Abstract B18: Mechanisms of regulation and synthetic lethal strategies against PALB2 and APRIN, two DNA double-strand break repair proteins
Bibliographic record
Abstract
Abstract One typical mechanism to promote genomic instability, a hallmark of cancer, is to inactivate tumor suppressors, such as PALB2. It has recently been reported that mutations in PALB2 increase the risk of breast cancer by 8-9 fold. PALB2 was identified BRCA2 interacting protein, essential for BRCA2 anchorage to nuclear structures and for its function in double-strand break repair. Inherited mutations in PALB2 are associated with a predisposition for ovarian, breast and pancreatic cancers. The basis of the tumorigenic potential of PALB2 is thought to be related to functions in homologous recombination. Therefore, the regulation of PALB2 during the DNA damage response and the effect of cancer-causing mutation is of high interest. Two mechanisms of regulation of PALB2 will be presented. The first mechanism regulates PALB2 localization to DNA damage sites in S-phase. To date, predicting the functional consequences of PALB2 mutations has been challenging as they lead to different aggressive phenotypes. Here, we performed a structure-function analysis of PALB2 using PALB2 truncated mutants (R170fs, L531fs, Q775X and W1038X), and uncovered a second PALB2 regulation mechanism by which cancer cells could drive genomic instability. We will present these regulatory mechanisms and synthetic lethal strategies to kill PALB2 deficient cells harbouring such mutations using PARP inhibitors. These strategies also apply to APRIN, A BRCA2 interactor, which also promote double-strand break repair by homologous recombination. Citation Format: Anthony M. Couturier, Rémi Buisson, Joris Pauty, Amélie Rodrigue, Marie-Christine Caron, Yan Coulombe, Niraj Joshi, Lee Zou, Jean-Yves Masson. Mechanisms of regulation and synthetic lethal strategies against PALB2 and APRIN, two DNA double-strand break repair proteins [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 B18.
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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 | 0.000 | 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 | 0.001 |
| 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".