Molecular dissection of primary mediastinal germ cell tumors.
Bibliographic record
Abstract
417 Background: Mediastinal non-seminomas (M-NS) have a poor prognosis compared to non-M-NS germ cell tumours (GCT) (i.e. primary gonadal or mediastinal seminomas (PG-S and M-S) and primary gonadal non-seminoma (PG-NS). M-NS tumors, while having pathological and serological similarity to other nonseminomas, are clinically and biological distinct and are considered IGCCC poor risk. In this study we aimed to evaluate the somatic mutation rate and prevalence of actionable/informative mutations in M-NS compared to M-S and primary GCT to inform consideration of targeted/precision therapy in these patients. Methods: Pre-treatment formalin fixed paraffin embedded specimens were collected from eleven patients with mediastinal and primary GCT patients (4 M-NS, 2 M-S, 3 PG-NS and 2 PG-S). High-density tumor areas were selected for DNA extraction and targeted sequencing of 578 established pan-cancer genes was performed (Roche Nimblegen SeqCaP EZ Comprehensive Cancer Design). Results: Consistent with the known landscape of testicular cancer, we identified five tumors with amplification of chromosome 12p, as well as hotspot mutations in KIT (n = 2) and KRAS (n = 1). Three of the 4 M-NS tumors had a non-synonymous mutation rate > 1 per Mb, which is higher than the primary TGCT and M-S sequenced here (range 0-0.5 per Mb) and the established low mutation rate for TGCT of 0.3-0.9 mutations/Mb. Mutations in TP53 (n = 2) and PTEN (n = 1) were only identified in patients with M-NS. The 2 patients with a TP53 mutation had a high non-synonymous mutation rate (1.3/Mb and 7.3/Mb), extensive metastatic disease with liver metastasis and high tumor markers (β-HCG: 1281 IU/L and α-FPT: 8500 ng/ml) at diagnosis. Both died of their disease and were the only patients in the cohort to have died. Conclusions: This study suggests that M-NS GCTs harbour more somatic alterations than non-M-NS GCTs, potentially underlying their poor prognosis. Our data are consistent with previous reports of an association between TP53 mutations and poor outcomes. Confirmation of our findings could lead to multi-center studies of targeted/precision therapies in patients with M-NS.
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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 | 0.000 | 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".