Abstract B12: Differences in neoplastic transformation potential between OSE and FTE
Bibliographic record
Abstract
Abstract Introduction: The most common and aggressive histotype of ovarian cancer is high-grade serous carcinoma (HGSC), which accounts for approximately 90% of deaths. Furthermore, the risk of developing HGSC is increased by having a mutation in the BRCA1 and BRCA2 gene. There is considerable evidence detailing the fallopian tube epithelia (FTE) as the site of origin of the disease, yet the ovarian surface epithelium (OSE) is still proposed as the site of origin by some. Currently, no studies have compared in vivo/xenografts models derived from FTE and OSE of BRCA mutation carriers. We suggest that in vivo/xenograft models can prove a useful tool for understanding the disease origins, meanwhile accounting for the genetic characteristics of the disease. Methodology: Immortalized and transformed cell lines, from both FTE and OSE, were derived from both BRCA1 and BRCA2 mutation carriers and non-carriers. In particular, 16 OSE cell lines were created--3 from BRCA1 carriers and noncarriers. Cell lines were transfected with hTERT and SV40, and either vectors overexpressing cMYC and hRASV12. 8 of these lines with cMYC or hRASV12 were injected into the mammary fat pad of 6-week-old female NSG mice (NOD.Cg-Prkdcscid). Similarly, 16 FTE lines were generated from 2-BRCA1 and 1 BRCA2 heterozygous mutation and 3 non-BRCA carriers overexpressing hTERT and SV40 with either cMYC or hRASV12. Results: To date, tumors have developed from mice injected with ovarian surface epithelial cells and fallopian tube epithelial cells at the mammary fat pad and the intraperitoneal cavity. FTE cells injected intraperitoneally produced ascites and displayed tumors lining the abdominal cavity and major organs. The parental immortal lines of 4 cases were karyotyped: FTE-37 and FTE-19 (controls); FTE-13 (BRCA2 mutant) and FTE-98 (BRCA1 mutant) cell lines demonstrated varying types of tetraploidy while the control (BRCA wild type) had fewer tetraploid chromosomes. Western blot analyses demonstrated that tumors express PAX8 and epithelial markers associated with HGSC. STR profiling using GenePrint 10 also revealed that injected FTE cells grown in vitro clustered with xenograft tumors of the same cell line, demonstrating that cell line and tumors retained the same characteristics during tumor development. It is hypothesized that SV40 alone is sufficient to stimulate genomic instability in the FTE cells. Several cell lines grown in culture with expression of hRASV12 demonstrated increased proliferation relative to normal control cells. Conclusions: Our results suggest that tumor development occurs at different rates in vivo and is dependent on multiple factors including genetic mutation, expression of oncogenes, and patient-derived characteristics. We demonstrated that cells grown in culture exhibit unstable chromosomal architecture characteristic of ovarian carcinomas, which is one of many potential factors that promotes neoplastic change in the tissue. Understanding how these factors act in promoting tumorigenesis will enable us to understand the molecular changes that occur in vivo prior to the development of ovarian serous carcinoma. Citation Format: Ramlogan Sowamber, Mauricio Medrano, Noor Salman, Zahra Maamir, Nick Chauvin, Mahmoud Bitar, Patricia Shaw, Sophia HL George. Differences in neoplastic transformation potential between OSE and FTE. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B12.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".