Abstract 2335: Heterozygous <i>PALB2</i> mutations cause replication stress and DNA repair defects in carrier derived lymphoblastoid cell lines
Bibliographic record
Abstract
Abstract During the last decade, PALB2 has been defined as a high-risk breast cancer susceptibility gene alongside BRCA1 and BRCA2. Heterozygous mutation in PALB2 increases the lifetime breast cancer risk of female carriers to an average of 53%, but the risk estimate is affected by family history, studied population, and the specific pathogenic variant. We have previously shown that lymphoblastoid cell lines (LCLs) of persons heterozygous for PALB2 c.1592delT, a Finnish founder mutation, show defects in DNA replication and damage response. Now we examine how various heterozygous, protein-truncating PALB2 founder mutations from different populations affect cell function, and whether the observed phenotype correlates with disease risk. The study cohorts come from Canada, Australia, and Finland and consist of 80 LCLs of PALB2 mutation carriers (c.1592delT, c.2323C>T, c.3113G>A or c.3323delA) and suitable population controls. There is some evidence that these variants are associated with different magnitudes of breast cancer risk, and PALB2 c.3113G>A has been associated with an exceptionally high cancer risk of 91% (95% CI 44-100) to age 70. Utilizing these LCLs, we have studied DNA damage response, cell cycle progression, and DNA replication with various methods. DNA fiber assay results show that PALB2 mutation carriers elongate their DNA more slowly during replication, likely due to increased fork stalling, but compensate this by increased dormant origin firing. The strongest replication phenotype was observed for PALB2 c.3113G>A carriers. High content analysis shows that most of the mutation carriers had compromised RAD51 foci formation after DNA damage, whereas 53BP1 foci levels were elevated. These results indicate that during DNA double-strand break repair, heterozygous PALB2 mutation carriers may rely more on alternative, error-prone pathways that are independent of RAD51, thus contributing to genomic instability. Additionally, we are currently performing RNA-Seq to determine if the LCLs show adaptation of their gene expression in response to pathogenic PALB2 variants. Citation Format: Niina Laurila, Kerstin Borgmann, Muthiah Bose, Felix Meyer, Katri Pylkäs, Bing Xia, William Foulkes, Melissa Southey, Helmut Pospiech, Robert Winqvist. Heterozygous PALB2 mutations cause replication stress and DNA repair defects in carrier derived lymphoblastoid cell lines [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2335.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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".