Genomic analysis defines distinct pancreatic and neuronal subtypes of lung carcinoid
Bibliographic record
Abstract
Abstract Lung carcinoids (L‐CDs) are rare, poorly characterised neuroendocrine tumours (NETs). L‐CDs are more common in women and are not the consequence of cigarette smoking. They are classified histologically as typical carcinoids (TCs) or atypical carcinoids (ACs). ACs confer a worse survival. Histological classification is imperfect, and there is increasing interest in molecular markers. We therefore investigated global transcriptomic and epigenomic profiles of 15 L‐CDs resected with curative intent at Royal Brompton Hospital. We identified underlying mutations and structural abnormalities through whole‐exome sequencing (WES) and single nucleotide polymorphism (SNP) genotyping. Transcriptomic clustering algorithms identified two distinct L‐CD subtypes. These showed similarities either to pancreatic or neuroendocrine tumours at other sites and so were named respectively L‐CD‐PanC and L‐CD‐NeU. L‐CD‐PanC tumours featured upregulation of pancreatic and metabolic pathway genes matched by promoter hypomethylation of genes for beta cells and insulin secretion ( p < 1 × 10 −6 ). These tumours were centrally located and showed mutational signatures of activation‐induced deaminase/apolipoprotein B editing complex activity, together with genome‐wide DNA methylation loss enriched in repetitive elements ( p = 2.2 × 10 −16 ). By contrast, the L‐CD‐NeU group exhibited upregulation of neuronal markers (adjusted p < 0.01) and was characterised by focal spindle cell morphology ( p = 0.04), peripheral location ( p = 0.01), high mutational load ( p = 2.17 × 10 −4 ), recurrent copy number alterations, and enrichment for ACs. Mutations affected chromatin remodelling and SWI/SNF complex pathways. L‐CD‐NeU tumours carried a mutational signature attributable to aflatoxin and aristolochic acid ( p = 0.05), suggesting a possible environmental exposure in their pathogenesis. Immunologically, myeloid and T‐cell markers were enriched in L‐CD‐PanC and B‐cell markers in L‐CD‐NeU tumours. The substantial epigenetic and non‐coding differences between L‐CD‐PanC and L‐CD‐NeU open new possibilities for biomarker selection and targeted treatment of L‐CD. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".