Abstract 844: Germline <i>TP53</i> missense mutations at codon338 confer adult-onset cancer risk through weakened p53 protein oligomeric stability that impairs its tumor suppressive mechanisms
Bibliographic record
Abstract
Abstract Pathogenic TP53 germline variants predispose carriers to a high lifelong cancer risk in Li-Fraumeni syndrome (LFS). LFS presents as a broad phenotypic spectrum with highly variable age-of-onset and tumor types. The mechanisms leading to these phenotypic differences remain largely unknown, and many less frequent variants are not clinically defined as pathogenic or benign. Two missense mutations in the tetramerization domain of the p53 protein, F338S and F338C, have recently been of clinical interest; however, they are currently classified as variants of uncertain significance. Normally, p53 assembles as a tetrameric complex to bind DNA and transcriptionally regulate the expression of target genes involved in the cellular response to stress, acting as a crucial barrier to malignant transformation. Alterations to p53 structure can therefore lead to malfunction and ultimately tumor formation. Our structural analysis of the tetramerization domain demonstrates that F338S and F338C have significantly lower thermal stability compared to the wildtype protein. Furthermore, our functional assessments of apoptosis and the suppression of colony formation indicate that both variants operate with reduced tumor suppressor activity, although they maintain near wildtype functionality. We anticipate that our results will help to better understand why these mutations cause a history of predominantly adult-onset cancers in the affected families and could justify refining surveillance measures for these individuals. Citation Format: Nicholas W. Fischer, Jaime Turk, Noel Ong, Shili Duan, Lilia Kaustov, Christian Kratz, Kristian Pajtler, Raymond Kim, Cheryl Arrowsmith, David Malkin. Germline TP53 missense mutations at codon338 confer adult-onset cancer risk through weakened p53 protein oligomeric stability that impairs its tumor suppressive mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 844.
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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 | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.022 | 0.003 |
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".