Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: Discovery and validation studies Ovarian Cancer and Us OVARIAN CANCER and US Ovarian Cancer and Us

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Friday, July 29, 2016

Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: Discovery and validation studies



open access
 

Highlights

  • Dense sequencing of an ovarian cancer identifies founder non-coding mutations .
  • Fallopian tube SOX2 overexpression is a common premalignant feature in ovarian cancer .
  • The expression of SOX2 and MYC in the fallopian tube appears mutually exclusive .

    In summary, in this study we demonstrated that SOX2 overexpression occurs in a fraction of women with BRCA1 and BRCA2 mutations prior to ovarian cancer initiation and in the majority of patients with HGSOCs irrespective of tumor stage. These findings could be exploited for filling the current gap in early detection strategies for ovarian cancer. We believe that this is the first report of the expansion of SOX2-expressing cells in the FTE of HGSOCs. This finding has important implications, as it provides a potentially powerful tool for screening for HGSOCs. Utilizing our findings as potential biomarker should take high priority.

Article Outline

  1. 1. Introduction
  2. 2. Materials and Methods
    1. 2.1. Overall Description of the Study Design
    2. 2.2. Translational Studies
      1. 2.2.1. Ethical Approval
      2. 2.2.2. Clinical History and Sample Collection of Patient 11152
      3. 2.2.3. Precautions for Tissue Handling to Diminish the Risk of Cross Contamination of DNA
      4. 2.2.4. Section Processing for Laser Capture Microdissection
      5. 2.2.5. Macrodissection of FTE
    3. 2.3. DNA Extraction
    4. 2.4. Sequencing
      1. 2.4.1. Targeted Sequencing
      2. 2.4.2. Sanger Sequencing
      3. 2.4.3. Digital Droplet PCR
    5. 2.5. Sequencing Analysis
      1. 2.5.1. Whole Genome Sequencing
      2. 2.5.2. Performing Gene Ontology Enrichment Analysis
      3. 2.5.3. Analysis of Targeted Sequencing Data
      4. 2.5.4. Analysis of ChIP-sequence Tracks
      5. 2.5.5. Motif Analysis for the BB5 Variant
    6. 2.6. Fallopian Tubes Primary Epithelial Cell Culture
    7. 2.7. Viral Transduction
    8. 2.8. Cloning, Mutant Generation and Chicken Embryo Transfection
    9. 2.9. Chromatin Immunoprecipitation (ChIP) Assay
    10. 2.10. CRISPR Vector Construction, Cell Culture and Transfection
    11. 2.11. Immunofluorescence
    12. 2.12. Immunohistochemistry
  3. 3. Results
    1. 3.1. Laparoscopy-guided Prospective Multi-region Sampling in an Ovarian Cancer Patient
    2. 3.2. Non-coding Mutations Cluster at Potential cis Regulatory Elements of Genetic Drivers of Stem Cell Differentiation
    3. 3.3. The BB5 Mutation Occurred at the Pre-neoplastic Lesion of the Tumor and Marked a Region That Was Frequently Mutated in HGSOCs
    4. 3.4. Expansion of FTE Cells Strongly Expressing SOX2 is a Feature of HGSOCs
    5. 3.5. The BB5 Region Is a Repressor of SOX2 Expression
  4. 4. Discussion
  5. Funding Sources
  6. Conflicts of Interests
  7. Contributions
  8. References

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