Abstract 3528: <i>PTCH53</i> as a potential secondary modifier in Li-Fraumeni syndrome
Bibliographic record
Abstract
Abstract Germline mutations in the TP53 gene have been established as the underlying genetic event in Li-Fraumeni syndrome (LFS), predisposing affected families to a wide spectrum of early onset cancers. Despite rapid progress in elucidating the role of wild-type p53 in maintenance of genome stability, and mutant p53 in cellular transformation, much of the molecular basis underlying LFS remains unclear. Lack of predictability in age of onset, type(s) of cancers, and likelihood of subsequent malignancies prompts further research to examine secondary modifiers on the underlying TP53 genotype. Patched-domain containing 4 (a.k.a PTCHD4 or PTCH53) is a repressor of canonical Hedgehog signaling that is also described to be transcriptionally activated by p53. Furthermore, our group has identified significant hypomethylation at the PTCH53 locus in a mutant TP53 LFS cohort, compared to TP53 wildtype carriers. These results suggest a potential role of PTCH53 in modifying LFS phenotype. The study examines the expression profile of PTCH53 in the presence of different germline TP53 mutations using primary LFS patient-derived fibroblasts, and aims to elucidate the functional role of PTCH53. PTCH53 transcriptional expression was assessed using digital droplet PCR in 10 LFS non-transformed fibroblast cell lines representing a spectrum of heterozygous germline TP53 mutations. Our data demonstrate that PTCH53 expression indeed depends on TP53 genotype where different TP53 mutations correspond with varied PTCH53 mRNA levels. Nonetheless, mutant TP53 fibroblasts have overall lower PTCH53 transcripts compared to wild-type TP53 fibroblasts. Fold-change increase in PTCH53 expression was detected upon doxorubicin and γ-irradiation induced activation of the p53 protein. These results suggest that induction of p53 via DNA damage activates a signaling cascade involving PTCH53 up-regulation. Further experiments will examine the functional consequences to PTCH53 de-regulation via shRNA knockdown and CRISPR knockout models, and will examine possible modifying effects of PTCH53 on the functional phenotype (cell viability, colony formation and migration potentials) of cell lines harboring different p53 mutants. Elucidating the functional profile of PTCH53 in the context of Li-Fraumeni syndrome will contribute to understanding the complex molecular basis underlying this cancer predisposition syndrome. Citation Format: Anna J. Pan, Benjamin Brew, Lauren Erdman, Anna Goldenberg, David Malkin. PTCH53 as a potential secondary modifier in Li-Fraumeni syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3528. doi:10.1158/1538-7445.AM2017-3528
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".