S51 Multi-site target capture sequencing confirms intra-tumour heterogeneity of pleural mesothelioma
Bibliographic record
Abstract
Background Pleural mesothelioma is a rare, aggressive cancer. It is characterised by intra-tumour genomic heterogeneity (ITH) that has a direct impact on a patient’s clinical outcome including selection and response to therapy. Methods To gain insight into spatial ITH, we have conducted target gene sequencing of 26 tumour samples and matched blood samples from four mesothelioma patients. For each patient tumour samples were taken from multiple affected regions including lateral, diaphragmatic, and mediastinal sites. Histology and immunohistochemistry were conducted on all samples. Results We observed quite marked genetic heterogeneity across tumours for three patients. In the remaining patient NF2 mutations was detected in all tumour samples with high variant allele frequencies (≥50% in three samples and >30% in the other three) pointing to an early clonal origin. Immunohistochemistry showed focal or total loss of protein BAP1 in all patients but mutations or single copy number aberrations (sCNA) were only seen in two patients. Aberrations of SETD2, on chromosome 3, were detected in single samples from two patients. Mutations in the SWI/SNF chromatin remodelling member ARID1A, and its homolog ARID1B, were also identified heterogeneously in three patients: ARID1B was present in 4/6 samples in one patient and in 1/7 samples for a second patient, ARID1A in 1/7 samples in a third patient. ARID1A mutated tumours may be targeted in vitro with EZH2 inhibitors thus it may be considered as a potential therapeutic target for a subset of pleural mesothelioma patients. Mutations in MET, TSC1 and SF3B1 were detected in single samples from two patients. sCNA of the cytobands containing SUFU (Hedgehog pathway) on chromosome 10q24.32 was detected in two samples from one patient, and RBFOX1 on chromosome 16p13.13 was detected in two different samples from the same patient. RBFOX1 is within a chromosomal region that has been implicated in autoimmunity. Conclusions Spatial profiling of pleural mesothelioma revealed marked inter and intra- patient heterogeneity, with only one patient showing an apparent founder mutation in NF2. Although alterations affecting Hippo, Hedgehog or SWI/SNF pathways may define subsets of responders to therapies, it is possible that underlying heterogeneity will result in poor response.
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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 | 0.001 | 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".