Abstract PR01: A functional variomic chemi-genetic screen in C. elegans identifies new synthetic lethal interactions with PARP inhibition that are conserved from worm to human
Bibliographic record
Abstract
Abstract Poly ADP-ribose polymerase (PARP) inhibitors are anti-cancer therapeutics that are synthetic lethal (SL) with mutations affecting the homologous recombination genes BRCA1 or BRCA2. Previous work from our lab found that cohesin mutations, which are common in a range of tumour types, also confer sensitivity to PARP inhibition. We want to extend the SL profile of PARP inhibitors to identify the full spectrum of genetic variants that result in sensitivity to PARP inhibitors alone or in combination with DNA damaging agents. To this end, we are using the model organism Caenorhabditis elegans to screen for new SL interactions with PARP inhibitors. C. elegans provides an excellent in vivo system with which to investigate SL interactions with cancer-associated mutations, as many of the pathways and genes implicated in cancer are conserved between humans and C. elegans. In many ways, C. elegans is an animal model that combines the technical advantages of a single celled organism, such as yeast, with increased developmental complexity and a gene complement more akin to humans. We have developed a high throughput in vivo variomics approach using the C. elegans Million Mutation Project strain collection to screen 2,000 mutagenized and sequenced strains containing >800,000 homozygous genetic variations. To date we have found 16 strains that were sensitive to the PARP inhibitor olaparib. Frequency analysis of the variants in the sensitive strains identified multiple mutations affecting mus-81 and eme-1, which comprise the structure specific Mus81 endonuclease. Further investigation of the interaction with the Mus81 endonuclease mutants found that PARP inhibitor-treated mus-81 and eme-1 mutants exhibit profound somatic proliferation defects characterized by persistent anaphase bridges and that the mus-81 PARP inhibitor-mediated synthetic lethality was not suppressed by loss of non-homologous end joining proteins. We found that the synthetic lethality between MUS81 mutations and PARP inhibitor treatment is conserved in human cells. Similar to C. elegans, PARP inhibitor treated MUS81 knockout cells accumulate anaphase bridges and exhibit a phenotype distinct from PARP inhibitor treated BRCA2 knockout cells. Our variomic screening approach has identified new SL interactions with PARP inhibitors and has expanded our understanding of the mechanism underlying PARP inhibitor-mediated synthetic lethality. Citation Format: Nigel J. O’Neil, Melanie L. Bailey, Philip Hieter. A functional variomic chemi-genetic screen in C. elegans identifies new synthetic lethal interactions with PARP inhibition that are conserved from worm to human [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr PR01.
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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) | 0.001 | 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 | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".