Abstract B22: Capturing L1 retrotransposon-mediated DNA transductions in endometriosis associated ovarian cancers as a way to track tumor development
Bibliographic record
Abstract
Abstract Endometrioid ovarian cancer (ENOC) and clear cell ovarian cancer (CCOC) share a common precursor lesion, endometriosis (ectopic growth of uterine lining), hence the designation endometriosis-associated ovarian cancer (EAOC). Women with endometriosis have up to three-fold increased risk of developing ENOC and CCOC. Efforts have been made to look for biomarkers that can help identifying women at risk of developing cancer; however, there are currently no biomarkers that stratify risk of cancer development. We performed whole-genome sequencing (WGS) on 29 ENOC and 35 CCOC cases and observed a frequent transduction event originating from an active LINE-1 (L1) retrotransposable element in the TTC28 gene. Such event occurred in 34% (10/29) of ENOC, and 31% (11/35) of CCOC cases. L1 retrotransposons are repetitive, mobile genetic elements capable of taking downstream DNA fragments and inserting them into random genomic locations via a process called 3’ transduction. Approximately 70-100 different potentially active L1s are epigenetically silenced in normal tissues, but tend to be reactivated in cancers. We subsequently used PCR to validate these TTC28-L1 transductions, and compared their presence to single nucleotide variations (SNVs) and frameshift mutations in formalin-fixed, paraffin-embedded (FFPE) tumor tissues from different tumor sites for 4 ENOC and 3 CCOC cases. We found that these transduction events along with classical driver mutations were almost ubiquitous across the tumor sites, suggesting these L1 events likely occurred early in the malignant transformation of EAOCs. We developed a low-input, probe-based capture assay to test the presence of TTC28-L1 transductions as an alternative method to performing WGS. Oligonucleotide probes tiling 1 kb downstream of active L1s are used to capture DNA fragments containing the transduced DNA, and the fragments are sequenced on the MiSeq next-generation sequencing platform. Analyses are performed using the Geneious software and the published bioinformatics tool Socrates, specific for detecting DNA fragments with split reads (fragments with ends aligning to different parts of the genome). We successfully validated the assay on 9 cases with WGS data: 7 EAOC cases with TTC28-L1 transductions and 2 EAOC cases without TTC28-L1 transductions. DNA extracted from frozen tumor and buffy coat (normal control) were used for each case, and FFPE tissues were used for selected cases. All reads containing the transduction events aligned to genomic coordinates corresponding to the WGS data. While L1-mediated DNA transductions are often passenger events during tumorigenesis, our data suggest that they likely occur early in ovarian cancer tumorigenesis. Our data show that this probe-based capture assay provides an alternative method to WGS, and may be useful in detecting active 3’ transductions in novel cases to track the development of ovarian tumors. Citation Format: Zhouchunyang Xia, Dawn Cochrane, Michael Anglesio, Winnie Yang, Miguel Alcaide, Tayyebeh Nazeran, Janine Senz, Amy Lum, Ali Bashashati, Yikan Wang, Ryan Morin, Sohrab Shah, David Huntsman. Capturing L1 retrotransposon-mediated DNA transductions in endometriosis associated ovarian cancers as a way to track tumor development. [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 B22.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.006 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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 teacher head, 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".