN0-1M0-1, Gr. 2 (stages I–IV), who received their elective treatment in the National Medical Research Centre for Oncology in 2015 to 2019. The study was based on samples of genomic DNA from paraffinized blocks of tumor and “healthy” tissues. Relative copy numbers of 8 genetic loci (c-Myc, CDK12, CDKN1B, PRPF19, ERBB2, DDB1, GAB2, COL6A3) was assessed by RT-qPCR technique. Relative copy quantitation of a genetic locus was calculated as 2-ΔCt. The dose of the locus studied was considered equal to diploid set (2n) if RCQtumor/healthy was about 1. If RCQtumor/healthy was>1.5 or<0.5, then the locus dose was considered increased (≥ 3n) or decreased (≤ 1n), respectively.Results: For all genetic loci, an increase of relative copy quantitation in the ovarian tumor cells was observed compared to that in “healthy” tissues. There was a significant (р<0.05) aberrant copy quantitation of 4 genes: c-Myc (р=0.001), DDB1 (р=0.002), PRPF19 (р=0.0001), and CDKN1B (р=0.001). We identified differential thresholds for these genes that made it possible to predict an unfavorable disease course in the patients (р<0.05). The strongest association with the risk of adverse outcomes was found for increased copy number of PRPF19 (odds ratio (OR) 7.3; р=0.0001) and c-Myc (OR 6.8; р=0.001). Conclusion: In this study, we determined the prognostic value of 4 oncogenic drivers, namely, DDB1, PRPF19, CDKN1B, and с-Myc, whose increased copy number was associated with an adverse disease prognosis in ovarian cancer patients.

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Targeting MYC dependency in ovarian cancer through inhibition of CDK7 and CDK12/13

eLife ◽

10.7554/elife.39030 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 32

Author(s):

Mei Zeng ◽

Nicholas P Kwiatkowski ◽

Tinghu Zhang ◽

Behnam Nabet ◽

Mousheng Xu ◽

...

Keyword(s):

Ovarian Cancer ◽

Small Molecules ◽

Cancer Patients ◽

Copy Number ◽

Ovarian Cancer Cells ◽

Tumor Growth Inhibition ◽

High Grade ◽

Serous Ovarian Cancer ◽

Copy Number Alterations ◽

Myc Oncogene

High-grade serous ovarian cancer is characterized by extensive copy number alterations, among which the amplification of MYC oncogene occurs in nearly half of tumors. We demonstrate that ovarian cancer cells highly depend on MYC for maintaining their oncogenic growth, indicating MYC as a therapeutic target for this difficult-to-treat malignancy. However, targeting MYC directly has proven difficult. We screen small molecules targeting transcriptional and epigenetic regulation, and find that THZ1 - a chemical inhibiting CDK7, CDK12, and CDK13 - markedly downregulates MYC. Notably, abolishing MYC expression cannot be achieved by targeting CDK7 alone, but requires the combined inhibition of CDK7, CDK12, and CDK13. In 11 patient-derived xenografts models derived from heavily pre-treated ovarian cancer patients, administration of THZ1 induces significant tumor growth inhibition with concurrent abrogation of MYC expression. Our study indicates that targeting these transcriptional CDKs with agents such as THZ1 may be an effective approach for MYC-dependent ovarian malignancies.

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